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Background: Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). Methods: We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. Results: We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. Conclusions: BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity. [ABSTRACT FROM AUTHOR]

Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa. [ABSTRACT FROM AUTHOR]

The present study was conducted on a group of women with breast cancer (60 women) and a group of healthy women as a control group (30 women) aged (27-85) years. Samples were collected from women with breast cancer from the Teaching Oncology Hospital - Medical City, Baghdad for the period from the first of October 2023 until the end of February 2024. The activity of servivin was asses and the level of glutathione, glutathione peroxidase, malondialdehyde and the following results were obtained: 1-There was a significant increase in the group of breast cancer women for both servivin, and malondialdehyde compared to the control group. 2- There was a significant decrease in the level of glutathione-and glutathione peroxidase . 3-The existence of a significant correlation between survivin and each of GSH and GPX. Conclusions: The results of the present study showed a significant increase in the level of survivin in women with breast cancer in conjunction with a significant correlation with GSH, GPX, MDA and BMI, which supports the possibility of considering survivin as an indicator for breast cancer diagnosis. [ABSTRACT FROM AUTHOR]

Purpose of the review: The objective of this review is to provide an analysis of early-phase clinical trials investigating vaccine therapies for triple-negative breast cancer (TNBC). Specifically, the focus is on ongoing trials that are actively recruiting or in progress, while excluding vaccines that target neoantigens or those that have already completed trials. Recent findings: Over the past decade, notable transformations have occurred in the strategy of breast cancer vaccine design. Traditional approaches to identifying tumor antigens, such as SEREX, have been replaced with modern techniques, such as RNA sequencing, HLA typing, and immunoinformatics. These new methods enable the identification and characterization of tumor antigens. Notably, current clinical investigations into tumor targets extend beyond mutated self-proteins or proteins that are overexpressed following neoplastic transformation. Clinical researchers are currently examining protein targets associated with cancer stem cells or non-malignant immune regulatory cell types within the tumor microenvironment. However, the application of up-to-date antigen delivery methods for certain types of breast cancer vaccine therapies still lags behind. Another significant transformation in comparison to previous breast cancer vaccine therapies is the emphasis on stimulating robust T-cell responses against breast cancer cells, independent of any B-cell response directed at the tumor. Summary: In conclusion, we critically assessed the tumor antigens targeted by vaccine immunotherapies in these new clinical trials, the delivery methods used for these antigens, and conclude by discussing potential future directions for the development of new TNBC vaccine therapies. [ABSTRACT FROM AUTHOR]

ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg–0.7 µg/kg, with a half-life of approximately 13–29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1–2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. NCT04272203 [ABSTRACT FROM AUTHOR]

In order to investigate the effects of RNAi-mediated survivin and hypoxia-inducible factor 1α (HIF-1α) gene silencing on the proliferation and apoptosis of gastric cancer BGC-823 cells, small interfering RNAs (siRNAs) targeting survivin and HIF-1α mRNAs, respectively, as well as scrambled siRNAs (SCRs) were designed and synthesized, namely siRNA-survivin group, siRNA-HIF-1α group, and SCR group. The hypoxia-sensitive gastric cancer BGC-823 cells were identified and transfected in vitro with Hifectin II under hypoxic conditions, and the expression of survivin and HIF-1α was assessed by RT-PCR and Western blotting assays, respectively. The ability of apoptosis, proliferation, invasion, and migration was measured, and the results showed that HIF-1α expression was significantly increased in BGC-823 cells under hypoxic conditions, and survival-targeted siRNA transfection decreased the expression of survivin under hypoxic conditions, while co-transfection of survivin-targeted siRNA and HIF-1α-targeted siRNA down-regulated both survivin and HIF-1α expression. Compared with the blank control group, the co-transfected siRNA group exhibited distinct characteristics, with decreased invasion and migration ability, increased apoptosis, and significantly decreased cell proliferation under hypoxic conditions. It was confirmed that the downregulation of survivin and HIF-1α in BGC-823 cells may induce anticancer effects by enhancing apoptosis and decreasing proliferation, migration, and invasion ability. The novelty lies in the application of RNAi technology to silence the expression of both survivin and HIF-1α genes in gastric cancer BGC-823 cells by single and combined interference in an established gastric cancer cell model and observed the mechanism of its effect on the proliferation and apoptosis of gastric cancer cells. Concerning the success of this highly active antiretroviral therapy of gene disruption therapies, which is the first of its kind in the world, we wonder whether we can find other better gene targets for more kinds of tumor therapy. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare and correlate between non-diabetic MetS, newly diagnosed drug naive pre-diabetic MetS patients vs. lean, apparently healthy and normoglycemic controls the plasma levels of cardiometabolic risk biomarkers' of pharmacotherapy (appraised using colorimetric and chromatography assays of gut dysbiosis carnitine, choline, ybutyrobetaine, TMAO, Zonulin, survivin, Leukocyte cell-derived chemotaxin 2 (LECT2) and antioxidative stressors (catalase, superoxide dismutase (SOD) and Trolox total antioxidative capacity), adiposity, and atherogenicity with non-insulin based surrogate insulin resistance (sIR) indices. Methods: ANOVA comparisons and Spearman's rank correlations were conducted in this cross-sectional study of 30 normoglycemic lean subjects (control), 30 nonprediabetic MetS subjects and 30 MetS/pre-diabetic (PreDM) enrolled. Results: MetS-PreDM group presented significantly higher values of FPG (P²<0.001,P³ =0.009) and A1C (P values <0.001) than both normoglycemic MetS and control groups. However, MetS-PreDM and normoglycemic MetS recruits had appreciably higher values of DBP, SBP, TG, and non-HDL-C but significantly lower values of HDL-C (P values <0.001) than the controls. Explicitly no significance in variance was noticeable among any of the study arms (P value < 0.05) for any of the hematological indices. Nevertheless, Both MetS groups (nonprediabetic and PreDM) had substantially higher values for each of adiposity, atherogenecity and surrogate insulin resistance (non insulin based) indices (P²<0.001) vs. controls' respectively. Both Survivin and LECT2 levels were significantly higher in PreDM MetS group (P value < 0.05 vs. nondiabetic MetS participants). Conversely all 5 gut dysbiosis biomarkers (carnitinine, choline, γBB, TMAo and Zonulin) which proved significantly lower vs. those of either controls (nondiabetic lean or MetS). Surprisingly, a significant variation in all tested 7 biomarkers' plasma levels were found between nondiabetic MetS and PreDM-MetS groups (P³ < 0.05). Interestingly all 3 antioxidative stressors were on the decline as anticipated; where catalase, SOD % inhibitions and trolox total antioxidative capacities were significantly lower in both MetS recruits vs. controls. Importantly the discrepancy between normoglycemic nonprediabetic MetS vs. the MetS-PreDM (P³ < 0.05) may have not ranked up to significance in indices, clinical parameters or biomarkers. Notably in pooled MetS (both normoglycemic and pre-diabetics participants (N =60)). Most exquisitely survivin with dysbiosis choline and γBB correlated positively and pronouncedly with carnitine in pooled MetS participants. Also in a striking similarity, cardiometabolic LECT2 has a marked direct relation with each of dysbiosis carnitine and γBB. TMAO, nevertheless, related inversely and significantly with all 3 dysbiosis biomarkers, likewise Zonulin associated disproportionally with both choline and γBB. Exceptionally TMAO- TYG and Zonulin-TYG-WHpR paired in substantial and inverse relations in pooled normoglycemic and preDM MetS participants (n=60). To superbly signify the anticipated deterioration in metabolism via gut microbiota-insulin insensitivity interconnectivity; all dysbiosis biomarkers (carnitine, choline, γBB, TMAO, Zonulin and survivin) correlated highly remarkably and proportionally with all non insulin based surrogate insulin resistance indices in 60 MetS recruits (both normoglycemic and prediabetic; equally). Unequivocally γBB associated directly and pronouncedly with almost all adiposity indices. Surprisingly VAI correlated negatively with Zonulin in the same MetS population. FBG associated exceptionally with carnitine and YButyrobetaine (γBB). Substantially A1c correlated proportionally (P values <0.05) with MetS pooled cases dysbiosis' carnitine, choline, yBB, and cardiometabolic surviving. Outstandingly both SBP and DBP had direct and marked linkage to LECT2 and so did DBP with choline's plasma levels. Remarkably TMAO related negatively and pronouncedly with MetS cases levels of FBG, A1c, TG, LDL-C, and so did also zonulin with both A1c and LDL-C. Conclusions: Given the intergroup discrepancies in dysbiosis and cardiometabolic biomarkers along with their elective correlations with MetS-related indices and clinical parameters; our study cannot rule out any potentiality in molecular crosstalk and interplay of those biomarekers with the pathophysiology of MetS and preDM with their related dysregularities. Carnitine, choline, Ybutyrobetaine, TMAO, Zonulin, survivin, and LECT2 can be putatively surrogate biomarkers to use as prognostic/predictive tools for the diagnosis/prevention and potential targets for MetS treatment. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer‐related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. Methods: We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. Results: Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease‐free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro‐tumoral and radioresistant phenotype in surviving cells. Conclusions: Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC. [ABSTRACT FROM AUTHOR]

Abstract Background Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). Methods We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. Results We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. Conclusions BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and β-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental design We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

Background: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental design: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a hypertensive disorder that affects pregnancy, mother, and fetus. Early diagnosis of PE remains a challenge. This study aimed to investigate the association between survivin two (rs9904341 and rs17878467) SNPs and PE risk in healthy pregnant women compared to women with preeclampsia. A sample of 166 healthy pregnant women and 160 cases with preeclampsia was included and genotyped for rs9904341 with polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and rs17878467 with amplification-refractory mutation system (ARMS) PCR. The genotypic and allelic assessments were performed using various statistical approaches. The frequency of rs9904341 and rs17878467 polymorphisms was not significantly different between PE and healthy pregnant women. rs9904341: codominant (p = 0.5), dominant (p = 0.24), recessive (p = 0.61), over-dominant model (p = 0.38), and log additive (p = 0.25). rs17878467: codominant (p = 0.41), dominant (p = 0.23), recessive (p = 0.4), over-dominant model (p = 0.42), and log additive (p = 0.24). The frequency of survivin rs9904341 CG and CC genotypes was higher in severe PE women compared to controls and this polymorphism was associated with PE severity only in the dominant model (OR = 1.84, CI 1.04–3.26, P = 0.034). There was a significant association between survivin rs9904341 polymorphism and PE severity. No relationship was found between survivin rs9904341 and rs17878467 polymorphisms and PE onset. The allelic and genotypic frequencies of survivin rs9904341 and rs17878467 polymorphisms are not significantly different between the preeclampsia and control groups in all genetic models. Haplotype analysis showed lower frequency G rs9904341 T rs17878467 haplotype in PE woman and this haplotype was associated with lower risk of PE (OR = 0.54, CI 0.33–0.91, P = 0.02). [ABSTRACT FROM AUTHOR]

CLL B cells express elevated pro-survival BCL2, and its selective inhibitor, venetoclax, significantly reduces leukemic cell load, leading to clinical remission. Nonetheless, relapses occur. This study evaluates the hypothesis that progressively diminished BCL2 protein in cycling CLL cells within patient lymph node niches contributes to relapse. Using CFSE-labeled, purified CLL populations known to respond with vigorous cycling in d6 cultures stimulated with TLR9-activating ODN (oligodeoxynucleotide) + IL15, we show that BCL2 protein progressively declines during consecutive cell divisions. In contrast, MCL1 and survivin are maintained/slightly elevated during cycling. Delayed pulsing of quiescent and activated CLL cultures with selective inhibitors of BCL2 or survivin revealed selective targeting of noncycling and cycling populations, respectively, raising implications for therapy. To address the hypothesis that BCL2-repressive miRs (miR15a/miR16-1), encoded in Chr13, are mechanistically involved, we compared BCL2 protein levels within ODN + IL15-stimulated CLL cells, with/without del(13q), yielding results suggesting these miRs contribute to BCL2 reduction. In support, within ODN-primed CLL cells, an IL15-driven STAT5/PI-3K pathway (required for vigorous cycling) triggers elevated p53 TF protein known to directly activate the miR15a/miR16-1 locus. Furthermore, IL15 signaling elicits the repression of BCL2 mRNA within 24 h. Additional comparisons of del(13q)+ and del(13q)−/− cohorts for elevated p53 TF expression during cycling suggest that a documented miR15a/miR16-1-mediated negative feedback loop for p53 synthesis is active during cycling. Findings that robust CLL cycling associates with progressively decreasing BCL2 protein that directly correlates with decreasing venetoclax susceptibility, combined with past findings that these cycling cells have the greatest potential for activation-induced cytosine deaminase (AICDA)-driven mutations, suggest that venetoclax treatment should be accompanied by modalities that selectively target the cycling compartment without eliciting further mutations. The employment of survivin inhibitors might be such an approach. [ABSTRACT FROM AUTHOR]

• Survivin as an effective diagnostic marker of bladder cancer was confirmed. • Sensitivity of survivin mRNA was higher than that of survivin protein. • Immunohistochemical detection of survivin is more effective for diagnosis. Early detection, diagnosis, and treatment take on critical significance in preventing and treating bladder cancer. As indicated by numerous studies, survivin can serve as a biomarker of bladder cancer, whereas the results of a wide variety of studies have been controversial. This paper is to assess the accuracy of survivin in the diagnosis of bladder cancer by a meta-analysis. The studies regarding the diagnosis of bladder cancer using survivin were systematically retrieved from the CNKI, WanFang, CBM, VIP, Web of science, cochrane library and pubmed were extracted, and the literature quality was assessed. Meta-analysis was conducted using STATA 16.0 MP. 2,082 relevant studies were searched, and 40 studies were finally covered for meta-analysis. The pooled specificity and pooled sensitivity of survivin mRNA was 0.95 (95% CI : 0.91, 0.97) and 0.94 (95% CI : 0.88, 0.97). The pooled specificity and pooled sensitivity of survivin protein reached 0.95 (95% CI : 0.90, 0.97) and 0.87 (95% CI : 0.78, 0.92). The pooled positive likelihood ratio, pooled negative likelihood ratio, the area under the curve, and diagnostic odds ratio for survivin mRNA reached 17.7 (95% CI : 10.3, 30.6), 0.07 (95% CI : 0.04, 0.12), 0.98 (95% CI : 0.97, 0.99) and 266 (95% CI : 114, 621), respectively. For survivin protein was 16.4 (95% CI : 7.9, 33.9), 0.14 (95% CI : 0.08, 0.24), 0.97 (95% CI : 0.95, 0.98) and 117 (95% CI : 38, 357), respectively. Survivin takes on great significance in diagnosing bladder cancer. However, due to some limitations in the number and quality of covered studies, this conclusion should be validated through additional higher quality clinical studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Survivin is overexpressed in a wide variety of human cancers and is associated with increased chemotherapy resistance, recurrence, and shorter patient survival. Although survivin was first identified as an inhibitor of apoptosis based on its sequence homology, recent studies show that survivin primarily plays a role in the regulation of cell division, as a component of the chromosome passenger complex, which can be localized to the centromere, the spindle midzone, or midbody in a cell cycle-dependent manner. Disruption of survivin function generally leads to mitotic catastrophe and is associated with elevated levels of aneuploidy. In contrast, ectopic expression of survivin can promote cell survival under certain conditions and is implicated in mediating resistance to various cancer drugs, possibly by interactions with molecules that modulate apoptotic pathways. A potential role of survivin in the regulation of mitochondrial functions and processes of autophagy has emerged. Because of its prevalent overexpression in cancer and very limited expression in normal tissues, survivin has been proposed as an ideal therapeutic target, and various approaches have been investigated for survivin inhibition. Here we provide a critical review of our current understanding of the role of survivin in promoting malignancy and strategies for the development of survivin-targeted therapy for cancer. Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer. [ABSTRACT FROM AUTHOR]

The fluoroquinolone class of antibiotics includes derivatives of the drug ciprofloxacin. These substances have recently been advocated for the treatment of cancer. In the current study, we examined the cytotoxicity and apoptosis-inducing potential of a novel synthetic ciprofloxacin derivative in the human myeloid leukemia KG1-a cell line. With an IC50 of 25µM, this ciprofloxacin derivative, 7-(4-(2-(benzhydryloxy)-2-oxoethyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4 dihydroquinoline-3- carboxylic acid (4-BHPCP), was an active drug. Through Hoechst 33,258 staining and Annexin V/PI double staining experiments, the apoptotic activity of the 4-BHPCP was assessed morphologically. Real-time quantitative PCR was used to assess changes in the expression level of certain apoptosis-related genes, including Bcl-2, Bax, and Survivin (qRT PCR). The results of the qRT PCR analysis demonstrated that 4-BHPCP promotes apoptosis in the KG1-a cell line by down-regulating Survivin and Bcl2, up-regulating Bax, and increasing the Bax/Bcl2 transcripts in a time-dependent manner. These results imply that this novel chemical may be a promising therapy option for acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Aims: Cognitive impairment is associated with reduced hippocampal neurogenesis; however, the causes of decreased hippocampal neurogenesis remain highly controversial. Here, we investigated the role of survivin in the modulation of hippocampal neurogenesis in AD. Methods: To investigate the effect of survivin on neurogenesis in neural stem cells (NSCs), we treated mouse embryonic NSCs with a survivin inhibitor (YM155) and adeno‐associated viral survivin (AAV‐Survivin). To explore the potential role of survivin expression in AD, AAV9‐Survivin or AAV9‐GFP were injected into the dentate gyrus (DG) of hippocampus of 7‐month‐old wild‐type and 5XFAD mice. Cognitive function was measured by the Y maze and Morris water maze. Neurogenesis was investigated by BrdU staining, immature, and mature neuron markers. Results: Our results indicate that suppression of survivin expression resulted in decreased neurogenesis. Conversely, overexpression of survivin using AAV‐Survivin restored neurogenesis in NSCs that had been suppressed by YM155 treatment. Furthermore, the expression level of survivin decreased in the 9‐month‐old 5XFAD compared with that in wild‐type mice. AAV‐Survivin‐mediated overexpression of survivin in the DG in 5XFAD mice enhanced neurogenesis and cognitive function. Conclusion: Hippocampal neurogenesis can be enhanced by survivin overexpression, suggesting that survivin could serve as a promising therapeutic target for the treatment of AD. [ABSTRACT FROM AUTHOR]

The anti‐apoptotic proteins, Bcl‐2 and Survivin, are consistently overexpressed in numerous human malignancies, notably in colorectal cancer. 2,4‐Di‐tert‐butylphenol (2,4‐DTBP) is a naturally occurring phenolic compound known for its diverse biological activities, including anti‐cancer properties. The mechanism behind 2,4‐DTBP‐induced inhibition of cell proliferation and apoptosis in human colorectal cancer cells, specifically regarding Bcl‐2 and Survivin, remains to be elucidated. In this study, we employed both in silico and in vitro methodologies to underpin this interaction at the molecular level. Molecular docking demonstrated a substantial binding affinity of 2,4‐DTBP towards Bcl‐2 (ΔG = −9.8 kcal/mol) and Survivin (ΔG = −5.6 kcal/mol), suggesting a potential inhibitory effect. Further, molecular dynamic simulations complemented by MM‐GBSA calculations confirmed the significant binding of 2,4‐DTBP with Bcl‐2 (dGbind = −54.85 ± 6.79 kcal/mol) and Survivin (dGbind = −32.36 ± 1.29 kcal/mol). In vitro assays using HCT116 colorectal cancer cells revealed that 2,4‐DTBP inhibited proliferation and promoted apoptosis in both a dose‐ and time‐dependent manner. Fluorescence imaging and scanning electron microscopy illustrated the classical features associated with apoptosis upon 2,4‐DTBP exposure. Cell cycle analysis through flow cytometry highlighted a G1 phase arrest and apoptosis assay demonstrated increased apoptotic cell population. Notably, western blotting results indicated a decreased expression of Bcl‐2 and Survivin post‐treatment. Considering the cytoprotective roles of Bcl‐2 and Survivin through the inhibition of mitochondrial dysfunction, our findings of disrupted mitochondrial bioenergetics, characterized by reduced ATP production and oxygen consumption, further accentuate the functional impairment of these proteins. Overall, the integration of in silico and in vitro data suggests that 2,4‐DTBP holds promise as a therapeutic agent targeting Bcl‐2 and Survivin in colorectal cancer. [ABSTRACT FROM AUTHOR]

Isobavachalcone (IBC) as a bioactive chalcone isolated from the seeds of Psoralea corylifolia Linn has shown promising anticancer activities. However, its main anticancer mechanism in colorectal cancer cells has not been well-explored. Recently, the interaction of therapeutic compounds with survivin, an antiapoptotic marker, has been indicated to be a potential approach for advancing anticancer compounds. Therefore, in this study, IBC was evaluated for its anticancer activities against metastatic colorectal adenocarcinoma, LoVo, followed by exploring its interaction with survivin. It was observed that incubation of the human LoVo colorectal cancer cells with the IBC at 24 h resulted in a significant reduction in cell viability with an IC50 of about 35 µM as well as a significant membrane damage. Also, it was deduced that IBC could result in the formation of excessive ROS, lipid peroxidation, reduction of SOD/CAT activity, as well as downregulation of Nrf2 and HO-1 mRNA levels. Further studies showed that IBC could induce MMP reduction, cytochrome c (Cyt c) release, overexpression of Bax/Bcl-2 mRNA ratio as well as caspase-9 and −3. Moreover, it was deduced that IBC mitigated the expression of survivin at mRNA and protein levels. Then, binding parameters indicated that IBC strongly binds to one molecule of survivin at physiological temperature. Also, it was revealed that IBC substantially induced the conformational changes of survivin. Ultimately, through hydrogen bonding and hydrophobic forces, IBC has a substantial binding affinity with survivin (–9.80 kcal/mol) at a region that is critical to the dimerization process, according to molecular docking studies. Overall, this study showed that IBC may be used in future research to assess its clinical and in vivo behaviors in the modulation of colorectal cancer mediated by deactivation and downregulation of antiapoptotic survivin.

While the relationship between cellular apoptosis and proliferation rates in COVID patients remains underexplored in existing literature, various viruses are known to impact these fundamental process to modulate response to infection. This paper aims to assess apoptosis and proliferation rates in individuals recently infected with Coronavirus, both before and after vaccination, comparing them with healthy controls. Peripheral blood cells from newly diagnosed COVID-19 patients revealed a significant increase in proliferation and apoptosis levels in fresh lymphocytes and granulocytes compared to healthy donors. Notably, as none of the patients were under corticosteroid therapy or cytotoxic drugs, the study underscores the critical role of white blood (WBC) apoptosis in viral pathogenesis, potentially contributing significantly to COVID-19′s pathogenicity. Elevated levels of soluble Fas ligand (FaSL) and the pro-inflatmmatory cytokine IL-38 were identified in COVID-19 patients, indicating potential immune dysregulation. Furthermore, individual who received the vaccine or recovered from COVID-19 exhibited higher survivin rates, suggesting a protective role for survivin in migitating lung damage. These findings suggest the prospect of developing a strategy to prevent WBC apoptosis, offering potential benefits in averting lymphopenia associated with severe COVID-19 ouctomes.

Objective To investigate the possibility of treating keloid by inhibiting Survivin (BIRC5) expression using the network pharmacological analysis method, and to look for specific therapeutic drugs. Methods From January 2021 to October 2023, Department of Plastic Surgery, Heze Municipal Hospital searched relevant databases such as PubMed, Oncomine, String, Uniprot, KEGG, Therapeutic Target Database (TTD) and Drugbank to investigate Survivin (BIRC5) as a potential target for keloid therapy. Results By searching the PubMed database found evidences for the treatment of keloids by inhibiting the expression of Survivin (BIRC5). By searching the Oncomine database, the String database and the KEGG database found indirect evidences for the treatment of keloid by inhibiting the expression of Survivin (BIRC5). By searching TTD database and Drugbank database found some drugs that have the potential to treat keloid, such as the anti-human Survivin (BIRC5) antisense oligonucleotide ISIS 23722 and LY2181308, Berberine and Reserpine. Conclusion Inhibition of Survivin (BIRC5) expression in fibroblasts to promote apoptosis of fibroblasts may be an effective treatment for keloid. However, further researches are needed to confirm this conclusion. [ABSTRACT FROM AUTHOR]

Survivin holds significant importance as a member of the inhibitor of apoptosis protein (IAP) family due to its predominant expression in tumours rather than normal terminally differentiated adult tissues. The high expression level of survivin in tumours is closely linked to chemotherapy resistance, heightened tumour recurrence, and increased tumour aggressiveness and serves as a negative prognostic factor for cancer patients. Consequently, survivin has emerged as a promising therapeutic target for cancer treatment. In this review, we delve into the various biological characteristics of survivin in cancers and its pivotal role in maintaining immune system homeostasis. Additionally, we explore different therapeutic strategies aimed at targeting survivin. [ABSTRACT FROM AUTHOR]

Starting in 2019, coronavirus disease 2019 (COVID-19) caused an epidemic that was growing rapidly and has harmed millions of people globally. It has been demonstrated that survivin regulates lymphocyte survival, a main route involved in COVID-19 pathogenesis. Survivin belongs to the inhibitor of apoptosis protein (IAP) family, and its primary functions comprise regulating mitosis and inhibiting apoptosis. Since lower survivin expression has been shown to increase the sensitivity of lymphocytes to apoptotic induction, we looked into the function of survivin and its corresponding pathways in COVID-19 pathogenesis. The expression of survivin, X-linked inhibitor of apoptosis protein (XIAP), caspases 3, 7, 9, and poly (ADP-ribose) polymerase (PARP) was evaluated at both mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) derived from healthy donors and patients with severe and moderate COVID-19 by qRT-PCR and Western blotting, respectively. Then, we enforced apoptosis to COVID-19 patient-derived lymphocytes, and the percent was assessed by flow cytometry. Survivin and XIAP were less expressed in PBMCs derived from COVID-19 patients as apoptosis inhibitors than PARP, cleaved-PARP, caspase 9, and cleaved caspases 3 and 7, according to the results of real-time PCR and Western blot analysis. Additionally, according to the flow cytometry results, the down-regulation of survivin served as a potential factor in the lymphocyte depletion observed in patients with COVID-19. The role of survivin and its related pathway was first discovered in the development of COVID-19 and may serve as a potential prognostic and therapeutic target. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of miR-203a-3p on the invasion and migration of esophageal cancer cells and to analyze the targeted regulatory relationship with Survivin. Methods Esophageal cancer TE-1 cells and normal esophageal mucosal epithelial HEEC cells in logarithmic growth phase were collected. The miR-203a-3p and Survivin mRNA were tested by RT-qPCR. The targeted regulatory relationship between miR-203a-3p and Survivin was analyzed by dual luciferase reporter assay. The TE-1 cells were divided into the control group, miR-203a-3p simulation group, miR203a-3p inhibitory group, and negative control group, respectively. Cells in the miR-203a-3p simulation group were transfected with miR-203a-3p mimic, miR-203a-3p-inhibited group with miR-203a-3p inhibitor, and negative control group with miR-203a-3p NC, while cells in the control group were not transfected. Transfection efficiency was verified by RT-qPCR. Cell viability was measured by MTT at 2, 12, 24, 36 and 48 h after transfection, cell migration was measured by Scratch assay and cell invasion was measured by Transwell invasion assay. Results The mRNA expression of miR-203a3p was lower and the mRNA expression of Survivin was higher in the esophageal cancer cells than in the normal esophageal mucosal epithelial cells(both P<0. 05). TargetScan database analysis showed that the Survivin gene had seven consecutive nucleotide sequences at the 3′UTR end that could be complementary to miR-203a-3p. The result of dual luciferase reporter assay showed that TE-1 cells co-transfected with Survivin-WT and plasmid-miR-203a-3p mimic plasmids had lower activity than other cells(P<0. 05). The cell viability at 12, 24, 36 and 48 h was as follows: the miR-203a-3p inhibition group > the control group and the negative control group > the miR-203a-3p simulation group(all P<0. 05). The cell migration distance and the number of invasive cells were in the following order: the miR-203a-3p inhibition group > the control group and negative control group> the miR-203a-3p simulation group(all P<0. 05). Conclusion High expression of miR-203a-3p inhibits the migration and invasion of esophageal cancer cells, and the mechanism may be related to the targeted negative regulation of Survivin. [ABSTRACT FROM AUTHOR]

Therapeutic targeting of Sp1 transcription factor and survivin, are studied in various cancers due to their consistent overexpression. These markers result in poorer cancer prognoses and their downregulation has been investigated as an effective treatment approach. Mithramycin-A and Tolfenamic acid are two drugs with innate anti-cancer properties and are suggested to be able to target Sp1 through GC/GT DNA binding interference, however in-depth binding and mechanistic studies are lacking. Through docking analysis, we investigated Mithramycin-A and Tolfenamic acid in terms of their specific binding interactions with Sp1 and survivin. Through further molecular dynamics simulations including Root Mean Square (RMS) Fluctuation and RMS Deviation, rGYr, and H-bond analysis, we identified critical residues involved in drug interactions with each protein in question. We show Mithramycin-A as the superior binding candidate to each protein and found that it exhibited stronger binding with Sp1, and then survivin. Subsequent molecular dynamics simulations followed the same trend as initial binding energy calculations and showed crucial amino acids involved in each Mithramycin-A-protein complex. Our findings warrant further investigation into Mithramycin-A and its specific interaction with Sp1 and their downstream targets giving a better understanding of Mithramycin-A and its potential as an effective cancer treatment. [Display omitted] • Docking studies showed binding affinity for both Mithramycin and tolfenamic acid with Sp1 and BIRC5. • Docking analysis confirmed that Mithramycin exhibits higher binding affinity in compared to Tolfenamic acid. • Molecular Docking/Dynamic Simulation studies are consistent with in vitro results using Ewing sarcoma cells. • Intermolecular H-bonds revealed novel bonds and interactions forming post Molecular Dynamic simulations. [ABSTRACT FROM AUTHOR]

Challenges to docetaxel use in prostate cancer treatment include several resistance mechanisms as well as toxicity. To overcome these challenges and to improve the therapeutic efficacy in heterogeneous prostate cancer, the use of multiple agents that can destroy different subpopulations of the tumor is required. Brusatol, a multitarget inhibitor, has been shown to exhibit potent anticancer activity and play an important role in drug response and chemoresistance. Thus, the combination of brusatol and docetaxel in a nanoparticle platform for the treatment of prostate cancer is expected to produce synergistic effects. In this study, we reported the development of polymeric nanoparticles for the delivery of brusatol and docetaxel in the treatment of prostate cancer. The one-factor-at-a-time method was used to screen for formulation and process variables that impacted particle size. Subsequently, factors that had modifiable effects on particle size were evaluated using a 24 full factorial statistical experimental design followed by the optimization of drug loading. The optimization of blank nanoparticles gave a formulation with a mean size of 169.1 nm ± 4.8 nm, in agreement with the predicted size of 168.333 nm. Transmission electron microscopy showed smooth spherical nanoparticles. The drug release profile showed that the encapsulated drugs were released over 24 h. Combination index data showed a synergistic interaction between the drugs. Cell cycle analysis and the evaluation of caspase activity showed differences in PC-3 and LNCaP prostate cancer cell responses to the agents. Additionally, immunoblots showed differences in survivin expression in LNCaP cells after treatment with the different agents and formulations for 24 h and 72 h. Therefore, the nanoparticles are potentially suitable for the treatment of advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: It is believed that pancreatic intraepithelial neoplasia is an important element of pancreatic carcinogenesis. Apoptosis is the process of programmed cell death. Survivin is one of the proteins that inhibit apoptosis. Caspase-3 is a cysteine protease, and plays important roles in the process of apoptosis. Aim of the research: The authors focus on analyzing the expression of survivin and caspase-3 in unchanged tissue and tissue from PanIN lesions. This study may help to better understand the cause-and-effect chain from low-grade intraepithelial neoplasia to high-grade neoplasia and invasive cancer. Material and methods: The study used tissue material obtained from 70 patients operated on at the 2nd Department of General, Gastroenterological and Oncological Surgery at the Medical University of Bialystok due to pancreatic diseases: adenocarcinoma (38 patients), chronic pancreatitis (23 patients), pancreatic cysts (9 patients). A total of 239 tissue samples were isolated for clinical examination. Results: There were statistically significant differences in survivin expression by sex (p < 0.05) and age (p < 0.05). The level of survivin expression was higher in male patients and patients over 60. There were statistically significant differences between the expression levels of survivin as well as caspase-3 depending on the degree of PanIN [PanIN 1A vs PanIN 1b survivin 15% vs. 38.8% (p < 0.05), and caspase-3 17%; vs. 26.9% (p < 0.05). PanIN 2 vs. PaIN3 survivin 62.4% vs. 85.7% (p < 0.05), caspase-3 36.1% vs. 54.3% (p < 0.05)]. Conclusions: The expression level of survivin and caspase-3 is inextricably linked with the progression of pancreatic intraepithelial neoplasia. The more advanced neoplasia is, the higher is the expression level. [ABSTRACT FROM AUTHOR]

Arsenic is a toxic metalloid found in the environment in different organic and inorganic forms. Molecular mechanisms implicated in arsenic hepatotoxicity are complex but include oxidative stress, apoptosis, and autophagy. The current study focused on the potential protective capacity of melatonin against arsenic‐induced hepatotoxicity. Thirty‐six male Wistar rats were allocated into control, arsenic (15 mg/kg; orally), arsenic (15 mg/kg) plus melatonin (10, 20, and 30 mg/kg; intraperitoneally), and melatonin alone (30 mg/kg) groups for 28 days. After the treatment period, the serum sample was separated to measure liver enzymes (AST and ALT). The liver tissue was removed and then histological alterations, oxidative stress markers, antioxidant capacity, the levels of Nrf2 and HO‐1, apoptosis (Bcl‐2, survivin, Mcl1, Bax, and caspase‐3), and autophagy (Sirt1, Beclin‐1, and LC3 II/I ratio) proteins, as well as the expression level of miR‐34a, were evaluated on this tissue. Arsenic exposure resulted in the enhancement of serum AST, ALT, and substantial histological damage in the liver. Increased levels of malondialdehyde, a lipid peroxidation marker, and decreased levels of physiological antioxidants including glutathione, superoxide dismutase, and catalase were indicators of arsenic‐induced oxidative damage. The levels of Nrf2, HO‐1, and antiapoptotic proteins diminished, while proapoptotic and autophagy proteins were elevated in the arsenic group concomitant with a low level of hepatic miR‐34a. The co‐treatment of melatonin and arsenic reversed the changes caused by arsenic. These findings showed that melatonin reduced the hepatic damage induced by arsenic due to its antioxidant and antiapoptotic properties as well as its regulatory effect on the miR‐34a/Sirt1/autophagy pathway. [ABSTRACT FROM AUTHOR]

With a prevalence of 12.5% of all new cancer cases annually, breast cancer stands as the most common form of cancer worldwide. The current therapies utilized for breast cancer are constrained and ineffective in addressing the condition. siRNA-based gene silencing is a promising method for treating breast cancer. We have developed an aptamer-conjugated dendritic multilayered nanoconjugate to treat breast cancer. Initially, we transformed the hydroxyl groups of the hyperbranched bis-MPA polyester dendrimer into carboxylic groups. Subsequently, we linked these carboxylic groups to tetraethylenepentamine to form a positively charged dendrimer. In addition, the mucin-1 (MUC1) aptamer was attached to the dendrimer using a heterobifunctional polyethylene glycol. Characterizing dendrimers involved 1H NMR and dynamic light scattering techniques at every production stage. A gel retardation experiment was conducted to evaluate the successful binding of siRNA with targeted and non-targeted dendrimers. The targeted dendrimers exhibited no harmful effects on the NIH-3T3 fibroblast cells and RBCs, indicating their biocompatible characteristics. Confocal microscopy demonstrated significant higher uptake of targeted dendrimers than non-targeted dendrimers in MCF-7 breast cancer cells. The real-time PCR results demonstrated that the targeted dendrimers exhibited the most pronounced inhibition of the target gene expression compared to the non-targeted dendrimers and lipofectamine-2000. The caspase activation study confirmed the functional effect of survivin silencing by dendrimer, which led to the induction of apoptosis in breast cancer cells. The findings indicated that Mucin-1 targeted hyperbranched bis-MPA polyester dendrimer carrying siRNA could successfully suppress the expression of the target gene in breast cancer cells.

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 μM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer.

Abstract Background Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection. Methods Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan–Meier method and compared with the log-rank test. Results GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044). Conclusions Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.

Abstract Background Neuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran. Aim To determine efficacy and modes of action of the survivin-Ran inhibitor LLP-3 as a potential novel therapy of NB. Methods Survivin and Ran mRNA expression in NB tumors was correlated to patient survival. Response to LLP-3 in NB cell lines was determined by assays for viability, proliferation, apoptosis, clonogenicity and anchorage-independent growth. Interaction of survivin and Ran was assessed by proximity-linked ligation assay and their subcellular distribution by confocal immunofluorescence microscopy. Expression of survivin, Ran and proteins important for OXPHOS and glycolysis was determined by Western blot, hexokinase activity by enzymatic assay, interaction of survivin with HIF-1α by co-IP, and OXPHOS and glycolysis by extracellular flux analyzer. Results High mRNA expression of survivin and Ran is correlated with poor patient survival. LLP-3 decreases viability, induces apoptosis, and inhibits clonogenic and anchorage-independent growth in NB cell lines, including those with MYCN amplification, and mutations of p53 and ALK. LLP-3 inhibits interaction of survivin with Ran, decreasing their concentration both in the cytoplasm and the nucleus. LLP-3 impairs flexibility of energy metabolism by inhibiting both OXPHOS and glycolysis. Metabolic inhibition is associated with mitochondrial dysfunction and attenuated hexokinase activity but is independent of HIF-1α. Conclusion LLP-3 attenuates interaction and concentration of survivin and Ran in NB cells. It controls NB cells with diverse genetic alterations, associated with inhibition of OXPHOS, aerobic glycolysis, mitochondrial function and HK activity. Thus, LLP-3 warrants further studies as a novel drug against NB.

Abstract Background Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder characterised by synovial hypertrophy, proliferation, and pannus formation encroaching on articular structures resulting in uncontrolled spread of joint destruction. Survivin is an anti-apoptotic protein that plays an important role in tissue growth and tumour development. The objective of this research is to study the role of Survivin as a predictor of treatment response to anti-tumor necrosis factor (anti-TNF) in RA patients who had failure of conventional disease modifying anti rheumatic drugs (DMARDs) treatment. Results All patients had active RA evaluated with DAS 28 activity score: 73.3% of them had high disease activity, while 22.7% were in moderate activity. Serum survivin level ranged from 725 pg/ml to 2750 pg/ml. Its level was significantly higher in patients than in controls with a p value of

Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa.

Survivin, an important inhibitor of apoptosis protein, contributes to cancer cells’ resistance to apoptosis, proliferation, and survival. It is a promising biomarker and therapeutic target due to being highly expressed in cancer cells relative to normal cells and universally expressed in almost all cancer types. Cancer cells release survivin to the tumour microenvironment (TME) not only as a free protein but also encapsulated in extracellular vesicles (EVs), especially small EVs (sEVs). The release of encapsulated survivin from cancer cells can be taken up by neighbouring cells, eliciting pathological responses such as tumorigenesis and metastasis. Consequently, EV survivin holds potential as a diagnostic, prognostic, and therapeutic biomarker for several types of cancer, including breast cancer, prostate cancer, pancreatic cancer, and glioblastoma. EV survivin expression is significantly elevated in cancer patients and correlates with unfavourable clinicopathologic parameters. Although no clinical studies have explored EV survivin as a therapeutic target, future research should explore survivin-based therapies in combination with EV-targeting therapies to effectively disrupt its roles in tumorigenesis and metastasis.

Background: Circular RNAs (circRNAs) play a crucial role in regulating various physiological processes. However, the precise regulatory mechanisms of circRNF220s in osteosarcoma (OS) are not well understood. Methods: The abundances of circRNF220, miR-330-5p, and survivin were determined using qRT-PCR. To assess the m6A accumulation in circRNF220, a methylated RNA immunoprecipitation (Me-RIP) assay was conducted. Cellular multiplication, motility, and invasion were examined using the cell Counting Kit-8 (CCK-8), EdU, colony formation, Transwell, and wound-healing assays. The binding relationships were measured through RNA immunoprecipitation (RIP) and luciferase reporter assays. In vivo functionality was assessed using xenograft models. Results: CircRNF220 was identified as being overexpressed in both OS cells and tissues. In vitro experiments demonstrated that silencing circRNF220 impeded the proliferation, invasion, and motility of OS cells. Similarly, in vivo studies confirmed that downregulating circRNF220 inhibited the growth of OS. Further mechanistic investigations unveiled that METTL3-modulated circRNF220 regulated the progression of OS by upregulating survivin expression through acting as a sponge for miR-330-5p. Conclusion: The modulation of METTL3-regulated circRNF220 has been found to promote the progression of OS by modulating the miR-330-5p/survivin axis. This novel finding suggests a potentially unique approach to managing OS. [ABSTRACT FROM AUTHOR]

Simple Summary: Elevated expression of BIRC5/survivin, a protein crucial for cell division, is linked to unfavorable outcomes in neuroblastoma (NB), a prevalent pediatric tumor. Novel therapeutic approaches are consequently warranted. Therefore, we examined the effects of S12 and LQZ-7I, small molecules that disrupt survivin's interaction with itself and other proteins, on NB cells in vitro and in vivo. We demonstrate that these drugs effectively suppress the growth of NB cells, partly by hindering cell division. In contrast, incomplete inhibition of BIRC5 transcription did not diminish NB growth. We conclude that inhibitors of survivin protein interaction hold promise as a novel therapeutic class against NB and should be further investigated. Increased expression of BIRC5/survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB), the most common extracranial tumor of childhood. Transcriptional inhibitors of survivin have been tested in adult cancers and inhibitors of survivin homodimerization are emerging. We compared genetic inhibition of survivin transcription with the inhibition of survivin homodimerization by S12 and LQZ-7I, chosen from a larger panel of survivin dimerization inhibitors with activity against NB cells. Mice hemizygous for Birc5 were crossed with NB-prone TH-MYCN mice to generate Birc5+/-/MYCNtg/+ mice. The marked decrease of survivin transcription in these mice did not suffice to attenuate the aggressiveness of NB, even when tumors were transplanted into wild-type mice to assure that immune cell function was not compromised by the lack of survivin. In contrast, viability, clonogenicity and anchorage-independent growth of NB cells were markedly decreased by S12. S12 administered systemically to mice with subcutaneous NB xenotransplants decreased intratumoral hemorrhage, albeit not tumor growth. LQZ-7I, which directly targets the survivin dimerization interface, was efficacious in controlling NB cell growth in vitro at markedly lower concentrations compared to S12. LQZ-7I abrogated viability, clonogenicity and anchorage-independent growth, associated with massively distorted mitotic spindle formation. In vivo, LQZ-7I effectively reduced tumor size and cell proliferation of NB cells in CAM assays without apparent toxicity to the developing chick embryo. Collectively, these findings show that inhibiting survivin homodimerization with LQZ-7I holds promise for the treatment of NB and merits further investigation. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) are the most common types of cancers in the head and neck region (HNSCC). Despite very aggressive treatment modalities, the five-year survival rate has not changed for decades and is still around 60%. The search for potential specific biomarkers of aggressiveness or outcome indicators could be of great benefit in improving the treatment of these patients. One of the potential biomarkers is survivin, the protein product of the BIRC5 gene. In this study, we investigated the occurrence of BIRC5 gene polymorphisms in 48 patients with OSCC and OPSCC compared with healthy controls. A total of 18 polymorphisms were found, 11 of which occurred in HNSCC with a minor allele frequency (MAF) of more than 5%. Five polymorphisms (rs3764383, rs9904341, rs2071214, rs2239680, rs2661694) were significantly associated with tumor size, tumor stage, and advanced regional disease, but had no impact on survival. [ABSTRACT FROM AUTHOR]

Background: Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection. Methods: Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan–Meier method and compared with the log-rank test. Results: GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044). Conclusions: Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET. [ABSTRACT FROM AUTHOR]

Genipin, a natural compound derived from the fruit of Gardenia jasminoides Ellis, was reported to have activity against various cancer types. In this study, we determined the underlying mechanism for genipin‐induced cell death in human oral squamous cell carcinoma (OSCC). The growth‐inhibitory effects of genipin in human OSCC cells was examined by the Cell Counting Kit‐8 and soft agar assays. The effects of genipin on apoptosis were assessed by nuclear morphological changes by 4′,6‐diamidino‐2‐phenylindole staining, measurement of the sub‐G1 population, and Annexin V‐fluorescein isothiocyanate/propidium iodide double staining. The underlying mechanism of genipin activity was analyzed by western blot analysis, subcellular fractionation of the nucleus and cytoplasm, immunocytochemistry, and quantitative real‐time polymerase chain reaction. Genipin inhibited the growth of OSCC cells and induced apoptosis, which was mediated by a caspase‐dependent pathway. Genipin reduced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and its nuclear localization. Furthermore, inhibition of p‐STAT3Tyr705 levels following genipin treatment was required for the reduction of survivin and myeloid cell leukemia‐1 (Mcl‐1) expression, leading to apoptotic cell death. The genipin‐mediated reduction in survivin and Mcl‐1 expression was caused by transcriptional and/or posttranslational regulatory mechanisms. The results provide insight into the regulatory mechanism by which genipin induces apoptotic cell death through the abrogation of nuclear STAT3 phosphorylation and suggest that genipin may represent a potential therapeutic option for the treatment of human OSCC. Significance statement: STAT3 is frequently overexpressed in various cancers, including OSCC, indicating that it can be an oncogenic factor and cancer therapy targeting STAT3 is thought to be a promising therapeutic option.In the present study, we investigated the possibility of genipin as an anticancer drug candidate by targeting STAT3 kinase in oral cancer cell lines.The importance of our findings is genipin can mediate STAT3 signaling to induce apoptosis for treating human oral cancer and, to the best our knowledge, it is the first study showing the deactivation of STAT3 by genipin for apoptosis in oral cancer. [ABSTRACT FROM AUTHOR]

Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases. [ABSTRACT FROM AUTHOR]

Purpose: Chemoresistance is a primary factor for treatment failure and tumor recurrence in non-small cell lung cancer (NSCLC) patients. The oncoprotein survivin is commonly upregulated in human malignancies and is associated with poor prognosis, but its effect on carcinogenesis and chemoresistance in NSCLC is not yet evident, and to explore an effective inhibitor targeting survivin expression is urgently needed. Methods: The protumor characteristics of survivin and antitumor activities of bergenin in NSCLC cells were examined by MTS, colony formation assays, immunoblot, immunohistochemistry, and in vivo xenograft development. Results: Survivin was upregulated in non-small cell lung cancer (NSCLC) tissues, while its depletion inhibited NSCLC tumorigenesis. The current study focused on bergenin, identifying its effective antitumor effect on NSCLC cells both in vivo and in vitro. The results showed that bergenin could inhibit cell proliferation and induce the intrinsic pathway of apoptosis via downregulating survivin. Mechanistically, bergenin reduced the phosphorylation of survivin via inhibiting the Akt/Wee1/CDK1 signaling pathway, thus resulting in enhanced interaction between survivin and E3 ligase Fbxl7 to promote survivin ubiquitination and degradation. Furthermore, bergenin promoted chemoresistance in NSCLC cells re-sensitized to pemetrexed treatment. Conclusions: Survivin overexpression is required for maintaining multiple malignant phenotypes of NSCLC cells. Bergenin exerts a potent antitumor effect on NSCLC via targeting survivin, rendering it a promising agent for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies. [ABSTRACT FROM AUTHOR]

Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate worldwide despite the remarkable advances in its treatment. Origanum majorana Essential Oil (OMEO) has been shown to be effective against non-small cell lung cancer (NSCLC) cells, decreasing their viability and colony growth in vitro, as well as inhibiting tumor growth in chick embryo chorioallantoic membranes (CAM) and nude mice in vivo. OMEO is mainly composed of four monoterpenes, namely terpinen-4-ol, sabinene hydrate, α-terpinene, and γ-terpinene. In this study, we aimed to investigate the potential anticancer effects of these monoterpenes, either alone or in combination, on NSCLC. Our findings indicate that these four monoterpenes significantly decreased NSCLC cell viability in a concentration-dependent manner, reduced their colony growth in vitro, and also downregulated survivin expression in these cells. Moreover, different combined mixtures of these monoterpenes further enhanced their anticancer effects on cellular viability, with a terpinen-4-ol and sabinene hydrate combination being the most potent. We also found that terpinen-4-ol, in combination with sabinene hydrate, markedly enhanced the anticancer effect of the individual monoterpenes on NSCLC viability within a shorter treatment duration through, at least in part, survivin downregulation. Furthermore, this combination enhanced the inhibition of colony growth in vitro and the tumor growth of NSCLC cells xenografted onto chick embryo CAM in vivo. Altogether, our study highlights the potential of these monoterpenes for use in further pre-clinical investigations against various cancer hallmarks. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a representative malignant brain tumor characterized by a dismal prognosis, with survival rates of less than 2 years and high recurrence rates. Despite surgical resection and several alternative treatments, GBM remains a refractory disease due to its aggressive invasiveness and resistance to anticancer therapy. In this report, we explore the role of fibronectin type III domain containing 3B (FNDC3B) and its potential as a prognostic and therapeutic biomarker in GBM. GBM exhibited a significantly higher cancer-to-normal ratio compared to other organs, and patients with high FNDC3B expression had a poor prognosis (p < 0.01). In vitro studies revealed that silencing FNDC3B significantly reduced the expression of Survivin, an apoptosis inhibitor, and also reduced cell migration, invasion, extracellular matrix adhesion ability, and stem cell properties in GBM cells. Furthermore, we identified that FNDC3B regulates PTEN/PI3K/Akt signaling in GBM cells using MetaCore integrated pathway bioinformatics analysis and a proteome profiler phospho-kinase array with sequential western blot analysis. Collectively, our findings suggest FNDC3B as a potential biomarker for predicting GBM patient survival and for the development of treatment strategies for GBM. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB), the most common extracranial solid malignancy in children, carries a poor prognosis in high-risk disease, thus requiring novel therapeutic approaches. Survivin is overexpressed in NB, has pro-mitotic and anti-apoptotic functions, and impacts on oxidative phosphorylation (OXPHOS) and aerobic glycolysis. The subcellular localization and hence function of survivin is directed by the GTPase Ran. Aim: To determine efficacy and modes of action of the survivin-Ran inhibitor LLP-3 as a potential novel therapy of NB. Methods: Survivin and Ran mRNA expression in NB tumors was correlated to patient survival. Response to LLP-3 in NB cell lines was determined by assays for viability, proliferation, apoptosis, clonogenicity and anchorage-independent growth. Interaction of survivin and Ran was assessed by proximity-linked ligation assay and their subcellular distribution by confocal immunofluorescence microscopy. Expression of survivin, Ran and proteins important for OXPHOS and glycolysis was determined by Western blot, hexokinase activity by enzymatic assay, interaction of survivin with HIF-1α by co-IP, and OXPHOS and glycolysis by extracellular flux analyzer. Results: High mRNA expression of survivin and Ran is correlated with poor patient survival. LLP-3 decreases viability, induces apoptosis, and inhibits clonogenic and anchorage-independent growth in NB cell lines, including those with MYCN amplification, and mutations of p53 and ALK. LLP-3 inhibits interaction of survivin with Ran, decreasing their concentration both in the cytoplasm and the nucleus. LLP-3 impairs flexibility of energy metabolism by inhibiting both OXPHOS and glycolysis. Metabolic inhibition is associated with mitochondrial dysfunction and attenuated hexokinase activity but is independent of HIF-1α. Conclusion: LLP-3 attenuates interaction and concentration of survivin and Ran in NB cells. It controls NB cells with diverse genetic alterations, associated with inhibition of OXPHOS, aerobic glycolysis, mitochondrial function and HK activity. Thus, LLP-3 warrants further studies as a novel drug against NB. [ABSTRACT FROM AUTHOR]