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Hydroxychloroquine sulfate (HCQ) is currently being repurposed for cancer treatment. The antitumor mechanism of HCQ is inhibition of cellular autophagy, but its therapeutic potential is severely limited by poor solubility, lack of tumor targeting and lower cellular uptake. Therefore, utilization of human H-chain apoferritin (HFn) composed only of heavy subunits is an attractive approach for tumor targeting drug delivery. This study focused on pH-triggered encapsulation of HCQ within the inner cavity of HFn to form HFn@HCQ nanoparticles for tumor-targeted drug delivery. Characterization using a range of techniques has been used to confirm the successful establishment of HFn@HCQ. HFn@HCQ exhibited pH-responsive release behavior, with almost no drug release at pH 7.4, but 80% release at pH 5.0. Owing to its intrinsic binding to transferrin receptor 1 (TfR1), HFn@HCQ was significantly internalized through TfR1-mediated endocytosis, with a 4.4-fold difference of internalization amount across cell lines. Additionally, HFn@HCQ enhanced the antitumor effect against four different cancer cell lines when compared against HCQ alone, especially in TfR1 high-expressing cells, where the inhibitory effect was 3-fold higher than free HCQ. The autophagy inhibition of HFn@HCQ has been demonstrated, which is a major pathway to induce cancer cell death. According to current findings, HFn based drug delivery is a promising strategy to target and kill TfR1 overexpressing tumor cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent Hsp90 inhibitor. Target inhibitory activity result showed that one compound dubbed as 12-1 exhibited strong inhibitory activity against Hsp90 with an IC 50 value of 9 nM. In tumor cell viability experiment, compound 12-1 robustly repressed the proliferation against six human tumor cells with IC 50 values all in nanomolar range scoring over VER-50589 and geldanamycin. 12-1 was able to induce apoptosis of tumor cells and arrest the tumor cell cycle in G0/G1 phase. Meanwhile, western blot results showed that 12-1 could significantly downregulated the expression of two Hsp90 client proteins CDK4 and HER2. Finally, molecular dynamic simulation showed that compound 12-1 could fit well with ATP binding site on N-terminal of Hsp90., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy., (© 2023. The Author(s).)

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC 50 values of 2.65 μM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC 50 of 10.9 μM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T 1/2  = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Summarize and critically evaluate the existing studies to determine the effects of exercise on chemotherapy-induced peripheral neuropathy in cancer patients., Methods: We searched PubMed, Scopus, Web of Science, and Cochrane Library databases for randomized controlled trials reporting exercise intervention in cancer patients with chemotherapy-induced peripheral neuropathy. The outcomes of interest included chemotherapy-induced peripheral neuropathy symptoms, physical function (balance control, muscle strength, and functional status), and quality of life. The Cochrane Collaboration's tool was employed to assess the risk of bias., Results: The search identified 1309 studies, 16 of which eligible. Our meta-analysis revealed that exercise intervention significantly improved the quality of life (SMD = 0.83, 95% CI = 0.58 to 1.08, I 2  = 0%, P < 0.00001) and relieved neuropathic pain (MD =  - 4.93, 95% CI =  - 5.60 to - 4.26, I 2  = 0%, P < 0.00001). The muscular strength of the upper (SMD = 1.10, 95% CI = 0.68 to 1.51, I 2  = 25%, P < 0.00001) and the lower limbs (SMD = 0.84, 95% CI = 0.42 to 1.26, I 2  = 36%, P < 0.00001) increased and balance performance (SMD = 1.05, 95% CI = 0.62 to1.48, I 2  = 0%, P < 0.00001) was better in the exercise group than in the group with usual care. However, no evidence was found that exercise intervention could improve CIPN symptoms., Conclusions: The results of this study showed that combined exercise could be an effective option for improving quality of life, physical function (balance control and muscle strength), and neuropathic pain in cancer patients with chemotherapy-induced peripheral neuropathy. Further exploration of appropriate exercise prescriptions is needed to improve other outcomes., Implications for Cancer Survivors: Specific and appropriate exercise intervention for cancer patients with chemotherapy-induced peripheral neuropathy should be recommended because these interventions can improve their quality of life and physical function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Most cancer-related deaths are a result of metastasis. The development of small molecular inhibitors reversing cancer metastasis represents a promising therapeutic opportunity for cancer patients. This pan-cancer analysis identifies oncogenic roles of membrane-associated phosphatidylinositol transfer protein 3 (PITPNM3), which is crucial for cancer metastasis. Small molecules targeting PITPNM3 must be explored further. Here, PITPNM3-selective small molecular inhibitors are reported. These compounds exhibit target-specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer cells. Besides, by using nanoparticle-based delivery systems, these PITPNM3-selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in mouse xenograft models and organoid models. Notably, the results establish an important metastatic-promoting role for PITPNM3 and offer PITPNM3 inhibition as a therapeutic strategy in metastatic breast cancer., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2 macrophage phenotype. TAMs are known to promote tumor progression and are associated with poor clinical outcomes. CD47 on tumor cells and SIRPα on TAMs facilitate a "don't-eat-me" signal which prevents cancer cells from immune clearance. Therefore, blockade of the CD47-SIRPα interaction represents a promising strategy for tumor immunotherapy. Here, we present the results on ZL-1201, a differentiated and potent anti-CD47 antibody with improved hematologic safety profile compared with 5F9 benchmark. ZL-1201 enhanced phagocytosis in combination with standards of care (SoC) therapeutic antibodies in in vitro coculture systems using a panel of tumor models and differentiated macrophages, and these combinational effects are Fc dependent while potently enhancing M2 phagocytosis. In vivo xenograft studies showed that enhanced antitumor activities were seen in a variety of tumor models treated with ZL-1201 in combination with other therapeutic mAbs, and maximal antitumor activities were achieved in the presence of chemotherapy in addition to the combination of ZL-1201 with other mAbs. Moreover, tumor-infiltrating immune cells and cytokine analysis showed that ZL-1201 and chemotherapies remodel the tumor microenvironment, which increases antitumor immunity, leading to augmented antitumor efficacy when combined with mAbs., Significance: ZL-1201 is a novel anti-CD47 antibody that has improved hematologic safety profiles and combines with SoC, including mAbs and chemotherapies, to potently facilitate phagocytosis and antitumor efficacy., Competing Interests: C.W. Szeto reports other from Zai Lab (US) during the conduct of the study. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Glioblastoma multiforme (GBM) is one of the deadliest cancers of the brain. Its ability to infiltrate healthy brain tissues renders it difficult to remove surgically. Furthermore, it exhibits high rates of radio- and chemoresistance, making the survival rates of patients with GBM poor. Therefore, novel effective therapies for GBM remain urgently in demand. Niclosamide is an anti-helminthic drug and recently it has been receiving attention due to its reported anticancer effects in cancer models, including GBM. Furthermore, camptothecin (CPT) is a naturally-occurring alkaloid and has been previously reported to be a potential chemotherapeutic agent by targeting the nuclear topoisomerase I. In the present study, the possible combined chemotherapeutic effects of niclosamide and CPT on the human glioblastoma cell line U87 MG was investigated by MTT assay and western blot analysis. Niclosamide exhibited synergistic activities with CPT to suppress the proliferation of U87 MG cells. Additionally, niclosamide suppressed cell proliferation and induced cell death mainly by triggering ER stress and autophagy, whilst CPT induced cell apoptosis mainly through p53-mediated mitochondrial dysfunction and activation of the MAPK (ERK/JNK) pathways. Overall, these findings suggest that co-administration of niclosamide and CPT may provide a novel therapeutic treatment strategy for GBM., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2022 Valdez et al.)

Peptide dendrimers have a broad application in biomedical science due to their biocompatibility, diversity, and multifunctionality, but the precision synthesis of high-molecule weight peptide dendrimers remains challenging. We here report the facile and liquid-phase synthesis of molecular level precision and amino-acid built-in polylysine (PLL) dendrimers with molecular weights as high as ∼60 kDa. Three types of polyhedral oligosilsesquioxane (POSS)-cored PLL dendrimers with phenylalanine, tyrosine, or histidine as building blocks were synthesized. The precise structures of the dendrimers were confirmed by MALDI-TOF MS, GPC, and 1 H NMR spectroscopy. The interior functionalized peptide dendrimers improved the encapsulation capability of SN38 and sustained the release profiles. Enhanced molecular interactions between the peptide dendrimers and drugs were explored by both NMR experiments and computer simulations. The peptide dendrimer/SN38 formulations showed potent antitumor activity against multiple cancer cell lines. We believe that this strategy can be applied to the synthesis of tailor-made functional peptide dendrimers for drug-specific delivery and other diverse biomedical applications.

The vascular wall is the first physiologic barrier that circulating nanoparticles (NPs) encounter, which also is a key biological barrier to cancer drug delivery. NPs can continually scavenge the endothelium for biomarkers of cancer, and the chance of NPs' extravasation into the tumors can be enhanced. Here, we envision P-selectin as a target for specific delivery of drug nanocrystals to tumors. The cupric diethyldithiocarbamate nanocrystals (CuET NCs) were first prepared by an antisolvent method, and then nanocrystals were coated with fucoidan via physical interaction. The fucoidan-coated CuET nanocrystals (CuET@Fuc) possess high drug loading and have the ability to interact with human umbilical vein endothelial cells expressing P-selectin, which transiently enhances the endothelial permeability and facilitates CuET@Fuc extravasation from the peritumoral vascular to achieve higher tumor accumulation of drugs than bare CuET NCs. The CuET NC shows poorer anticancer efficacy than CuET@Fuc at the same dose of CuET. Upon repeated dosing of CuET@Fuc for 2 weeks, no mortality was observed in treated melanoma-bearing mice, while the mortality in the control group and excipient-treated groups reached 23%. The growth rate of melanoma in the CuET@Fuc-treated group was significantly lower than those in other groups. Furthermore, an acute toxicity study revealed that CuET@Fuc is a safe formulation for cancer treatment.

In our previous study, we demonstrated that norcantharidin (NCTD) is a potential therapeutic agent for renal interstitial fibrosis (RIF). Recently, we found that lncRNA Gm26669 (Gm26669) contributed to the development of RIF and could be regulated by NCTD. However, the upstream mechanisms of Gm26669 and whether the anti-RIF effects of NCTD are related to its regulatory action on Gm26669 remain unclear. Our bioinformatics analysis indicated that special protein1 (Sp1), a transcription factor, may bind to the promoter of Gm26669. In the present study, we observed a significant increase in the nuclear translocation of Sp1 using both in vivo and in vitro models of RIF. Furthermore, the knockdown of Sp1 inhibited the expression of collagen type I (CoL-I) and fibronectin (Fn). Mechanistically, Sp1 promoted the expression levels of CoL-I and Fn by directly binding to the promoter of Gm26669 to elevate its expression level. Moreover, we found that NCTD alleviated RIF by inhibiting Gm26669 and the nuclear translocation of Sp1. Collectively, above results suggested that NCTD might prevent RIF via targeting the Sp1/Gm26669 axis, thus providing a new theoretical basis for the clinical application of NCTD in the treatment of RIF., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A novel delivery system for cisplatin was constructed based on electrostatics-mediated assemblies of gold nanoclusters and PEGylated cationic peptide (cisplatin@GC-pKs). Encapsulated cisplatin in the as-formed micelle like assemblies was observed to demonstrate improved cellar uptake and enhanced chemotherapeutic efficiency in the cisplatin-resistant lung cancer cells. In vivo assays further confirmed that cisplatin@GC-pKs had profound anti-tumor efficiency due to deep penetration and accumulation of nanoscale cisplatin@GC-pKs via the enhanced permeability and retention (EPR) effect at tumor tissues. The constructed cisplatin@GC-pKs in this work demonstrated enhanced anti-tumor activity for lung cancer therapy, as well as a potential treatment strategy for a variety of cisplatin-resistance related malignancies.

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo . Meanwhile, the utilization of iRGD-targeted PPC 815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.

Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88 L265P mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88 L265P and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4 NS/MS ), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4 NS/MS including those with TP53 mutations. In conclusion, genetic testing for MYD88 L265P , TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

HDACs as important targets for cancer therapy have attracted extensive attentions. In this work, a series of sixteen hydroxamic acid based HDAC inhibitors were designed and synthesized with 4,5,6,7-tetrahydrobenzothiazole as the structural core. Majority of them exhibited potent inhibitory activities against HDACs and one leading compound 6h was dug out. 6h was proven to be a pan-HDAC inhibitor and displayed high cytotoxicity against seven human cancer cell lines with IC 50 values in low micromolar range. 6h could arrest cell cycle in G2/M phase and induce apoptosis in A549 cells. Moreover, compound 6h exhibited remarkable anti-migration and anti-angiogenesis activities. At the same time, 6h was able to elevate the expression of acetylated α-tubulin and acetylated histone H3 in a dose-dependent manner. Docking simulation revealed that 6h fitted well into the active sites of HDAC2 and 6. Finally, compound 6h also exerted potent antitumor effects in an A549 zebrafish xenograft model. Our study demonstrated that compound 6h was a promising candidate for further preclinical studies., (Copyright © 2021. Published by Elsevier Inc.)

Functional fullerene derivatives exhibit fantastic inhibitory capabilities against cancer survival and metastasis, but the absence of clarified biological molecular targets and ambiguous regulation mechanisms set barriers for their clinical transformation. Cancer metastasis is the primary cause of mortality and initiated with increased cell migration, making cell motility regulation a high-value therapeutic target in precision medicine. Herein, a critical molecular target of the aminated fullerene derivative (C 70 -EDA), myosin heavy chain 9 (MYH9), was initially identified by a pull-down assay and MS screening. MYH9 is a cytoplasm-located protein and is responsible for cell motility and epithelial-mesenchymal transition regulation. Omics data from large-scale clinical samples reveals that MYH9 gets overexpressed in various cancers and correlates with unfavorable prognosis, indicating that it is a potential antineoplastic target. It is unveiled that C 70 -EDA binds to the C-terminal of MYH9, triggering the transport of MYH9 from the cytoplasm to the cell edge, blocking the MYH9-involved cell mobility, and inhibiting the metastasis-associated EMT process. This work provides a precise biological target and new strategies for fullerene applications in cancer therapy.

In the era of asparaginase-based therapy for extranodal natural killer/T cell lymphoma (ENKTL), the clinical outcomes of ENKTL have notably improved. However, as a rare subtype of ENKTL, the therapeutic effect and prognostic factors of non-nasal type ENKTL remain unclear. Thus, we performed this study to analyze the clinical characteristics and to establish a prognostic model specifically for the non-nasal disease. We performed a retrospective study of consecutive patients newly diagnosed with non-nasal type ENKTL and mainly received asparaginase-based therapy at Sun Yat-sen University Cancer Center (SYSUCC) between January 2011 and December 2019, to analyze the prognostic factors and to propose a prognostic model. We validated the prognostic model in an independent cohort. In total, 98 non-nasal type ENKTL patients were included in the training cohort. Multivariate analyses showed that prognostic factors for OS were elevated LDH levels, involvement of bone marrow and serum total protein (TP) < 60 g/L. We developed a new prognostic model named the non-nasal type ENKTL prognostic index (NPI) by grouping the prognostic factors: group 1, no risk factors; group 2, one risk factor; and group 3, two or three risk factors, which were associated with 3-year OS rates of 84.1% (95% CI, 70.9-97.2), 46.8% (27.7-65.8), and 14.9% (0-32.9), respectively (P < 0.001). These results were validated and confirmed in an independent cohort. The new model is efficient in distinguishing non-nasal-type ENKTL patients with various outcomes in the contemporary era of asparaginase-based therapy.

Conjugated molecules with coplanar strong donor and acceptor (D-A) units have been widely used in the design of near-infrared (NIR) photothermal agents to increase an absorption band through intramolecular charge transfer and to control intramolecular motions in aggregated states. However, such conjugated D-A systems have strong dipolar moments and intermolecular interactions, which may inhibit other channels of photothermal conversion and are often susceptible to nucleophiles, especially in the presence of light irradiation. Now, we report a molecular guideline to develop novel NIR organic photothermal nanoagents based on conjugated boron dipyrromethene (BODIPY) oligomers. This oligomerization is helpful not only for their tunable NIR absorptions in the ground state with distinctly redshifted absorption maxima up to 1002 nm and high extinction coefficients but also for their highly efficient photothermal conversion because of the possible motion of the BODIPY motifs around the ethene linked group in the excited state. These oligomers were fabricated as ultra-photostable nanoagents for multiple imaging-guided phototherapies, which efficiently accumulated in tumors, and gave complete tumor ablation with NIR laser irradiation. This strategy of "ground-state conjugation, excited-state rotation" provides a novel guideline to develop advanced theranostic molecules with NIR absorption.

Objectives: Traditional cancer therapy and regular immunotherapy are ineffective for treating triple-negative breast cancer (TNBC) patients. Recently, chimeric antigen receptor-engineered natural killer cells (CAR NK) have been applied to target several hormone receptors on different cancer cells to improve the efficacy of immunotherapy. Furthermore, epidermal growth factor receptor (EGFR) is a potential therapeutic target for TNBC. Here, we demonstrated that EGFR-specific CAR NK cells (EGFR-CAR NK cells) could be potentially used to treat patients with TNBC exhibiting enhanced EGFR expression., Materials and Methods: We investigated the cytotoxic effects of EGFR-CAR NK cells against TNBC cells in vitro and in vivo. The two types of EGFR-CAR NK cells were generated by transducing lentiviral vectors containing DNA sequences encoding the single-chain variable fragment (scFv) regions of the two anti-EGFR antibodies. The cytotoxic and anti-tumor effects of the two cell types were examined by performing cytokine release and cytotoxicity assays in vitro, and tumor growth assays in breast cancer cell line-derived xenograft (CLDX) and patient-derived xenograft (PDX) mouse models., Results: Both EGFR-CAR NK cell types were activated by TNBC cells exhibiting upregulated EGFR expression and specifically triggered the lysis of the TNBC cells in vitro. Furthermore, the two EGFR-CAR NK cell types inhibited CLDX and PDX tumors in mice., Conclusions: This study suggested that treatment with EGFR-CAR NK cells could be a promising strategy for TNBC patients., (© 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Transcatheter arterial chemoembolization (TACE) is the preferred treatment for patients with advanced hepatocellular carcinoma (HCC), but it lacks safe and effective embolic agents. 5-Fluorouracil (5-FU) is a broad-spectrum anticancer drug, but its clinical application is limited due to drug resistance and toxic side effects. Therefore, in this study, we developed a new liquid embolic agent with 5-FU as the model drug. We found that this liquid embolic agent possesses good gelling properties and embolic effects. An in vitro drug release model of the agent conformed to the Weibull model. Cumulative release of the drug over 7 d was ∼90%, consisting of an initial burst followed by sustained release. Cytotoxicity testing showed that each liquid embolic composition is cytocompatible and only mildly cytotoxic. Pharmacokinetic experiments showed that the formulation significantly prolongs the t 1/2 of 5-FU (approximately five times that of 5-FU solution) and 5-FU residence time in the body (approximately three times that of 5-FU solution). These results indicate that the liquid embolic agent has embolic capacity and could be used as a potential therapeutic method for TACE.

Background: Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy., Method: Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade., Results: In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53 wt , Trp53 mut , and Trp53-deficient (Trp53 -/- ) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8 + T cells in Trp53 wt tumors and M1 macrophages in Trp53 mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53 wt and Trp53 mut tumors upon combination treatment., Conclusion: Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53 mut tumors.

Therapeutic target identification and corresponding drug development is a demanding task for the treatment of lung adenocarcinoma, especially the most malignant proximal-proliferative subtype without druggable protein kinase mutations. Using a cell-SELEX-generated aptamer, we discovered a new tumor driver protein, leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which is specifically overexpressed in the most lethal subtype of lung adenocarcinoma. Targeted LRPPRC protein knockdown is a promising therapeutic strategy for the undruggable LUAD (lung adenocarcinoma). Nevertheless, LRPPRC is mainly located in mitochondria and degraded by protease. Current protein knockdown approaches, such as proteolysis-targeting chimeras (PROTACs), have limitations in their applications to the proteins degraded through proteasome-independent ways. Here, we designed an aptamer-assisted high-throughput method to screen small molecules that could bind to LRPPRC directly, disrupt the interaction of LRPPRC with its stabilizing chaperon protein, and lead to LRPPRC degradation by mitochondrial protease. The screened compound, gossypolacetic acid (GAA), is an old medicine that can accomplish the new function for targeted LRPPRC knockdown. It showed significant antitumor effects even with the LRPPRC-positive patient-derived tumor xenograft (PDX) model. This work not only extended the application of aptamers to screen small-molecule inhibitors for the undruggable lung cancers, but more importantly provided a new strategy to develop protein knockdown methods beyond the proteasome system.

Purpose: To deliver the chemotherapeutics through the nanoparticles, the delivery system should accumulate at the tumor site first and then penetrate through the interstitium into the interior. The specific tumor-targeting pathway mediated via the receptor-ligand binding could achieve the desirable accumulation of nanoparticles, and the nanoparticles with smaller sizes were required for penetration., Methods and Materials: We constructed a size-shrinkable nanocluster modified with a tumor-targeting motif IF-7 (IF-7-MNC) based on a pH-sensitive framework which could be disintegrated in an acid environment to release the micelles aggregated inside. The micelles were constructed by amphiphilic block copolymers PEG-PLA to encapsulate paclitaxel (PTX), while the cross-linked framework consisting of TPGS-PEI was used as a net to gather and release micelles. This nanoplatform could specifically bind with the tumor receptor Annexin A1 through the ligand IF-7 and then shrunk into small micelles with a desirable size for penetration., Conclusion: IF-7-MNC of 112.27±6.81 nm could shrink into micelles in PBS (0.01 M, pH 5.0) with sizes of 14.89±0.32 nm. The cellular-uptake results showed that IF-7-MNC could be significantly internalized by A549 cells and HUVEC cells, while the penetration of IF-7-MNC could be more prominent into the 3D-tumor spheroids compared with that of MNC. The biodistribution results displayed that the fluorescence of IF-7-MNC in the tumor site at 24 hrs was 4.5-fold stronger than that of MNC. The results of anti-tumor growth demonstrated that IF-7-MNC was more favorable for the tumor therapy than MNC, where the inhibitory rate of tumor growth was 88.29% in the PTX-loaded IF-7-MNC (IF-7-PMNC) treated group, significantly greater than PMNC treatment group ( p <0.05)., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2019 Chen et al.)

The development of cancer in patients with schizophrenia is affected by genetic and environmental factors and antipsychotic medication. Several studies found that schizophrenia was associated with decreased risk of some cancers, and the neuroleptic medication might help to reduce the risk of colorectal cancer (CRC). Phenothiazine drugs including trifluoperazine (TFP) are widely used antipsychotic drugs and showed some antitumor effects, we here investigated the potential application of TFP in the treatment of colon cancer. A series doses of TFP were treated to the colon cancer cell line HCT116 and the inhibitory concentration (IC 50 ) of TFP for HCT116 was determined by cell counting kit-8. The results indicated that the treatment of TFP impaired the cell vitality of HCT116 in a dose- and time-dependent manner. Meanwhile, the Edu assay demonstrated that the proliferation was also inhibited by TFP, which was accompanied with the induction of apoptosis and autophagy. The expression of CCNE1, CDK4, and antiapoptosis factor BCL-2 was downregulated but the proapoptosis factor BAX was upregulated. The autophagy inhibitor chloroquine could significantly reverse the TFP-induced apoptosis. Moreover, the ability of migration and invasion of HCT116 was found to be suppressed by TFP, which was associated with the inhibition of epithelial-mesenchymal transition (EMT). The function of TFP in vivo was further confirmed. The results showed that the administration of TFP remarkably abrogated the tumor growth with decreased tumor volume and proliferation index Ki-67 level in tumor tissues. The EMT phenotype was also confirmed to be inhibited by TFP in vivo, suggesting the promising antitumor effects of TFP in CRC., (© 2019 Wiley Periodicals, Inc.)

Polytherapy (or drug combination cancer therapy (DCCT)), targeting multiple mechanisms associated with tumor proliferation, can efficiently maximize therapeutic efficacy, decrease drug dosage, and reduce drug resistance. However, most DCCT strategies cannot coordinate the specific delivery of a drug combination in an accurately tuned ratio into cancer cells. To address these limitations, the present work reports the engineering of circular bivalent aptamer-drug conjugates (cb-ApDCs). The cb-ApDCs exhibit high stability, specific recognition, excellent cellular uptake, and esterase-triggered release. Furthermore, the drug ratios in cb-ApDCs can be tuned for an enhanced synergistic effect without the need for complex chemistry. Therefore, cb-ApDCs provide a promising platform for the development of DCCT strategies for different drug combinations and ratios., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC 50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC 50  = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 µM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In the present research, a tumor-targeted gene carrier, PPP, was constructed through the modification of phenylboronic acid onto the surface of a polyamidoamine dendrimer, and then miR-34a delivery was employed as a model to evaluate its anti-tumor efficacy. The carrier PPP was identified to possess favorable miR-34a binding and condensation ability and meanwhile protect miR-34a against nuclease degradation. Through confocal laser scanning microscopy and flow cytometry analysis, PPP-mediated cellular uptake of miR-34a was found to proceed through a sialic acid-dependent endocytosis pathway and the nanoparticles could achieve endosome/lysosome escape within 6 h. Further, an anti-proliferative effect could be obtained after PPP/miR-34a transfection through the induction of cell apoptosis. Meanwhile, the inhibition of migration and invasion could be realized through blocking the Notch-1 signaling pathway after PPP/miR-34a treatment. Finally, PPP possessed acceptable safety and inhibited in vivo tumor growth through the in situ apoptosis of tumor sites, which relied on the specific tumor-targeting ability and long circulation time in the blood. In summary, the derivative PPP could be potentially utilized as an efficient carrier for miR-34a delivery to achieve an anti-tumor response in clinical use.

Osteosarcoma (OS) is one of the aggressive malignancies for young adults. Cdc20 (cell division cycle 20 homologue) has been reported to exhibit an oncogenic role in OS, suggesting that inhibition of Cdc20 could be a novel strategy for the treatment of OS. Since Cdc20 inhibitors have side effects, it is important to discover the new CDC20 inhibitors with non-toxic nature. In the present study, we determine whether natural agent diosgenin is an inhibitor of Cdc20 in OS cells. We performed MTT, FACS, Wound healing assay, Transwell, Western blotting, transfection assays in our study. We found diosgenin inhibited cell growth and induced apoptosis. Moreover, diosgenin exposure led to inhibition of cell migration and invasion. Notably, diosgenin inhibited the expression of Cdc20 in OS cells. Overexpression of Cdc20 abrogated the inhibition of cell growth and invasion induced by diosgenin. Our data reveal that inhibition of Cdc20 by diosgenin could be helpful for the treatment of patients with OS.

Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes., (© 2019 Elsevier Inc. All rights reserved.)

Multidrug resistance (MDR) is a major cause of failure in cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in cancer., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma which is heterogeneous both clinically and morphologically. Over the past decades, significant advances have been made in the understanding of the molecular genesis, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit., Objective: The current review aims to present a brief overview of signal pathways of DLBCL, which mainly focus on B-cell antigen Receptor (BCR), Nuclear Factor-κB (NF-κB), Phosphatidylinositol-3-Kinase (PI3K) - protein kinase B (Akt) - mammalian Target of Rapamycin (mTOR), Janus Kinase (JAK) - Signal Transducer and Activator (STAT), Wnt/β-catenin, and P53 pathways., Methods: Activation of signal pathways may contribute to the generation, development, chemotherapy sensitivity of DLBCL, and expression of pathway molecules is associated with the prognosis of DLBCL. Some agents targeting these pathways have been proved effective and relevant clinical trials are in progress. These agents used single or combined with chemotherapy/each other might raise the possibility of improving clinical outcomes in DLBCL., Conclusion: This review presents several signal pathways of DLBCL and targeted agents had a tendency to improve the curative effect, especially in high-risk or relapsed/refractory DLBCL., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Frequent local recurrence and metastasis are generally involved in human liposarcoma, but the management is a challenge. There is an urgent need for improved effective therapy. In the present study, we reported that SBF-1, a steroidal glycoside, inhibited the growth of cultured highly malignant human liposarcoma SW872-S cells in vitro and in vivo. SBF-1 down-regulated the phosphorylation of protein kinase B (AKT) and thus reduced cell adhesion to fibronectin and laminin. Then we found that SBF-1 inhibited the expression of oxysterol binding protein (OSBP) in SW872-S cells, indicating that OSBP may be involved in malignant liposarcoma cell survival. Cancer cell growth and AKT phosphorylation were inhibited significantly upon knockdown of OSBP in SW872-S cells in vitro. Taken together, these results suggest that SBF-1 causes an apparent loss of OSBP function in SW872-S cells, resulting in growth inhibition. Based on our findings, OSBP serves as a potential therapeutic target for human liposarcoma., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

VEGFR2 (vascular endothelial growth factor receptor 2) is the main trigger of VEGF-mediated angiogenic signal and targeting VEGFR2 pathway to inhibit tumor angiogenesis represents a promising strategy for cancer therapy. We elucidated that a novel compound, PBA2 exhibited potent anti-tumor effects both in vitro and in vivo with limited toxicity. ELISA assay revealed that PBA2 had a strong suppressive activity against VEGFR2 related to angiogenesis. Furthermore, PBA2 considerably disrupted tube formation of endothelial cells in vitro and systemic administration of PBA2 exerted decreased tumor angiogenesis in vivo. Functional tests demonstrated that PBA2 concentration-dependently impeded the migration and proliferation of endothelial cells. PBA2 had no effects on the expression level of VEGF both in the detected cancer cells and endothelial cells. VEGFR2 and its downstream Akt and Erk pathways were blocked by PBA2 in a concentration-dependent manner both in vitro and in vivo. Overall, we first demonstrated that PBA2, targeting VEGFR2 related to angiogenesis, presented remarkable anti-angiogenic and anti-tumor activities through attenuating VEGFR2 mediated pathway in vitro and in vivo with limited toxicity. These observations posed that PBA2 could be a potential drug candidate for developing anti-angiogenic tyrosine kinase inhibitor in cancer therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic ® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1 H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background/aims: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy., Methods: The cell proliferation was detected by MTT assay. The flow cytometry was used to detect the expression of cell surface protein and to detect the accumulation and efflux of rhodamine 123 (Rh123) or doxorubicin (Dox) in cells. The RT-PCR and Western blot were performed to detect the gene expression and protein expression levels, respectively., Results: We found that ceritinib enhanced the efficacy of substrate chemotherapeutic agent in ABCB1-overexpressing K562/adr leukemia cells both in vitro and in vivo models, but neither in sensitive parental K562 leukemia cells nor in ABCC1-overexpressing HL-60/adr leukemia cells. Mechanistically, ceritinib significantly increased the intracellular accumulation of Rh123 or Dox but did neither alter ABCB1 expressions at both protein and mRNA levels nor block the phosphorylations of AKT and ERK1/2 at the concentration of MDR reversal. Importantly, ceritinib also increased the intracellular accumulation of Dox and enhanced the efficacy of Dox in primary leukemia cells in ex-vivo., Conclusion: Our results suggested that ceritinib enhanced the efficacy of substrate chemotherapeutic agent on inhibition of leukemia cell growth in vitro, in vivo and ex-vivo, which linked to block ABCB1 function, pumping out its substrate conventional chemotherapeutic agent, thereby increasing the intracellular accumulation. These suggest the combination of ceritinib and substrate chemotherapeutic drugs maybe an effective treatment of resistant leukemia patients with ABCB1-mediated MDR., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

A novel highly controllable process of Carbon Encapsulated Magnetic Nanoparticles (CEMNs) synthesis in arc discharge plasma has been developed. In this work, both the size distribution and the purity of the CEMNs have been made more controllable by adding an external magnetic field. It is shown that with the increase of the external magnetic field, the CEMNs get a better separation from the carbon impurities and the size distribution become narrower. This conclusion is valid for Fe, Ni and Fe+Ni CEMNs synthesis. In order to assess biomedical potential of these CEMNs, the cytotoxicity has also been measured for the human breast adenocarcinoma cell line MDA-MB-231. It was concluded that the CEMNs with the concentration in cell of about 0.0001-0.01ug/ml are not toxic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

With many desirable features, such as being more effective and having multiple effects, antiangiogenesis has become one of the promising cancer treatments. The aim of this study was to design and synthesize a new targeted bioresponsive nanosystem with antiangiogenesis properties. The mUPR@Ru(POP) nanosystem was constructed by the polymerization of Ulva lactuca polysaccharide and N -isopropyl acrylamide, decorated with methoxy polyethylene glycol and Arg-Gly-Asp peptide, and encapsulated with anticancer complex [Ru(phen)2p-MOPIP](PF 6 ) 2 ·2H 2 O. The nanosystem was both pH responsive and targeted. Therefore, the cellular uptake of the drug was greatly improved. Moreover, the mUPR@Ru(POP) had strong suppressive effects against vascular endothelial growth factor (VEGF)-induced angiogenesis through apoptosis. The mUPR@Ru(POP) significantly inhibited VEGF-induced human umbilical vein endothelial cell migration, invasion, and tube formation. These findings have presented new insights into the development of antiangiogenesis drugs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Cancer is the leading cause of death worldwide, and metastasis is the main attribute to cancer death. CXCR4 and its natural ligand CXCL12 have been known to play a critical role in tumorigenesis, angiogenesis and metastasis. Therefore, designing a new CXCR4 antagonist to prevent tumor metastasis will be of great significance. Herein, a novel chemically synthesized peptide (E5) that has an ability to target CXCR4/CXCL12 axis was loaded in micelle glycol-phosphatidylethanolamine (PEG-PE) block copolymer to form micelle-encapsulated E5 (M-E5). We demonstrated that M-E5 exhibited higher affinity for CXCR4-overexpressing MCF-7 and HepG2 tumor cells as compared to free E5, and efficiently inhibited the tumor cells migration. Mechanistic studies implied that PEG-PE micelle can encapsulate E5 and improve E5 targeting efficiency for CXCR4 by accumulating E5 on the tumor cell membrane. Furthermore, through encapsulation of chemotherapeutic drug doxorubicin (Dox) in PEG-PE micelle, we proved that PEG-PE micelle could serve as a co-carrier for both E5 and Dox (M-E5-Dox). M-E5 enhanced the efficiency of Dox by down-regulating the phosphorylation level of Akt, Erk and p38/MAPK proteins. In conclusion, PEG-PE micelle demonstrated a promising delivery system for E5, and M-E5 is expected to be a potential therapeutic agent that will help to improve the clinical benefits in current therapies used for solid tumors.

A series of novel ROS inducers were designed by merging the fragments of piperlongumine and dicoumarol. Most of these derivatives showed potent in vitro activity against three cancer cell lines and good selectivity towards normal lung cells. The most potent and selective compound 3e was proven to exhibit obvious ROS elevation and excellent in vivo antitumor activity with suppressed tumor growth by 48.46% at the dose of 5mg/kg. Supported by these investigation, these findings encourage further investigation around this interesting antitumor chemotype., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non-small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation. Mol Cancer Ther; 15(11); 2586-97. ©2016 AACR., (©2016 American Association for Cancer Research.)

Curcumin (CUR), a nontoxic polyphenol derived from the rhizome of turmeric (Curcuma longa), has been recognized as an anti-cancer and chemo-preventative agent. However, its clinical application for cancer treatment has been greatly limited due to its poor water-solubility and low bioavailability. To tackle this problem, Pluronic F68-CUR (F68-CUR) conjugate micelles, which are amphiphilic copolymers, were designed and synthesized in this study. These highly stable micelles with CUR concentrated in the core were formulated using the solvent evaporation method and were confirmed by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Physicochemical characterization of F68-CUR conjugate micelles revealed that high drug loading content (DL%; 0.248 mg CUR/1 mg F68) was achieved, and the average particle size of micelles was 115.2 ± 3.0 nm. Compared with free CUR, a significantly higher cytotoxicity against human breast cancer cell line MDA-MB-231 was observed in F68-CUR conjugate micelles. The IC 50 value of F68-CUR conjugate micelles was 1.95-fold lower than that of free CUR, indicating that the anti-cancer activity of CUR was significantly improved in the micelles. Furthermore, apoptotic studies demonstrated that F68-CUR conjugate micelles induced more cell apoptosis than that of free CUR. Taken together, these results demonstrate that F68-CUR conjugate micelles are promising to improve the clinical effectiveness of CUR in cancer treatment.

Glycyrrhetinic acid (GA), the main hydrolysate of glycyrrhizic acid extracted from the root of licorice, has been used in hepatocellular carcinoma (HCC) therapy. Particularly, GA as a ligand in HCC therapy has been widely explored in different drug delivery systems, including liposomes, micelles, and nanoparticles. There is considerable interest worldwide with respect to the development of GA-modified drug delivery systems due to the extensive presence of GA receptors on the surface of hepatocyte. Up until now, much work has been focused on developing GA-modified drug delivery systems which bear good liver- or hepatocyte-targeted efficiency both in vitro and in vivo. Owing to its contribution in overcoming the limitations of low lipophilicity and poor bioavailability as well as its ability to promote receptor-mediated endocytosis, GA-modified drug delivery systems play an important role in enhancing liver-targeting efficacy and thus are focused on the treatment of HCC. Moreover, since GA-modified delivery systems present more favorable pharmacokinetic properties and hepatocyte-targeting effects, they may be a promising formulation for GA in the treatment of HCC. In this review, we will give an overview of GA-modified novel drug delivery systems, paying attention to their efficacy in treating HCC and discussing their mechanism and the treatment effects.

The treatment of squamous carcinoma, especially multidrug resistance (MDR) tumors, represents one of the most formidable challenges in oncology. In this study, integrin-mediated Pluronic-based micellar system (c(RGDyK)-FP-DP) was proposed as a drug delivery system to enhance the in vivo anti-tumor efficacy in MDR human squamous carcinoma (KBv)-bearing. Following the recognition by integrin proteins express on the cell surface, cellular uptake and in vitro anti-tumor efficacy of c(RGDyK)-FP-DP were better than conventional PF-DP in KBv cells. The tumor homing specificity and further in vivo anticancer efficacy of c(RGDyK)-FP-DP were performed using subcutaneous KBv tumor-bearing mice model, respectively. Compared with PF-DP, c(RGDyK)-FP-DP demonstrated more drug accumulation in tumor and relatively less drug accumulation in heart, and an extended median survival time in the KBv tumor-bearing mice model. Furthermore, preliminary in vivo subacute toxicity evaluation was also conducted by the measurement of histopathology, blood cell counts and clinical biochemistry parameters. Results showed that no obvious toxicity was observed to the hematological system or heart after a series of intravenous administration of c(RGDyK)-FP-DP. In conclusion, our results suggested that c(RGDyK) peptide conjugated Pluronic micelles could be a promising vehicle for enhancing the treatment of MDR human squamous carcinoma.

Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As2O3) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As2O3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As2O3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As2O3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As2O3 treatment preferentially inhibited cell growth of GSCs but not matched non-stem tumor cells (NSTCs). Furthermore, As2O3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As2O3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs.

Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α's biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer.

Purpose: The major hurdle of current drug carrier against hepatocellular carcinoma (HCC) is the lack of specific and selective drug delivery to HCC. In this study, a novel glycyrrhetinic acid (GA) and poly(L-Histidine) (PHIS) mediated polymeric drug delivery system was developed to target HCC that have GA binding receptors and release its encapsulated anticancer drug in the acidic microenvironment of HCC., Methods: Firstly, GA and PHIS were conjugated to form poly (ethylene glycol)-poly(lactic-co-glycolic acid) (GA-PEG-PHIS-PLGA, GA-PPP) micelles by grafting reaction between active terminal groups. Secondly, andrographolide (AGP) was encapsulated to GA-PPP to make AGP/GA-PPP using the solvent evaporation method. The pH-responsive property of AGP/GA-PPP micelles was validated by monitoring its stability and drug release behavior in different pH conditions. Furthermore, selective hepatocellular uptake of GA-PPP micelles in vitro, liver specific drug accumulation in vivo, as well as the enhanced antitumor effects of AGP/GA-PPP micelles confirmed the HCC targeting property of our novel drug delivery system., Results: Average size of AGP/GA-PPP micelles increased significantly and the encapsulated AGP released faster in vitro at pH 5.0, while micelles keeping stable in pH 7.4. AGP/GA-PPP micelles were uptaken more efficiently by human Hep3B liver cells than that by human MDA-MB-231 breast cancer cells. GA-PPP micelles accumulated specifically in the liver and possessed long retention time in vivo. AGP/GA-PPP micelles significantly inhibited tumor growth and provided better therapeutic outcomes compared to free AGP and AGP/PEG-PLGA(AGP/PP) micelles without GA and PHIS decoration., Conclusions: This novel GA-PPP polymeric carrier is promising for targeted treatment of HCC.

Dual-functional drug delivery system was developed by decorating c(RGDyK) (cyclic RGD [arginine-glycine-aspartic acid] peptide) with Pluronic polymeric micelles (c[RGDyK]-FP-DP) to overcome the drawbacks of low transport of chemotherapeutics across the blood-tumor barrier and poor multidrug-resistant (MDR) tumor therapy. c(RGDyK) that can bind to the integrin protein richly expressed at the site of tumor vascular endothelial cells and tumor cells with high affinity and specificity was conjugated to the N-hydroxysuccinimide-activated PEO terminus of the Pluronic F127 block copolymer. In this study, decreased tumor angiogenic and increased apoptotic activity in MDR cancer cells were observed after the treatment with c(RGDyK)-FP-DP. c(RGDyK)-FP-DP was fully characterized in terms of morphology, particle size, zeta potential, and drug release. Importantly, in vitro antiangiogenesis results demonstrated that c(RGDyK)-FP-DP had a significant inhibition effect on the tubular formation of human umbilical vein endothelial cells and promoted cellular apoptotic activity in MDR KBv cells. In addition, the growth inhibition efficacy of KBv tumor spheroids after crossing the blood-tumor barrier was obviously increased by c(RGDyK)-FP-DP compared to other control groups. Results suggested that c(RGDyK)-decorated Pluronic polymeric micelles can take pharmacological action on both human umbilical vein endothelial cells and KBv MDR cancer cells, resulting in a dual-functional anticancer effect similar to that observed in our in vitro cellular studies.

Although doxorubicin (DOX) and paclitaxel (PTX) are widely used in clinic as chemotherapeutics, both drug substances are found to be glycoprotein P (P-gp) substrates which are liable to develop the multidrug resistance (MDR). Additionally, the use of single chemotherapeutic drug has known limitations such as high toxicity profile due to the relatively high doses and limited regimen of clinical application. To this end, Pluronic P105-DOX conjugate was successfully designed and developed which can be further used as a hydrophobic core to entrap another anti-cancer drug PTX with Pluronic F127 to form the dual drug-loaded mixed micelles (PF-DP) in our study, which would offer great advantages over conventional micelles, including easy fabrication, high loading capacity, and co-delivery of hydrophilic DOX and hydrophobic PTX to achieve synergistic effect of these two drug substances. Results showed that PF-DP possessed a good polydispersity and sustained release profile for both DOX and PTX in vitro. Studies on cellular uptake demonstrated both anti-cancer drugs in PF-DP can effectively accumulate in MDR cancer cells. Furthermore, in vitro cytotoxicity, cell apoptosis and cell cycle arrest studies indicated that PF-DP had better antitumor efficacy in MDR cancer cells compared to those of single-drug loaded micelles. It was also found that PF-DP can suppress the growth of tumor cells more efficiently than single drug formulations at the equivalent drug concentrations, suggesting synergistic effect could be achieved. More importantly, a much stronger antitumor efficacy in MCF-7/ADR tumor-bearing mice was observed in PF-DP group than that of combined administration of free DOX and PTX. Collectively, the dual drug-loaded Pluronic-based functional mixed micelles developed in this study might be a potential nano-drug delivery system for MDR cancer chemotherapy., (Copyright © 2015. Published by Elsevier B.V.)