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Purpose: This study aims to investigate the radiation enhancement effects of ultrasound-stimulated microbubbles (USMB) with X-rays and nanoparticles on pancreatic cancer cells in vitro. Methods: Sonazoid™ microbubbles were used for USMB treatment with a commercially available ultrasound unit. The characterization of the microbubbles before and after ultrasound exposure with different mechanical parameters was evaluated microscopically. Two pancreatic cancer cell lines, MIAPaCa-2 and PANC-1, were treated with different concentrations of microbubbles in combination with 150 kVp X-rays and hydrogen peroxide-modified titanium dioxide nanoparticles. Cell viability was evaluated using a water-soluble tetrazolium dye and a colony formation assay. In addition, intracellular reactive oxygen species (ROS) induced by the combined treatment were assessed. Results: The number of burst microbubbles increased with ultrasound's higher mechanical index and the exposure time. A significant radiation enhancement effect with a significant increase in ROS levels was observed in MIAPaCa-2 cells treated with USMB and 6 Gy X-rays, whereas it was not significant in PANC-1 cells treated with the same. When a higher concentration of USMB was applied with X-rays, no radiation enhancement effects were observed in either cell line. Moreover, there was no radiation enhancement effect by USMB between cells treated with and without nanoparticles. Conclusions: The results indicate that USMB treatment can additively enhance the therapeutic efficacy of radiation therapy on pancreatic cancer cells, while the synergistic enhancement effects are likely to be cell type and microbubble concentration dependent. In addition, USMB did not improve the efficacy of nanoparticle-induced radiosensitization in the current setting. Keywords: Microbubbles, nanoparticles, radiation therapy, radiosensitizer, ultrasound, Author(s): Masao Nakayama (corresponding author) [1,2,3]; Ayaha Noda [4]; Hiroaki Akasaka [1,5]; Takahiro Tominaga [4]; Giulia McCorkell [2]; Moshi Geso [2]; Ryohei Sasaki [1] INTRODUCTION Microbubbles have been used clinically [...]

Background: Pancreatic ductal adenocarcinoma (PDAC) has a rich and complex tumor immune microenvironment (TIME). M2 macrophages are among the most extensively infiltrated immune cells in the TIME and are necessary for the growth and migration of cancers. However, the mechanisms and targets mediating M2 macrophage infiltration in pancreatic cancer remain elusive. Methods: The M2 macrophage infiltration score of patients was assessed using the xCell algorithm. Using weighted gene co-expression network analysis (WGCNA), module genes associated with M2 macrophages were identified, and a predictive model was designed. The variations in immunological cell patterns, cancer mutations, and enrichment pathways between the cohorts with the high- and low-risk were examined. Additionally, the expression of FCGR3A and RNASE2, as well as their association with M2 macrophages were evaluated using the HPA, TNMplot, and GEPIA2 databases and verified by tissue immunofluorescence staining. Moreover, in vitro cell experiments were conducted, where FCGR3A was knocked down in pancreatic cancer cells using siRNA to analyze its effects on M2 macrophage infiltration, tumor proliferation, and metastasis. Results: The prognosis of patients in high-risk and low-risk groups was successfully distinguished using a prognostic risk score model of M2 macrophage-related genes (p = 0.024). Between the high- and low-risk cohorts, there have been notable variations in immune cell infiltration patterns, tumor mutations, and biological functions. The risk score was linked to the manifestation of prevalent immunological checkpoints, immunological scores, and stroma values (all p < 0.05). In vitro experiments and tissue immunofluorescence staining revealed that FCGR3A can promote the infiltration or polarization of M2 macrophages and enhance tumor proliferation and migration. Conclusions: In this study, an M2 macrophage-related pancreatic cancer risk score model was established, and found that FCGR3A was correlated with tumor formation, metastasis, and M2 macrophage infiltration. [ABSTRACT FROM AUTHOR]

Background: Caffeic acid (CA) is considered a promising phytochemical that has inhibited numerous cancer cell proliferation. Therefore, it is gaining increasing attention due to its safe and pharmacological applications. In this study, we investigated the role of CA in inhibiting the Interleukin-6 (IL-6)/Janus kinase (JAK)/Signal transducer and activator of transcription-3 (STAT-3) mediated suppression of the proliferation signaling in human prostate cancer cells. Materials and Methods: The role of CA in proliferation and colony formation abilities was studied using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and colony formation assays. Tumour cell death and cell cycle arrest were identified using flow cytometry techniques. CA treatment-associated protein expression of mitogen-activated protein kinase (MAPK) families, IL-6/JAK/STAT-3, proliferation, and apoptosis protein expressions in PC-3 and LNCaP cell lines were measured using Western blot investigation. Results: We have obtained that treatment with CA inhibits prostate cancer cells (PC-3 and LNCaP) proliferation and induces reactive oxygen species (ROS), cell cycle arrest, and apoptosis cell death in a concentration-dependent manner. Moreover, CA treatment alleviates the expression phosphorylated form of MAPK families, i.e., extracellular signal-regulated kinase 1 (ERK1), c-Jun N-terminal kinase (JNK), and p38 in PC-3 cells. IL-6 mediated JAK/STAT3 expressions regulate the proliferation and antiapoptosis that leads to prostate cancer metastasis and migration. Therefore, to mitigate the expression of IL-6/JAK/STAT-3 is considered an important target for the treatment of prostate cancer. In this study, we have observed that CA inhibits the expression of IL-6, JAK1, and phosphorylated STAT-3 in both PC-3 and LNCaP cells. Due to the inhibitory effect of IL-6/JAK/STAT-3, it resulted in decreased expression of cyclin-D1, cyclin-D2, and CDK1 in both PC-3 cells. In addition, CA induces apoptosis by enhancing the expression of Bax and caspase-3; and decreased expression of Bcl-2 in prostate cancer cells. Conclusions: Thus, CA might act as a therapeutical application against prostate cancer by targeting the IL-6/JAK/STAT3 signaling axis. [ABSTRACT FROM AUTHOR]

Background: The heterogeneity of prognosis and treatment benefits among patients with gliomas is due to tumor microenvironment characteristics. However, biomarkers that reflect microenvironmental characteristics and predict the prognosis of gliomas are limited. Therefore, we aimed to develop a model that can effectively predict prognosis, differentiate microenvironment signatures, and optimize drug selection for patients with glioma. Materials and Methods: The CIBERSORT algorithm, bulk sequencing analysis, and single-cell RNA (scRNA) analysis were employed to identify significant cross-talk genes between M2 macrophages and cancer cells in glioma tissues. A predictive model was constructed based on cross-talk gene expression, and its effect on prognosis, recurrence prediction, and microenvironment characteristics was validated in multiple cohorts. The effect of the predictive model on drug selection was evaluated using the OncoPredict algorithm and relevant cellular biology experiments. Results: A high abundance of M2 macrophages in glioma tissues indicates poor prognosis, and cross-talk between macrophages and cancer cells plays a crucial role in shaping the tumor microenvironment. Eight genes involved in the cross-talk between macrophages and cancer cells were identified. Among them, periostin (POSTN), chitinase 3 like 1 (CHI3L1), serum amyloid A1 (SAA1), and matrix metallopeptidase 9 (MMP9) were selected to construct a predictive model. The developed model demonstrated significant efficacy in distinguishing patient prognosis, recurrent cases, and characteristics of high inflammation, hypoxia, and immunosuppression. Furthermore, this model can serve as a valuable tool for guiding the use of trametinib. Conclusions: In summary, this study provides a comprehensive understanding of the interplay between M2 macrophages and cancer cells in glioma; utilizes a cross-talk gene signature to develop a predictive model that can predict the differentiation of patient prognosis, recurrence instances, and microenvironment characteristics; and aids in optimizing the application of trametinib in glioma patients. [ABSTRACT FROM AUTHOR]

Objectives: EGFR tyrosine kinase inhibitor (EGFR-TKI) therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer (NSCLC). However, the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness. Piperlongumine (PPL), an extract from the long pepper fruit (Piper longum), has been shown to possess anticancer properties. The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells. Methods: Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Cells were treated with PPL, ERL, GEF, and CIS alone, and in combination, cell viability was determined after 72 h. The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species (ROS) induction, and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry. The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers. Results: PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL, GEF, and CIS. Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines, which were associated with apoptotic induction, but without significant ROS induction. Compared to control, PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. Conclusion: PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS)‐responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS‐responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H+/Cl− ion channels activatable by elevated ROS levels in cancer cells. ROS‐induced decaging of the phenylboronate group triggers the rapid release of the channel‐forming units, leading to self‐assembly of the H‐bonded cascades facilitating the synergistic transport of H+ and Cl− ions, with H+/Cl− ion transport selectivity of 7.7. Upon activation, ROS‐C‐Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC50 of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H+/Cl− co‐transport, ROS‐C‐Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds. [ABSTRACT FROM AUTHOR]

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergized with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers. [ABSTRACT FROM AUTHOR]

RETRACTION: T. Liu, H. Zhang, S. Yi, L. Gu, and M. Zhou, “Mutual Regulation of MDM4 and TOP2A in Cancer Cell Proliferation,” Molecular Oncology 13, no. 5 (2019): 1047–1058, https://doi.org/10.1002/1878-0261.12457The above article, published online on 04 February 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Kevin Ryan; FEBS Press; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed inappropriate image panel duplications between this (Figures 3B, 4C, and 5C) and other articles published previously by an overlapping group of authors in a different scientific context. The authors were unable to provide a satisfactory explanation and the original raw data, which has led the editors to lose confidence in the data presented. Therefore, the editors consider the conclusions substantially compromised and are retracting the paper. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)‐natural killer (NK)‐cell therapy has emerged as a promising strategy in the treatment of haematological malignancies and solid cancers. Leveraging the innate immune properties of NK cells, CAR‐NK‐cell therapies offer potential advantages for cell therapy, including safety of use in the allogeneic setting and reduced risk of toxicity. This Nutshell provides an overview of the latest advancements in CAR‐NK‐cell therapy and the challenges that remain. [ABSTRACT FROM AUTHOR]

Irinotecan (CPT‐11), a chemotherapeutic agent used to treat several types of cancer, induces cytotoxic effects on healthy cells. The epidermal growth factor receptor (EGFR) plays a crucial role in various forms of cancer. Nimotuzumab (NmAb), a monoclonal antibody that targets the EGFR, is utilized in some countries to treat malignancies that have an overexpression of EGFR. Yet, there is a lack of literature on the potential anticancer properties of the CPT‐11 and NmAb combination on in vitro human cervical cancer cells. This study investigates the apoptosis mode of the CPT‐11 and NmAb combination on cervical HeLa cancer cells. The Annexin V/propidium iodide staining examination demonstrated that the combination of CPT‐11 and NmAb resulted in a decrease in the number of viable cells and more potent induction of cell apoptosis than the effects of CPT‐11 or NmAb alone in HeLa cells. Furthermore, the combined treatment resulted in elevated levels of reactive oxygen species (ROS) and Ca2+ compared to the treatment with CPT‐11 or NmAb alone. Cells that were pretreated with N‐acetyl‐l‐cysteine, a substance that scavenges ROS, and then treated with CPT‐11, NmAb, or a combination of CPT‐11 and NmAb exhibited higher numbers of viable cells compared to those treated with CPT‐11 or NmAb alone. The combination of CPT‐11 and NmAb resulted in significantly higher caspase‐3, ‐8, and ‐9 activity levels than CPT‐11 or NmAb alone, as measured by flow cytometer assay. The combination of CPT‐11 and NmAb in HeLa cells resulted in elevated endoplasmic reticulum stress‐, mitochondria‐, and caspase‐mediated proteins compared to treatment with CPT‐11 or NmAb alone. According to these observations, NmAb enhances the effectiveness of CPT‐11 in fighting cancer by stimulating cell death in the HeLa cells. Therefore, NmAb has the potential to improve the efficacy of CPT‐11 as a future cervical cancer treatment in humans. [ABSTRACT FROM AUTHOR]

ABSTRACT Our previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune‐oncology (I‐O) agents or adjuvants, such as programmed cell death protein 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I‐O agent or adjuvant. In this study, we investigated the effects of SHH on PD‐L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I‐O agents. Our results showed a marked reduction in PD‐L1 levels in multiple cancer cell lines and decreased PD‐1 and PD‐L1 levels in tumor‐associated macrophages. In a mouse model with collagen‐induced arthritis (CIA), SHH exhibited anti‐inflammatory effects comparable to methotrexate (MTX), a first‐line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL‐1β, IL‐6, and TNF‐α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro‐CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD‐L1 levels in cancer cells and reduces the severity of CIA by exerting anti‐inflammatory effects. Therefore, SHH holds promise as an I‐O agent without side effects such as exacerbation of RA. [ABSTRACT FROM AUTHOR]

Mechanically driven cellular preference for drug carriers can enhance selectivity in cancer therapy, underscoring the importance of understanding the physical aspects of particle uptake. In this study, it was hypothesized that elongated particles might be preferentially taken up by deformable, aggressive cancer cells compared to normal cells. Two film-stretching methods were tested for 0.8–2.4 μm polystyrene (PS) particles: one based on solubility in organic solvents and the other on heat-induced softening. The heat-induced method produced more homogenous particle batches, with a standard deviation in the particle aspect ratio of 0.42 compared to 0.91 in the solvent-based method. The ability of cells to engulf elongated PS particles versus spherical particles was assessed in two subsets of human melanoma A375 cells. In the more aggressive cancer cell subset (A375+), uptake of elongated PS particles increased by 10% compared to spherical particles. In contrast, the less aggressive subset (A375−) showed a 25% decrease in uptake of elongated particles. This resulted in an uptake ratio between A375+ and A375− that was 1.5 times higher for elongated PS particles than for spherical ones. To further demonstrate relevance to drug delivery, elongated paclitaxel-loaded biodegradable, slow-releasing poly(lactic-co-glycolic) acid (PLGA) particles were synthesized. No significant difference in cytotoxic effect was observed between A375+ and A375− cells treated with spherical drug-loaded particles. However, treatment with ellipsoidal particles led to a significantly enhanced cytotoxic effect in aggressive cells compared to less aggressive cells. These findings present promising directions for tailored cancer drug delivery and demonstrate the importance of particle physical properties in cellular uptake and drug delivery mechanisms. [ABSTRACT FROM AUTHOR]

Experimental studies on the cellular uptake of nanoparticles (NPs), useful for the investigation of NP‐based drug delivery systems, are often difficult to interpret due to the large number of parameters that can contribute to the phenomenon. It is therefore of great interest to identify insignificant parameters to reduce the number of variables used for the design of experiments. In this work, a model of the wrapping of elliptical NPs by the cell membrane is used to compare the influence of the aspect ratio of the NP, the membrane tension, the NP–membrane adhesion, and its variation during the interaction with the NP on the equilibrium state of the wrapping process. Several surrogate models, such as Kriging, Polynomial Chaos Expansion (PCE), and artificial neural networks (ANN) have been built and compared to emulate the computationally expensive model. Only the ANN‐based model outperformed the other approaches by providing much better predictivity metrics and could therefore be used to compute the sensitivity indices. Our results showed that the NP's aspect ratio, the initial NP–membrane adhesion, the membrane tension, and the delay for the increase of the NP–membrane adhesion after receptor dynamics are the main contributors to the cellular internalization of the NP, while the influence of other parameters is negligible. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Cardiac glycosides (CGs), traditionally prescribed for heart failure and arrhythmias, show anticancer potential. However, their mechanisms for preferential inhibition of tumour tissue and constituent malignant cells are not fully elucidated. This study aims to elucidate the therapeutic benefits of CGs in targeting specific tumours and dissect their multi‐targeting mechanisms that confer their cytotoxicity against malignant cells.We designed an integrated workflow to identify therapeutic CGs with high toxicity to certain cancers, investigating their multi‐target effects, assessing their toxicity to malignant cells and analysing the prognostic relevance of CGs' target genes. The computational findings were confirmed through gene knockdown, cell viability assays, reactive oxygen species (ROS) measurements and so forth.CGs modulate multiple genes crucial for ion homeostasis, oxidative stress and apoptosis, with a particularly strong inhibitory effects on uveal melanoma (UVM). Notably, digitoxin suppresses UVM cell proliferation and induces ROS levels by simultaneously targeting STAT3 and KLF5. Single‐cell transcriptomic analysis revealed that malignant cells are likely more vulnerable to CGs due to their higher expression of CG target genes compared with surrounding cells in the UVM microenvironment.Given UVM's limited options, our study highlights the potential of digitoxin as a promising novel therapeutic agent for this aggressive and rare ocular cancer. Our comprehensive approach is effective in identifying the potent, cancer‐specific therapeutic agents from herbal plants. [ABSTRACT FROM AUTHOR]

Nowadays, liver cancer is one of the most disturbing types of cancer that can affect either sex. Nanoparticles (NPs) of zein/sodium caseinate incorporating ibuprofen (IBU) and naringenin (NAR) have improved bioavailability and a high encapsulation efficiency (EE%). These nanoparticles are uniformly spherical. In vitro, cytotoxicity analysis on HepG2 cell lines, which are used to study human liver cancer, shows that encapsulated drugs (86.49% ± 1.90, and 78.52% ± 1.98 for NAR and IBU, respectively) have significantly lower IC50 values than individual drugs or their combined free form. In addition, the combination indices of 0.623 and 0.155 for IBU and NAR, respectively, show that the two have joint beneficial effects. The scratch wound healing assay results also show that the free drugs and the engineered NPs have a more significant anti-migratory effect than the untreated cells. The designed nanoparticles also reduce angiogenesis and proliferation while inducing apoptosis, according to in vitro results. In conclusion, a new approach to treating liver cancer may lie in the nanoencapsulation of numerous drugs within nanoparticles. [ABSTRACT FROM AUTHOR]

CRISPR-Cas9 system has emerged as a revolutionary gene-editing tool with huge therapeutic potential for addressing the underlying genetic causes of various diseases, including cancer. However, there are challenges such as the delivery method that must be overcome for its clinical application. In addition to the risk of nuclease degradation and rapid clearance of the CRISPR-Cas9 system by macrophages, the large size of Cas9, the high anionic charge density and hydrophilic nature of the RNA hinder their intracellular delivery and overall gene transfection efficiency. In this study, we engineered a novel Peptide-Based Nanoparticles ADGN for the delivery of long RNA. ADGN peptides can form stable self-assembled nanoparticles with CRISPR-Cas9 RNA. They have the ability to cross the cell membrane of various cell types, exhibiting a preference for cancer cells that overexpress laminin receptor and safeguard RNA prior their delivery into the cytoplasm. We demonstrate that ADGN peptides significantly promote CRISPR-Cas9 mediated knockout of the luciferase gene in vitro achieving 60 % efficiency with a preference for G insertion at the targeted site of luciferase gene. Moreover, we have provided evidence that these nanoparticles can also be systemically intravenously administrated in vivo in mice to deliver a functional CRISPR-Cas9 system to tumoral lung cells orthotopically implanted in the mouse, resulting in an effective gene knockout in mice. We also demonstrated that the in vivo distribution of ADGN-RNA is influenced by its peptides to RNA molar ratio. This study introduces a promising new Peptide-Based Nanoparticles for delivering CRISPR-Cas9 system in its RNA form applicable in both in vitro and in vivo models. [Display omitted] [ABSTRACT FROM AUTHOR]

Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers. KRAS mutant pancreatic cancer cells internalize albumin-bound MPD3 via enhanced macropinocytosis mechanism, leading to lysosomal degradation and the release of free docetaxel. Free docetaxel concurrently permeates into bystander cancer cells to induce cytotoxicity. Tumor specific apoptosis promotes expression of caspase-3, which cleaves extracellular albumin-bound MPD3 to release more free docetaxel to participate in the bystander killing of pan-KRAS cancer cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering. To address the limitation, we developed N -(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WD C LDNRIGRRQ C VKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as P H -cDR5 (high valence), P M -cDR5 (medium valence) and P L -cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells P M -cDR5 exhibited an IC50 of 94 pM, while P H -cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC 50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy. [Display omitted] [ABSTRACT FROM AUTHOR]

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10 s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma. [ABSTRACT FROM AUTHOR]

β-galactosidases (EC 3.2.1.23) are capable of catalysing two distinct types of reactions: transgalactosylation and hydrolysis. It is very important for the senescence of cancer cells. It is a lysosomal exoglycosidase involved in the catabolism of glycoconjugates by sequential release of β-linked terminal galactosyl residues. It has profound significance in cancer cell senescence. It can be derived from various sources including plants, animals, bacteria, yeasts, and filamentous fungi. Purification and thermodynamic characterization of β-galactosidase from Galium aparine seeds, and in vitro efficacy assessment of a breast cancer cell line. The enzyme was purified by using ammonium sulphate precipitation, dialysis, DEAE cellulose, and Sephadex G-100 chromatography. The enzyme was purified to 6.4 fold with a yield of 14 % and specific activity of 11.6 U/mg of protein. SDS-PAGE and MALDI-TOF analysis revealed that β-galactosidase is a monomer with a molecular weight of 35 kDa. The optimum pH and temperature for the purified enzyme were 6.0 and 50 ºC. The enzyme had K m and V max values of 0.25 mM and 32 µmol/min, respectively. The thermodynamic parameters (ΔHº, ΔGº, ΔSº) for the irreversible denaturation of the enzyme were also investigated at different temperatures (50–75 ºC). Lactose in milk was successfully hydrolyzed using a purified enzyme at a rate of 0.0121 min−1 and 12.12 min. This is better than other studied β-galactosidases. These results suggest the use of β-galactosidase from G. aparine for producing delactosed milk for the lactose-intolerant population and prebiotic synthesis. pH and optimum temperature and its activation by Ca2+ shows that it is suitable for milk processing. As a result, the enzyme was stable even at higher temperatures and had the potential to undergo catalysis, making it economically viable, primarily in the food and pharmaceutical industries. The present study is aimed to purification and thermodynamic characterization of enzyme to assess in vitro efficacy of β-galactosidase on MCF-7 cell line to delineate its therapeutic efficacy. [Display omitted] • β-galactosidase from prebiotic Galium aparine was purified 6.4 fold with 14 % yield. • β-galactosidase shows an indicator of the switch mechanism used by cells to enter senescence. • The purified enzyme hydrolyzed the milk lactose with a t1/2 of 14.74 min. • The treatment of the MCF-7 cell line with β-galactosidase inhibits cell growth • Thermostable industrially important enzyme from prebiotic Galium aparine seeds opens avenues for its use in industry. [ABSTRACT FROM AUTHOR]

One of the main challenges with many cancer immunotherapies is that biomarkers are needed for targeting. These biomarkers are often associated with tumors but are not specific to a particular tumor and can lead to damage in healthy tissues, resistance to treatment, or the need for customization for different types of cancer due to variations in targets. A promising alternative approach is to target the acidic microenvironment found in most solid tumor types. This can be achieved using the pH (Low) Insertion Peptide (pHLIP), which inserts selectively into cell membranes under acidic conditions, sparing healthy tissues. pHLIP has shown potential for imaging, drug delivery, and surface display. For instance, we previously used pHLIP to display epitopes on the surfaces of cancer cells, enabling antibody-mediated immune cell recruitment and selective killing of cancer cells. In this study, we further explored this concept by directly fusing an anti-CD16 nanobody, which activates natural killer (NK) cells, to pHLIP, eliminating the need for antibody recruitment. Our results demonstrated the insertion of pH-sensitive agents into cancer cells, activation of the CD16 receptor on effector cells, and successful targeting and destruction of cancer cells by high-affinity CD16+ NK cells in two cancer cell lines. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high‐energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K‐RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF‐mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the characteristics, diagnosis, and treatment of Warthin tumors (WTs) to explore the possibility of managing patients by observation. Methods: We reviewed the records of 1167 patients with benign parotid tumors who were seen in our department between September 1999 and April 2021. Among them, 387 cases were WT and 668 cases were pleomorphic adenoma. We evaluated preoperative diagnoses of WT by symptoms/signs, fine-needle aspiration cytology (FNAC), imaging, such as ultrasonography and magnetic resonance imaging, and technetium-99m pertechnetate (Tc-99m) scintigraphy. Fisher's exact test and the Mann–Whitney U test were used in statistical analyses. Results: Warthin tumors were treated by surgery in 238 cases and follow-up in 149 cases. The 238 patients were diagnosed as WT at the final pathology after surgery. Among them, 172 patients (72.3%) were determined as benign histological type by preoperative FNAC; in these 172 patients, 170 (71.4%) were correctly diagnosed as WT in the final pathology. Preoperative Tc-99m scintigraphy was performed in 69 patients diagnosed with WT by final pathology or FNAC, and the positive rate of Tc-99m scintigraphy in WT was 75.4%. Conclusions: Combining FNAC and Tc-99m scintigraphy, as well as considering clinical findings, enables the diagnosis of WT in most cases. In particular, WT is more common in the elderly, grows more slowly, and is less likely to be malignant. Therefore, if WT can be diagnosed preoperatively with a high rate of correct diagnosis, it could be an accurate and effective means of managing patients through follow-up without surgery. [ABSTRACT FROM AUTHOR]

Estramustine (EM), a clinically successful hormone‐refractory anti‐prostate cancer drug, exhibited potent anti‐proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH‐SY5Y and IMR‐32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre‐treatment of neuroblastoma cells with ROS scavengers (N‐acetyl cysteine and dithiothreitol) reduced the anti‐proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin‐1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule‐depolymerizing agents may be considered for developing pro‐ferroptosis chemotherapeutics. [ABSTRACT FROM AUTHOR]

Purpose: In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers. Methods: The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model. Results: MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3 weeks of administration was 601 mm3 in the S-1 group, 580 mm3 in the ceralasertib group, and 298 mm3 in the combination group. Conclusion: The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro. [ABSTRACT FROM AUTHOR]

Erucic acid (ErA) is a source of omega‐9 monounsaturated fatty acids. ErA exhibited antitumor effects by causing apoptosis and oxidative stress in tumor cells, with the exception of the HT‐29 human colorectal cancer cell line. The apoptotic and Ca2+ signaling pathways in tumor cells are triggered when mitochondrial Ca2+ and Zn2+ accumulation produce reactive free oxygen species (ROS), which in turn activate TRPM2. ErA‐induced ROS and TRPM2 stimulation may augment the anticancer action of cisplatin (CSP). We aimed to study the effects of ErA and CSP incubations on ROS, apoptosis, and cell death in the HT‐29 cells by activating TRPM2. The cells were divided into five groups: control, ErA (200 µM for 48 h), CSP (25 µM for 24 h), and ErA + CSP + TRPM2 antagonists (200 µM carvacrol and 25 µM N‐(p‐amylcinnamoyl)anthranilic acid for 24 h). The TRPM2 antagonists reduced ErA plus CSP‐induced increases in H2O2‐induced intracellular free Ca2+ concentration ([Ca2+]c) and adenosine diphosphate‐ribose‐caused TRPM2 currents. ErA and CSP were found to cause apoptosis and cell death by raising the intracellular free Zn2+ concentration (Zn2+]c), caspase‐3, −8, and −9, mitochondrial membrane dysfunction, and ROS, while lowering reduced glutathione, cell viability, and cell number. The oxidative, apoptotic, and tumor cell death effects of CSP in the cells were enhanced by the increase of ErA‐mediated [Ca2+]c and Zn2+]c entering mitochondria through the activation of TRPM2. In conclusion, we observed that the combination of ErA and CSP was synergistic via TRPM2 activation for the treatment of HT‐29 tumor cells. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are fusions of therapeutic drugs and antibodies conjugated by a linker, designed to deliver a therapeutic payload to cells expressing the target antigen. By delivering the highly cytotoxic agent directly to cancer cells, ADCs are designed to enhance safety and broaden the therapeutic window. Recently, ADCs have demonstrated promising efficacy in various solid tumors and are rapidly expanding their indications. The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor, with no new therapeutics since the advent of anti–PD-1 antibodies in 2016, highlighting a critical need for innovative therapies. Recent preliminary results suggest that ADCs could be promising treatment options for HNSCC as they explore a variety of target antigens, payloads, and linkers. However, for successful adaptation of ADCs in the treatment of HNSCC, addressing key challenges such as payload toxicities, antigen heterogeneity, and adaptive resistance will be essential. Current research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches, show promise for future advancements. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) is a highly potent chemotherapeutic agent, approved by FDA since 1974, for treating a broad spectrum of cancers. However, development of severe side effects and drug resistance are main issues that limit the clinical use of Dox. Herein, we aimed to investigate the sensitivity of Dox in a variety of human cancer cell lines. Eleven cell lines were tested in this study including 2 hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh7), 4 bladder cancer (BlCa) cell lines (UMUC-3, VMCUB-1, TCCSUP and BFTC-905), a lung cancer cell line (A549), a cervical carcinoma cell line (HeLa), a breast cancer cell line (MCF-7), a skin melanoma cell line (M21) and a noncancer human kidney cell line (HK-2). The MTT assay was employed for the determination of cytotoxicity. Cells were treated with various concentrations of Dox for 24 h. The half-maximal inhibitory concentration (IC50) of Dox was calculated to compare the Dox sensitivity among tested cell lines. The result showed that IC50 of Dox in HepG2, Huh7, UMUC-3, VMCUB-1, TCCSUP, BFTC-905, A549, HeLa, MCF-7, M21 and HK-2 cells were 12.2, > 20, 5.1, > 20, 12.6, 2.3, > 20, 2.9, 2.5, 2.8 and > 20 mM, respectively. BFTC-905 had the lowest IC50 value, therefore, it was the most sensitive to Dox. In contrast, Huh7, VMCUB-1 and A549 cells were resistant to Dox with IC50 values > 20 mM. Conclusions, we demonstrated that different human malignant cell lines had different sensitivity to Dox. BFTC-905 BlCa cell line had the highest sensitivity to Dox. Huh7, VMCUB-1 and A549 cell lines were resistant to Dox. Perhaps, the different Dox sensitivity in different cell lines was due to the different acquisition of Dox resistance mechanisms. Huh7, VMCUB-1 and A549 cell lines could be suitable cell models to investigate the molecular mechanism of Dox resistance in different cancers. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the second deadliest cancer worldwide. The side effects and resistance of existing chemotherapy drugs are the background for various studies looking for potential plant extracts as new anticancer agents. This study aims to determine the cytotoxic activity of simpor leaf extract from Belitung and its effect on apoptosis of WiDr colorectal cancer cells. The compound content in simpor leaf extract was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). The cytotoxic activity of simpor leaf extract at different concentrations (25, 50 and 100 ppm) was determined by the MTT test and apoptosis induction by Annexin V/PI flow cytometry analysis. Based on the GC-MS chromatogram results, 13 different compounds were detected. Analysis of the relationship between extract concentration and the percentage of WiDr cell inhibition showed that an extract concentration of 100 ppm was the concentration with the highest percentage of inhibition (20.12 % ± 4.99) compared to concentrations of 50 ppm (13.95 % ± 2.32) and 25 ppm (15.90 % ± 1.38) with an inhibitory concentration value (IC50) of simpor leaf extract of 10.45 ppm. Induction of WiDr cell apoptosis by the extract was influenced by the concentration of simpor leaf extract, which was increase in the percentage of apoptotic cells from 16 % at a concentration of 25 ppm to 70.5 % at a concentration of 100 ppm. The results of this study show that simpor leaf extract from Belitung is able to induce apoptosis in WiDr colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Oral epithelial dysplasia includes a range of clinical oral mucosal diseases with potentially malignant traits. Dental pulp stem cells (DPSCs) are potential candidates for cell-based therapies targeting various diseases. However, the effect of DPSCs on the progression of oral mucosal precancerous lesions remains unclear. Animal experiments were conducted to assess the effect of human DPSCs (hDPSCs). We measured the proliferation, motility and mitochondrial respiratory function of the human dysplastic oral keratinocyte (DOK) cells cocultured with hDPSCs. Mitochondrial transfer experiments were performed to determine the role mitochondria from hDPSCs in the malignant transformation of DOK cells. hDPSCs injection accelerated carcinogenesis in 4NQO-induced oral epithelial dysplasia in mice. Coculture with hDPSCs increased the proliferation, migration, invasion and mitochondrial respiratory function of DOK cells. Mitochondria from hDPSCs could be transferred to DOK cells, and activated mTOR signaling pathway in DOK cells. Our study demonstrates that hDPSCs activate the mTOR signaling pathway through mitochondrial transfer, promoting the malignant transformation of oral precancerous epithelial lesions. [ABSTRACT FROM AUTHOR]

In recent years, nanotechnology has revolutionized various sectors, particularly in nanomedicine, where nanomaterials are used for diagnosis, monitoring, control, prevention, and treatment. Among these, silver nanoparticles (AgNPs) stand out due to their remarkable antimicrobial and cytotoxic properties. Traditional chemical synthesis of AgNPs poses significant environmental and health risks. This study introduces a novel, eco‐friendly synthesis method using royal jelly (RJ), a nutrient‐rich secretion from honeybees, to produce AgNPs with potent anticancer effects. Our research provides a detailed investigation into RJ‐mediated AgNPs' modulation of the VEGFa/PI3K/Akt/MMP‐2 pathway in HeLa and A549 cancer cell lines. AgNP characterization was performed by applying UV–Vis spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM) in combination with selected area electron diffraction (SAED). Cell signaling system components were determined by ELISA analysis. The cells were subjected to staining with hematoxylin and eosin to visualize the treatment's effects. This study focuses on the green synthesis of AgNPs using RJ and its bioactivity against cancer cells. It provides a detailed characterization of the nanoparticles and examines their effects on cancer cells, specifically HeLa cervical cancer and A549 lung cancer cell lines. Green synthesized AgNPs demonstrate significant cytotoxic effects against HeLa and A549 cancer cell lines. The underlying molecular mechanisms contributing to their anticancer activity were elucidated. Our findings revealed a significant decrease in arginase activity upon exposure to AgNPs, accompanied by reductions in PI3K and phosphorylated and total Akt levels, indicative of pathway inhibition. Additionally, RJAgNP demonstrated a capacity to reduce nitric oxide levels and suppress angiogenesis‐related factors like VEGF and MMP‐2 and inflammation‐related factors like TNF‐α and COX‐2, thus impeding angiogenesis and metastasis. Moreover, our results shed light on the involvement of reactive oxygen intermediates (ROIs) in mediating apoptotic pathways, as evidenced by the increase in malondialdehyde (MDA) concentration and the corresponding decrease in Akt levels, ultimately promoting death in cancer cells. Our study contributes significantly to the field of nanomedicine and cancer therapy by introducing the use of green synthesis AgNPs using RJ and providing in‐depth insights into their molecular mechanisms of anticancer action. Our research findings demonstrate the anticancer potential of RJ‐AgNPs by targeting the VEGFa/PI3K/Akt/MMP‐2 pathway and modulation of ROS/RNS in cancer cells. [ABSTRACT FROM AUTHOR]

Synthesis of 5‐alkynyl furopyrimidine nucleoside analogs, with free‐ribose groups, was carried out, and their biological activity was evaluated. The substituents introduced at the C‐5 included propargyl and homopropargyl alcohols, 4‐methylphenyl (p‐tolyl), and 4‐pentylphenyl substituted alkynyl groups (56%–88%). Subsequently, alkyne function was coordinated to dicobalt hexacarbonyl unit, yielding the corresponding dicobalt hexacarbonyl 5‐alkynyl furopyrimidine nucleosides (51%–75%). All compounds contained 4‐pentylphenyl group attached at the C‐6 position of the bicyclic base, in line with most active antiviral structures. The antiproliferative effect of these modified nucleosides on cancer cells of different phenotypes was determined using in vitro studies. The tested compounds show antiproliferative effects with median inhibitory concentration (IC50) values of 16–23 and 9–15 μM for HeLa and K562 cells, respectively. The determination of reactive oxygen species (ROS) formation in K562 cells in the presence of modified nucleosides may suggest that the mode of action of the examined compounds may be attributed to the induction of oxidative stress. [ABSTRACT FROM AUTHOR]

The stated objective of the present research investigation was to use a simultaneous nanodrug delivery approach to optimize the therapeutic effectiveness of anticancer drugs against breast cancer cells. For this purpose, Poly (lactic-co-glycolic acid) nanoparticles with two anticancer drugs; methotrexate (MTX) and doxorubicin (DOX) denoted as DOX/MTX@PLGA NPs was developed by nanoprecipitation method. The developed polymeric DOX/MTX@PLGA NPs exhibited hydrodynamic particle diameter of 170.6 ± 10.0 nm with a poly dispersity index (PDI) of 0.17 and zeta potential value of -9.2 ± 0.31 mV, and spherical geometry analyzed by TEM. Furthermore, the nanoparticles exhibited a pH-responsive drug release profile, outstanding encapsulation efficiency, excellent colloidal stability across various physiological media and pH responsive drug release profile. Additionally, polymeric nanoparticles demonstrated higher cell uptake, in-vitro cytotoxicity, and a high rate of apoptosis in comparison to free DOX and MTX through a synergistic effect, likely as a result of their small particle size. In conclusion, our work presents a novel and distinct approach for boosting the therapeutic efficacy of anticancer drugs by delivering drugs to breast cancer cells simultaneously. [ABSTRACT FROM AUTHOR]

Background: The predisposition toward gastrointestinal disease is increasing as a result of dietary changes and overindulgence in food preparation. Ninety percent of stomach cancers are adenocarcinomas, a type of cancer of the gastrointestinal tract that is the leading cause of mortality worldwide. Purpose: Astilbin, a natural dihydroflavonol substance derived from a range of foods and medicinal herbs, has been shown in the current study to have anticancer potential against gastric cancer in AGS cell lines. Materials and Methods: The half maximal inhibitory concentration value was determined after astilbin was given to AGS cell lines at various doses. To verify apoptosis, the astilbin-treated cell line was subsequently stained with the dual dye acridine orange/ethidium bromide. AGS cell lines, the enzyme-linked immunosorbent assay (ELISA) approach was also used to investigate the inflammatory cytokines. Using ELISA, apoptotic marker expression including Bcl-2-associated X-protein, caspase-9 proteins, and B-cell lymphoma 2 was assessed in gastric cancer cells treated with astilbin. Results: The study's findings reveal that astilbin is a prime candidate for gastric cancer therapy since it causes apoptosis in AGS cells and has a stronger effect on the major inflammatory markers of the disease. Conclusion: The study provides comprehensive methodologies and tools for predicting absorption, distribution, metabolism, excretion, and toxicity properties, facilitating informed decision-making in the development and optimization of astilbin as a gastric cancer therapy. [ABSTRACT FROM AUTHOR]

Objective(s): Natural killer (NK) cells are the most professional innate immune cells that initiate extracellular apoptosis via cytotoxic granules in malignant cells. Antitumoral properties of NK- derived exosomes (Exos) are attributed to their parent cells. Loading drugs into Exos as a carrier can enhance their effect and enable targeted delivery. In the present study, we aim to deliver Doxorubicin (DOX) to the breast cancer spheroids by NK-Exos. Materials and Methods: Peripheral blood mononuclear cells (PBMC) were used to harvest NK cells, and NK-Exos were isolated from NK cell expansion medium using an Exo-spinTM kit. DOX was loaded via the ultrasonication method. AO/EtBr, Annexin/PI, DAPI, MTT, and spheroids of human breast cancer were used to track the cytotoxic effect of DOX-NK-Exos. The colony formation assay, scratch and transwell assays, Real-Time PCR for p53 and VEGF-A, and WB for protein expression were also performed. Results: When compared to free DOX, all viability tests validated the inhibitory effects of DOX-NK- Exos. The obtained results indicated that DOX-NK-Exos selectively reduced tumor cell viability and spared fibroblast and MCF-10A as noncancerous cells. Long after spheroid treatment, DOX-NK-Exos' remarkable effect persisted. Conclusion: Human breast carcinoma mass treated with DOX-NK-Exos underwent apoptosis and showed a strong inhibitory effect on proliferation. Thus, they can reduce the side effects of chemotherapeutics and can be used as drug carriers with selective toxicity. Additionally, the additive action of this combination formula results in a more severe loss in cell viability. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), as key components of tumor microenvironment (TME), exhibit phenotypic plasticity in response to environmental cues, causing polarization into either pro-inflammatory M1 phenotypes or immunosuppressive M2 phenotypes. Although TAM has been widely studied for its crucial involvement in the initiation, progression, metastasis, and immune regulation of cancer cells, there have been limited attempts to understand how the metastatic potentials of cancer cells influence TAM polarization within TME. Here, we developed a miniaturized TME model using a 3D hybrid system composed of murine melanoma cells and macrophages, aiming to investigate interactions between cancer cells exhibiting various metastatic potentials and macrophages within TME. The increase in spheroid size within this model was associated with a reduction in cancer cell viability. Examining macrophage surface marker expression and cytokine secretion indicated the development of diverse TMEs influenced by both spheroid size and the metastatic potential of cancer cells. Furthermore, a high-throughput microfluidic platform equipped with trapping systems and hybrid spheroids was employed to simulate the tumor-immune system of complex TMEs and for comparative analysis with traditional 3D culture models. This study provides insight into TAM polarization in melanoma with different heterogeneities by modeling cancer-immune systems, which can be potentially employed for immune-oncology research, drug screening, and personalized therapy. This study presents the development of a 3D hybrid spheroid system designed to model tumor-immune interactions, providing a detailed analysis of how melanoma cell metastatic potential influences tumor-associated macrophage (TAM) polarization. By utilizing a microfluidic platform, we are able to replicate and investigate the complex tumor-immune system of the tumor microenvironments (TMEs) under continuous flow conditions. Our model holds significant potential for high-throughput drug screening and personalized medicine applications, offering a versatile tool for advancing cancer research and treatment strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) comprises diverse cell types within an altered extracellular matrix (ECM) and plays a pivotal role in metastasis through intricate cell-cell and cell-ECM interactions. Fibroblasts, as key constituents of the TME, contribute significantly to cancer metastasis through their involvement in matrix deposition and remodeling mechanisms, modulated by their quiescent or activated states. Despite their recognized importance, the precise role of fibroblasts in cancer cell invasion remains incompletely understood. In this study, we investigated the impact of fibroblast activity on cancer cell progression using a 2D co-culture model. Michigan Cancer Foundation-7 (MCF7) breast cancer cells were co-cultured with normal human lung fibroblasts (NHLF), both with and without transforming growth factor β (TGFβ) treatment. Traction force microscopy (TFM) was employed to quantify traction and velocity forces associated with cellular migration. We observed that TGFβ-activated fibroblasts form a distinctive ring around cancer cells in co-culture, with increased traction and tension at the cell island boundary. This force distribution is associated with the localization of force-related proteins at these boundary regions, including vinculin and E-cadherin. Metabolic profiling revealed a strong OXPHOS signal specific to the activated fibroblasts, in contrast to normal fibroblasts, which primarily display migratory behavior and a more heterogeneous pattern of forces and metabolic activity in co-culture. Our findings offer valuable insights into the mechanical forces and metabolic dynamics governing cellular migration in the tumor microenvironment, where our co-culture model could complement in vivo studies and enable researchers to explore specific microenvironmental cues for a deeper understanding of TME mechanisms. Cancer models mimicking the dynamics of tumor microenvironment (TME) are an ideal tool to study cancer mechanisms and treatment. However, the full understanding of how cancer cells interact with their surroundings and other cells is still unknown. To tackle this, we developed a simple yet effective 2D co-culture model that allows us to control the arrangement of cell cultures precisely and use various imaging techniques to study interactions between cancer cells and fibroblasts. Here we could measure cell movements, force distribution, metabolic activity, and protein localization and interplay those factors in vitro. Our model helps us observe the underlying mechanisms between cancer cells and fibroblasts, contributing to our understanding of the dynamics in the TME. [Display omitted] [ABSTRACT FROM AUTHOR]

Anthraquinones (AQs) are very effective chemotherapeutic agent, however their fundamental shortcoming is high cardiotoxicity caused by reactive oxygen species (ROS). Therefore, development of improved antitumor drugs with enhanced efficacy but reduced side effects remains a high priority. In the present study we evaluated the cytotoxicity and ROS generation activity of chelate complex of redox-active anthraquinone 2-phenyl-4-(butylamino)naphtho[2,3-h]quinoline-7,12-dione (Q1) with iron and copper ions. Cytotoxicity study was performed using the lung cancer cell line A549 and breast cancer cell line MDA-MB-231. Q1 and Cu-Q1 complex demonstrate high activity in these experiments, but Fe-Q1 complex inactive. The ROS generation activity has been studied by EPR spin trapping technique using A549, MDA-MB-231 cell lines, and T lymphoblast cell line MOLT-4. It was shown that Q1 is able to penetrate into these cells and participate in redox reactions with the formation of a semiquinone radical. Fe(III) chelate complex formation results in much slower kinetics of ROS generation compared with pure Q1, which could be connected with a lower penetration through the cell membrane. [ABSTRACT FROM AUTHOR]

Cancer incidence has increased globally and has become the leading cause of death in the majority of countries. Many cancers have altered energy metabolism pathways, such as increased glucose uptake and glycolysis, as well as decreased oxidative phosphorylation. This is known as the Warburg effect, where cancer cells become more reliant on glucose to generate energy and produce lactate as an end product, even when oxygen is present. These are attributed to the overexpression of key glycolytic enzymes, glucose transporters, and related signaling pathways that occur in cancer cells. Therefore, overcoming metabolic alterations in cancer cells has recently become a target for therapeutic approaches. Natural products have played a key role in drug discovery, especially for cancer and infectious diseases. In this review, we are going to focus on terpenoids, which are gradually gaining popularity among drug researchers due to their reported anti‐cancer effects via cell cycle arrest, induction of apoptosis, reduction of proliferation, and metastasis. This review summarizes the potential of 13 terpenoid compounds as anti‐glycolytic inhibitors in different cancer models, primarily by inhibiting the glucose uptake and the generation of lactate, as well as by downregulating enzymes associated to glycolysis. As a conclusion, disruption of cancer cell glycolysis may be responsible for the anti‐cancer activity of terpenoids. [ABSTRACT FROM AUTHOR]

Cancer patients may encounter the onset of cardiovascular disease due to tumor advancement or chemotherapy, commonly known as "cardiotoxicity." In this respect, the conventional chemotherapy treatment protocol involves a mixture of different medications. These medications can be detrimental to cardiac tissue, consequently exposing the patient to the possibility of irreversible cardiac injury. The enhancement of oxidative stress and inflammation is an important mechanism of chemotherapeutic agents for developing cardiotoxicity. Regarding their dual pro- and anti-inflammatory functions, platelets can significantly influence the progression or suppression of cardiotoxicity. Therefore, the expression of platelet activatory markers can serve as valuable prognostic indicators for cardiotoxicity. The primary objective of this study is to examine the significance of platelets in cardiotoxicity and explore potential strategies that could effectively target malignant cells while minimizing their cytotoxic impact, such as cardiotoxicity and thrombosis. [ABSTRACT FROM AUTHOR]

Interleukin-37 is a cytokine with potent immunosuppressive properties that has been shown to have potential to treat autoimmune and chronic inflammatory diseases, as well as certain types of cancer. IL-37 is a 19 kDa protein which interacts with proteins in receptor-dependent and receptor-independent pathways. The expression of the IL-37 protein cloned into the pET-28a vector was optimized in Rosetta 2(DE3) after comparing its expression with Rosetta-gami 2(DE3) and Rosetta 2(DE3) pLysS, which was then used for the large-scale production of IL-37. IMAC purification of IL-37 yielded > 97% pure 0.9 mg/mL protein from auto-induced fermentation. The IC50 value of IL-37 was < 1 µM, which was similar to that of doxorubicin, and proliferation of > 80% of all cancer cells was inhibited by 100 µg/mL of IL-37 protein. IL-37 may be a promising theragnostic target for cancer due to its comparable IC50 value with that of doxorubicin. [ABSTRACT FROM AUTHOR]

This study focused on the chemical composition and biological activities of the essential oil derived from Grewia bulot, a plant species known for its medicinal properties. The analysis of Grewia bulot essential oil revealed the presence of 78 constituents. The major compounds were α-cadinol (13.5%), 1,8-cineole (12.7%), 1,10-di-epi-cubenol (9.8%), epi-α-cadinol (6.7%), (E,E)-α-farnesene (5.9%), (E)-citral (4.0%), selin-11-en-4-α-ol (4.0%), citronellol isobutanoate (3.9%), and geranic acid (3.7%). The essential oil exhibited promising antioxidant potential with an IC50 value of 452.65 ± 28.40 µg/mL in DPPH model. This oil did not show NO production inhibitory effect in RAW 264.7 cells. In addition, the essential oil exhibited significant cytotoxicity against KB, Hep-G2, MCF-7, and SK-LU-1 cancer cell lines, with IC50 values ranging from 44.04 ± 1.47 to 74.20 ± 3.71 μg/mL. [ABSTRACT FROM AUTHOR]

Medicinal plants such as Leutea avicennae Mozaff. (Apiaceae) have been shown some biological potential for preventing and treating diseases. Fractions and isolated compounds were tested on colon carcinoma (HT-29), cervical carcinoma (HeLa), breast carcinoma (MCF-7), and mouse embryonic fibroblast (NIH/3T3) cell lines. The BSLT method was used for the assessment of the general toxicity of the petroleum ether (PET), chloroform (CHCl3), ethyl acetate (EtOAc), and methanol (MeOH) fractions obtained from the aerial parts of L. avicennae. 1H-NMR and 13 C-NMR spectroscopy were used for structure elucidation. Five compounds, including two coumarins, osthole and umbelliferone, a diterpene phytol, β-sitosterol, and lauric acid, were isolated for the first time from L. avicennae. Osthole showed potent cytotoxic activity against MCF-7 and HT-29 cell lines with IC50 values of 4.23 ± 0.26 and 12.11 ± 0.13 µg/mL, respectively. Phytol demonstrated potent cytotoxic activity towards MCF-7 and HeLa cell lines with IC50 values of 6.80 ± 0.08 and 12.27 ± 0.18 µg/mL, respectively. [ABSTRACT FROM AUTHOR]

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Breast cancer is the type of cancer that causes death in the first place among women in 2022, with a rate of 6.9%. According to the data of the World Health Organization in 2024, 665,684 women died due to breast cancer in 2022. Cancer metastasis is the main reason why people die from cancer. Since changes in proliferation-related gene expression and protein levels that occur as a result of mutations that cause metastasis make cancerous cells more proliferatively aggressive, treatment opportunities remain limited. Sulfatide has the potential to be a p-selectin inhibitor, as it is a p-selectin-binding molecule that has an antimetastatic effect. Sulfatide mimicking material has previously been studied by sulfonation and acylation of chitosan. It was evaluated as an anticancer drug carrier because it did not have cytotoxic effects against cancer cells. In this study, a sulfatide-like molecule was obtained using alginate and it was found to have a cytotoxic effect against cancer cells. The compound that is newly synthesized in the presented article is an alternative to the group of sulfatide-like compounds that we have previously studied, which are thought to have an antimetastatic effect. The molecular disruption of the apoptosis mechanism in cancerous tissues leads to the resistance of cancerous cells to apoptosis, which in turn promotes cancer progression. For this reason, cancer studies focus on cell death, that is, apoptosis, as well as on cell proliferation. This study is the first to combine the simultaneous sulfation and acylation of alginate with the addition of magnetism, despite previous research on the sulfation, acylation, and alkylation of alginate (M-SA-SULF-A) and analysed it by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy, a vibrating sample magnetometer (VSM) and a mastersizer. Then we aim to examine the effect of newly modified magnetic stearic acid on apoptosis in MCF-7 cells by looking at the expressions of apoptosis-and metastatasis related genes through an array kit, and to reveal the molecular pathways that cause modified alginate's anti-cancer activity. Thus, we determined that magnetic stearic acid modified sulfated alginate may be an anti-cancer agent by regulating the expression of genes associated with apoptosis. [ABSTRACT FROM AUTHOR]

The combination of natural and synthetic polymers for nanomedicine development had many advantages, including less toxicity, biocompatibility, prolonged circulation, higher stability, and ease of surface modification. Here, a novel folic acid-conjugated Camptothecin-loaded-poly (lactic-co-glycolic) acid-glutenin nanoparticles (FA-CPT-PLGA-Glu NPs) was fabricated to treat breast cancer. FA-CPT-PLGA-Glu NPs target breast cancer cells via upregulated folate receptors and delivered their toxic payloads without disrupting healthy cells. First, CPT-loaded PLGA NPs were created using a modified emulsification/evaporation technique. Second, Glu-based CPT-PLGA NPs were synthesized using a layer-by-layer assembly, and their physiochemical properties were validated. CPT encapsulation efficiency and loading capacity into PLGA-Glu NPs were 74.95 ± 1.34% and 4.78 ± 1.08%, respectively. CPT-PLGA-Glu NPs exhibited sustained and controlled release of loaded-CPT from NPs, and the highest content was released in an acidic environment (pH 5.3), which will be advantageous for cancer treatment. Later, FA-CPT-PLGA-Glu NPs were synthesized by simple conjugation chemistry. The fabricated FA-CPT-PLGA-Glu NPs were around 100 nm in size, with a spherical form and crystalline nature. FA-CPT-PLGA-Glu NPs show strong cytotoxicity activity, and its IC50 value was 16.33 µg × mL− 1 against breast cancer cell line (MCF-7). This folate-receptor-targeted NPs are more effectively internalized into MCF-7 cells, causing ROS generation, cell growth inhibition, and apoptosis. The activity of caspase-3 and − 9 causes MCF-7 cells apoptosis by internalized CPT. Further, internalized CPT induces potential loss of mitochondrial transmembrane and damages the nuclear integrity of the cancer cells. These results showed that the FA-CPT-PLGA-Glu NPs target upregulated folate receptors on the surface of MCF-7 cells.. [ABSTRACT FROM AUTHOR]

Propyl gallate (PG) has been found to exert an inhibitory effect on the growth of different cell types, including lung cancer cells. However, little is known about the cytotoxicological effects of PG specifically on normal primary lung cells. The current study examined the cellular effects and cell death resulting from PG treatment in human pulmonary fibroblast (HPF) cells. DNA flow cytometry results demonstrated that PG (100-1,600 µM) had a significant impact on the cell cycle, leading to G1 phase arrest. Notably, 1,600 µM PG slightly increased the number of sub-G1 cells. Additionally, PG (400-1,600 µM) resulted in the initiation of cell death, a process that coincided with a loss of mitochondrial membrane potential (MMP; ΔΨm). This loss of MMP (ΔΨm) was evaluated using a FACS cytometer. In PG-treated HPF cells, inhibitors targeting pan-caspase, caspase-3, caspase-8, and caspase-9 showed no significant impact on the quantity of annexin V-positive and MMP (ΔΨm) loss cells. The administration of siRNA targeting Bax or caspase-3 demonstrated a significant attenuation of PG-induced cell death in HPF cells. However, the use of siRNAs targeting p53, Bcl-2, or caspase-8 did not exhibit any notable effect on cell death. Furthermore, none of the tested MAPK inhibitors, including MEK, c-Jun N-terminal kinase (JNK), and p38, showed any impact on PG-induced cell death or the loss of MMP (ΔΨm) in HPF cells. In conclusion, PG induces G1 phase arrest of the cell cycle and cell death in HPF cells through apoptosis and/or necrosis. The observed HPF cell death is mediated by the modulation of Bax and caspase-3. These findings offer insights into the cytotoxic and molecular effects of PG on normal HPF cells. [ABSTRACT FROM AUTHOR]

Background: The chemotherapy resistance often leads to chemotherapy failure. This study aims to explore the molecular mechanism by which MUC1 regulates paclitaxel resistance in lung adenocarcinoma (LUAD), providing scientific basis for future target selection. Methods: The bioinformatics method was used to analyse the mRNA and protein expression characteristics of MUC1 in LUAD. RT-qPCR and ELISA were used to detect the mRNA and protein expression, flow cytometry was used to detect CD133+ cells, and cell viability was detected by CCK-8 assay. The mRNA-seq was performed to analyse the changes in expression profile, GO and KEGG analysis were used to explore the potential biological functions. Results: MUC1 is highly expressed in LUAD patients and is associated with a higher tumour infiltration. In paclitaxel resistance LUAD cells (A549/TAX cells), the expression of MUC1, EGFR/p-EGFR and IL-6 were higher than that of A549 cells, the proportion of CD133+ cells was significantly increased, and the expression of cancer stem cell (CSCs) transcription factors (NANOG, OCT4 and SOX2) were significantly up-regulated. After knocking down MUC1 in A549/Tax cells, the activity of A549/Tax cells was significantly decreased. Correspondingly, the expression of EGFR, IL-6, OCT4, NANOG, and SOX2 were significantly down-regulated. The mRNA-seq showed that knocking down MUC1 affected the gene expression, DEGs mainly enriched in NF-κB and MAPK signalling pathway. Conclusion: MUC1 was highly expressed in A549/TAX cells, and MUC1-EGFR crosstalk with IL-6 may be due to the activation of NF-κB and MAPK pathways, which promote the enrichment of CSCs and lead to paclitaxel resistance. [ABSTRACT FROM AUTHOR]