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Background: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Phosphofructokinase 1 (PFK-1) is one of member of PFK, which plays an important role in reprogramming cancer metabolism, such as lactylation modification. Zinc finger E-box-binding homeobox 1 (ZEB1) has been demonstrated to be a oncogene in many cancers. Therefore, this study was performed to explore the effects of PFK-1 on the lactylation of ZEB1 in BC development. Methods: Cell viability was measured using the CCK-8 kit. The glucose assay kit and lactate assay kit were used to detect glucose utilization and lactate production. The DNA was purified and quantified by qRT-PCR. Results: In the present study, we found that ZEB1 expression levels were significantly elevated in bladder cancer cells. Impaired PFK-1 expression inhibits proliferation, migration, and invasion of BC cells and suppresses tumour growth in vivo. We subsequently found that knockdown of PFK-1 decreases glycolysis, including reduced glucose consumption, lactate production and total extracellular acidification rate (ECAR). Mechanistically, PFK-1 inhibits histone lactylation of bladder cancer cells, and thus inhibits the transcription activity of ZEB1. Conclusion: Our results suggest that PFK-1 can inhibit the malignant phenotype of bladder cancer cells by mediating the lactylation of ZEB1. These findings suggested PFK-1 to be a new potential target for bladder cancer therapy. [ABSTRACT FROM AUTHOR]

Except for cell-surface receptors, a range of transporters have been exploited as targets for the delivery of novel anti-tumour nanomaterials. Transporters, which are essential for delivering nutrients for the biosynthesis of mammalian cells, are significantly expressed in a range of tumour types; their expression is mostly tissue- and site-specific. The unique functional and expression characteristics of transporters make them ideal targets for mediating the selective delivery of nanomaterials to cancer cells, thus promoting cell accumulation, and enhancing the penetration of nanomaterials into biological barriers before they can specifically target cancer cells. In this review, we discuss the unique function of cancer-related transporters in the initiation and development of tumours, as well as the use of transporter-targeted nanocarriers in tumour-targeting therapy. First, the expression of various transporters in tumorigenesis and development is reviewed; this is followed by a discussion of the latest advances in targeted drug delivery strategies based on transporter nanocarriers. Finally, we review the molecular mechanisms and targeting efficiency of transporter-mediated nanocarriers. This review provides a state-of-the-art synthesis of this discipline and will facilitate the generation of new concepts for the design of highly efficacious and tumour-targeting nanocarriers. [ABSTRACT FROM AUTHOR]

DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition. [ABSTRACT FROM AUTHOR]

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments. [ABSTRACT FROM AUTHOR]

Purpose. Lung cancer is a relatively common type of cancer, and the incidence rate has been on the rise in recent years. MicroRNAs are a class of endogenous small RNA molecules, which are essential for the posttranscriptional regulation of genes. miR-29b is closely related to the occurrence and development of tumors, including prostate cancer, colon cancer, and breast cancer. However, few studies have been performed to explore the expression and pathway of miR-29b in non-small-cell lung cancer (NSCLC). Methods. Using bioinformatics analysis, we found that patients with low relative expression of the miR-29b gene have a low long-term survival rate. The results of in vitro research showed that when miR-29b expression was upregulated, the invasion, migration, and proliferation of A549 and NCI-H-1792 cells was inhibited, and the apoptosis was accelerated. Results. The results showed that FEM1B is a miR-29b target gene, and the expressions of FEM1B and miR-29b were negatively correlated. Like the upregulation of miR-29b expression, silencing the FEM1B expression could also impair the invasion, migration, and proliferation abilities of A549 and NCI-H-1792 cells. When FEM1B expression was restored, the inhibitory effect of miR-29b could be reversed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB) analysis showed that overexpression of miR-29b could inhibit the expression of FEM1B, AKT, vascular endothelial growth factor (VEGF), and Sirt3 in A549 and NCI-H-1792 cells and upregulate the expression of FOXO1 protein. Conclusion. The results of this study indicate that miR-29b inhibits the proliferation and deterioration of NSCLC cells by targeting FEM1B and inhibiting the activation of the FOXO1/AKT pathway. miR-29b may become a new target for the clinical diagnosis and treatment of lung cancer, and it is expected to become a new inhibitor of NSCLC. [ABSTRACT FROM AUTHOR]

Background: The fruits of Schisandra chinensis have been used traditionally as the medicinal materials in East Asia. Their extracts have been reported to be cytotoxic to several cancer cells and phytochemical research has identified numerous cytotoxic lignans. Objectives: We reviewed for the effects of cytotoxic lignans against various human cancer cells. Materials and Methods: Solvent extraction of fruits in aqueous methanol and fractionation of the extract into H2O, n-BuOH, and EtOAc fractions (Fr) were carried out. Column chromatography (CC) of the non-polar EtOAc Fr, which indicated cytotoxicity to cancer cells, was performed to isolate the cytotoxic lignin. They were identified on the basis of the intensive spectroscopic interpretation of IR, 1D-, 2D-NMR, and mass spectrometry data. The cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cell staining using Hoechst 32258 and propidium iodide. Results: Anwulignan was isolated and identified as a cytotoxic principal component. The IC50 value was calculated to be 22.01 ± 1.87, 156.04 ± 6.71, and 32.68 ± 2.21 μM for human stomach adenocarcinoma, human colon cancer (HT29), and human cervical cancer cells, respectively. Conclusion: Solvent extraction, systematic fractionation, and repeated CC for S. chinensis fruits led to the isolation of a lignin identified to be anwulignan based on various spectroscopic analyses. Anwulignan demonstrated very high cytotoxicity to most human cancer cell lines, and cell death was induced by apoptosis. [ABSTRACT FROM AUTHOR]

Oxaliplatin (L-OHP) is one of the effective chemotherapeutic drugs for colorectal cancer (CRC). Further investigation into the molecular mechanism of chemoresistance could improve outcomes for patients with colorectal cancer. Recently, microRNAs have been reported as a key in drug resistance of tumors. In this study, we aimed to investigate the effects of miR-153-5p in L-OHP-resistant CRC cells, and its underlying mechanism. Downregulation of miR-153-5p was observed in CRC cells, while upregulation of miR-153-5p enhances the chemosensitivity of CRC/L-OHP cells. The autophagy of CRC/L-OHP cells was markedly increased after exposure to L-OHP but abolished by the upregulation of miR-153-5p. Dual-luciferase reporter assays validated that Bcl-2 was a direct target of miR-153-5p. In conclusion, our data suggested that miR-153-5p was a mediator of cisplatin resistance in colorectal cancer by affecting Bcl-2-mediated autophagy, indicating a new therapeutic target for CRC treatment. MiR-153-5p was a mediator of cisplatin resistance in colorectal cancer by affecting Bcl-2-mediated autophagy [ABSTRACT FROM AUTHOR]

Repeated chromatographic separations of the EtOAc fraction of Schisandra chinensis fruits on silica gel, octadecyl silica gel, and Sephadex LH-20 led to the isolation and identification of seven dibenzocyclooctadiene lignans (1–7). The NMR data reported in the literature for angeloyl gomisin H (5) were shown to be incorrect. We unambiguously identified the compounds based on detailed analysis of the 1D and 2D NMR data, especially from HMBC and NOESY experiments. In addition, MTT assays and cell viability experiments verified the cytotoxicity of the isolated dibenzocyclooctadiene lignans against the human cancer cell lines AGS, HeLa, and HT-29. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is a malignant breast cancer subtype with poor prognosis. Recent studies have revealed the critical roles of dysregulated long non-coding RNAs (lncRNAs) in many cancer types, including TNBC. LncRNA WEE2 antisense RNA 1 (WEE2-AS1) has been reported to be able to promote the progression of hepatocellular carcinoma, but the function of WEE2-AS1 in TNBC is still unknown. Therefore, in this study, we specifically researched the role of WEE2-AS1 and probed its molecular mechanism in TNBC cells. Our results showed that WEE2-AS1 was up-regulated in TNBC cell lines, and WEE2-AS1 knockdown could inhibit TNBC cell proliferation, promote apoptosis, and suppress migration and invasion. Further, we found that miR-32-5p was down-regulated in TNBC cells and could be sponged by WEE2-AS1. Moreover, miR-32-5p could target its downstream gene transducer of ERBB2, 1 (TOB1), which was highly expressed and could play the oncogenic role in TNBC cells. Through rescue assays, we proved that WEE2-AS1/miR-32-5p/TOB1 axis could modulate cancer progression in TNBC cells. In conclusion, our results demonstrated the oncogenic function of lncRNA WEE2-AS1 in TNBC cells, providing a novel insight into TNBC therapy. • WEE2-AS1 knockdown inhibited TNBC cell proliferation, migration and invasion, and enhanced apoptosis. • WEE2-AS1 sponged miR-32-5p in TNBC cells. • MiR-32-5p targeted TOB1, whose knockdown exerted anti-oncogenic roles in TNBC cells. • WEE2-AS1/miR-32-5p/TOB1 axis contributed to cancer progression in TNBC cells. [ABSTRACT FROM AUTHOR]

Drug resistance in breast cancer (BC) cells continues to be a stern obstacle hindering BC treatment. Adriamycin (ADR) is a frequently employed chemotherapy agent used to treat BC. The exosomal transfer of microRNAs (miRNAs) has been reported to enhance the drug-resistance of BC cells. Herein, we first sought to elucidate the possible role of the exosomal transfer of miR-221-3p in the drug resistance of MCF-7 cells to ADR. Differentially expressed genes (DEGs) were initially screened through microarray analysis in BC drug resistance-related datasets. Next, the expression of miR-221-3p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was quantified in ADR-resistant MCF-7 (MCF-7/ADR) and ADR-sensitive MCF-7 (MCF-7/S) cell lines, after which exosomes were separated and identified in each cell line. Target relationship between miR-221-3p and PIK3R1 was validated by a dual-luciferase reporter assay. Next, the expression of miR-221-3p and PIK3R1 was altered to clarify their effects on the resistance of MCF-7 cells to ADR in vitro and in vivo. PIK3R1 was identified as a BC drug resistance-related DEG, with the regulatory miR-221-3p subsequently obtained. Moreover, the MCF-7/ADR cells exhibited a low expression of PIK3R1 and a high expression of miR-221-3p. Notably, PIK3R1 was identified as a target gene of miR-221-3p. The overexpression of miR-221-3p in MCF-7/ADR cell-derived exosomes promoted ADR resistance in MCF-7/S cells via the PI3K/AKT signaling pathway. The in vitro results were reproducible in in vivo assays. Taken together, drug-resistant BC cell-derived exosomal miR-221-3p can promote the resistance of BC cells to ADR by targeting PIK3R1 via the PI3K/AKT signaling pathway in vitro and in vivo. These findings provide encouraging insights and provide perspectives for further investigation into the BC drug resistance mechanism. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to analyze the clinicopathological features and prognosis of esophageal signet ring cell (SRC) carcinoma in China. Methods: Patients with poorly differentiated adenocarcinoma were identified in two hospitals from January 2006 to June 2016. The patients were divided into three groups according to component of SRCs: SRC≥50% group, SRC < 50% group and non-SRC poorly differentiated adenocarcinoma group. Results: Fifty-seven patients had carcinoma (SRC≥50%), and 79 patients had tumors containing <50% SRCs, and 535 patients was in non-SRC poorly differentiated adenocarcinoma group. There were no significant differences among the three groups in clinicopathological characteristics. Patients in SRC≥50% group had a lower overall survival rate (at 3-year 37.6%versus71.1%; at 5-year 0% versus 43.3%; p<0.001) compared with the control group. Even survival outcome of patients in SRC < 50%was inferior to that of in control group (at 3-year 53.0%versus71.1%; at 5-year 25.9% versus 43.3%; p<0.001). Female sex, large tumor size and increasing TNM stage were independent prognostic factors for SRC ≥50% esophageal carcinoma patients. Conclusions: The incidence of esophageal SRC carcinoma is relatively rare and the worst outcome is observed in the SRC≥ 50% group. It is necessary to explore new therapeutic modalities to achieve further improvements in the clinical outcome of these patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147), a glycoprotein enriched on the plasma membrane of tumor cells, promotes proliferation, invasion, metastasis, and survival of malignant tumor cells. In this study, we sought to examine the expression of EMMPRIN in breast tumors, and to identify the potential roles of EMMPRIN on breast cancer cells. METHODS: EMMPRIN expression in breast cancer tissues was assessed by immunohistochemistry. We used a lentivirus vector-based RNA interference (RNAi) approach expressing short hairpin RNA (shRNA) to knockdown EMMPRIN gene in breast cancer cell lines MDA-MB-231 and MCF-7. In vitro, Cell proliferative, invasive potential were determined by Cell Counting Kit (CCK-8), cell cycle analysis and matrigel invasion assay, respectively. In vivo, tumorigenicity was monitored by inoculating tumor cells into breast fat pad of female nude mice. RESULTS: EMMPRIN was over-expressed in breast tumors and breast cancer cell lines. Down-regulation of EMMPRIN by lentivirus vector-based RNAi led to decreased cell proliferative, decreased matrigel invasion in vitro, and attenuated tumor formation in vivo. CONCLUSION: High expression of EMMPRIN plays a crucial role in breast cancer cell proliferation, matrigel invasion and tumor formation. [ABSTRACT FROM AUTHOR]

Background & Aims: The biological relevance and regulation mechanism of aberrant miR-223 expression in human hepatocellular carcinoma (HCC) remain unknown. Our aim was to investigate miR-223 regulation in HCC. Methods: miR-223 and integrin αV dysregulation were verified in 57 HCC specimens. Immunohistochemical analysis of integrin αV and sulfatide levels was performed on another cohort of 103 HCC samples. Epigenetic analysis was used to explore the effect of sulfatide on miR-223 transcription. Orthotopic growth, and intrahepatic and pulmonary metastasis of tumors derived from SMMC-7721 cells expressing miR-223 or cerebroside sulfotransferase were monitored in mice. Results: miR-223 was reduced in HCC specimens and highly metastatic cell lines. Enhanced miR-223 expression had a negative effect on integrin αV-mediated cell migration. In vivo assays of metastasis in an orthotopically implanted model demonstrated that miR-223 effectively inhibited HCC metastasis. Further analysis demonstrated that integrin αV is negatively regulated by miR-223. Moreover, the integrin αV subunit was significantly positively correlated with highly expressed sulfatide in 103 HCC specimens. Intriguingly, miR-223 expression was suppressed by sulfatide in HCC in association with reduced recruitment of acetylated histone H3 and C/EBPα to the pre-miR-223 gene promoter, where monocytic leukemia zinc finger (MOZ) protein, a MYST-type histone acetyltransferase, lost its attachment. The expression of histone deacetylases, HDAC9 and HDAC10, were greatly stimulated by sulfatide and their recruitment to miR-223 gene promoter was enhanced. Conclusions: Downregulation of miR-223 in HCC is associated with the epigenetic regulation by highly expressed sulfatide and involved in tumor metastasis. [Copyright &y& Elsevier]

Abstract: Background: CYP26a1, which functioned mainly as a retinoic acid (RA) catabolic enzyme, has been shown to be oncogenic and to support cell survival in many breast carcinoma cells. Objectives: The purpose of the study was to investigate the antitumor effect of a DNA vaccine targeting CYP26a1 on breast tumors development in mice which highly express CYP26a1 and to further clarify its potential mechanism. Methods: After three times immunization of the DNA vaccine, the BALB/c mice were inoculated with the engineered 4T1 breast cancer cells expressing CYP26a1. Primary tumors were measured every 4days after tumor cell inoculation. The primary tumors were surgically removed and weighted after 30days of inoculation. The anti-CYP26a1 antibody titer of the antiserum was measured by an enzyme-linked immunosorbent assay (ELISA). The effect of the vaccine on apoptosis of the primary tumor was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Apoptosis-related proteins in primary tumor were detected by Western blotting. The expression of the Th1 and Th2 type cytokines was detected by RT-PCR. Results: The vaccine could elicit the production of anti-CYP26a1 antibody and significantly inhibit the growth of the primary tumor compared to the control groups (p <0.05). The vaccine induced the apoptosis of the primary tumor with the increase in expression of apoptosis-related proteins p53, Caspase3 and Fas. Furthermore, the vaccine increased the expression of the Th1 cytokine, but not the expression of Th2 cytokine. Conclusion: Our study shows that the vaccine targeting CYP26a1 significantly inhibits the primary tumor growth and progression by activating the apoptosis pathway and by eliciting both humoral and cellular immune responses. [Copyright &y& Elsevier]

Abstract: Neuropilin-2(Nrp2), which is a nontyrosine kinase transmembrane glycoprotein, can promote angiogenesis and is a poor prognostic factor in some human cancers. In the present study, to explore the expression and potential function of Nrp2 in salivary adenoid cystic carcinoma (SACC), immunohistochemistry was used to examine the Nrp2 expression in 50 SACCs and 20 normal salivary gland tissues nearby SACCs. The result showed that immunoreactivity for Nrp2 was detected in 47 of 50 SACCs, and its expression level had significant correlations with microvessel density, tumor size, TMN clinical stage, vascular invasion, and metastasis (P <0.05) of SACCs. In addition, inhibition of Nrp2 function by the receptor–ligand interaction-blocking antibody decreased cell migration, invasion, and angiogenic promotion without influences on the cell proliferation of Acc-3 cells. Taken together, the expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in SACCs. These results suggest that Nrp2 may be a potential therapeutic target for SACCs. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the influence of the recombinant human endostatin and gemcitabine combined with HIFU on the mouse xenograft model of pancreatic cancer. Methods: Use human pancreatic cancer cell line PANC-1 to set up the mouse xenograft model, then randomized into four arms. Each arm was treated with gemcitabine, endostatin, gemcitabine combined with endostatin and normal saline respectively. Observe the volume of the tumor, the serum VEGF level and MVD in the tumor tissue among the different arms. All mice were treated with HIFU, then pathological examination was done. Results: The tumor volume, serum VEGF level and MVD in the combined-therapy arm are all lower than the monotherapy arms and the control arm. The coagulation necrosis occurred in tumors after HIFU treatment. Conclusion: Endostatin and gemcitabine has better effect than gemcitabine or endostatin monotherapy on the animal xenograft model of human pancreatic cancer. HIFU combined with chemotherapy and/or targeted therapy may enhance the effect for pancreatic cancer. [Copyright &y& Elsevier]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Cisplatin resistance is an obstacle for the effective treatment of non-small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug-resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP-BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin-resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP-BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β-actin. Cisplatin and NVP-BEZ235 displayed the strongest synergy (CI50=0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP-BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP-BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G0G1 phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance-associated protein 1 and ATP-binding cassette sub-family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP-BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP-BEZ235 displayed synergistic antitumor effects on drug-resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux. [ABSTRACT FROM AUTHOR]

Background: In tumor treatment, protein tyrosine kinase inhibitors (TKIs) have been extensively utilized. However, the efficacy of TKI is significantly compromised by drug resistance. Consequently, finding an effective solution to overcome TKI resistance becomes crucial. Reactive oxygen species (ROS) are a group of highly active molecules that play important roles in targeted cancer therapy including TKI targeted therapy. In this review, we concentrate on the ROS-associated mechanisms of TKI lethality in tumors and strategies for regulating ROS to reverse TKI resistance in cancer. Main body: Elevated ROS levels often manifest during TKI therapy in cancers, potentially causing organelle damage and cell death, which are critical to the success of TKIs in eradicating cancer cells. However, it is noteworthy that cancer cells might initiate resistance pathways to shield themselves from ROS-induced damage, leading to TKI resistance. Addressing this challenge involves blocking these resistance pathways, for instance, the NRF2-KEAP1 axis and protective autophagy, to promote ROS accumulation in cells, thereby resensitizing drug-resistant cancer cells to TKIs. Additional effective approaches inducing ROS generation within drug-resistant cells and providing exogenous ROS stimulation. Conclusion: ROS play pivotal roles in the eradication of tumor cells by TKI. Harnessing the accumulation of ROS to overcome TKI resistance is an effective and widely applicable approach. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to drug resistance and difficult to treat. In this study, we grafted water-soluble pullulan with lovastatin (LV) to develop a novel amphiphilic conjugate, pullulan-encapsulated LV (PLV). The PLV conjugate was synthesized with three different ratios of pullulan to LV and characterized by Fourier transform infrared (FTIR). The degree of substitution (DS) of LV in terms of molar ratio was 7.87%, 3.58%, and 3.06% for PLV (1/2), PLV (1/3), and PLV (1/4), respectively, by proton NMR analysis. We selected the PLV (1/2) conjugate to prepare doxorubicin (DXR)-loaded PLV nanoparticles (PLV/DXR NPs) because of its superior properties. The average size and zeta potential for PLV (1/2) NPs were 177.6 nm and − 11.66 mV, respectively, determined by dynamic light scattering, and those for PLV/DXR NPs were 225.6 nm and − 10.51 mV, respectively. In vitro drug release profiling showed that PLV/DXR NPs sustainably released DXR within 72 h, which was more robust at pH 5.4 (97.90%) than pH 7.4 (76.15%). In the cytotoxicity study, PLV/DXR NPs showed greater inhibition of proliferation of TNBC MDA-MB-231 than non-TNBC MDA-MB-453 cells (IC50 0.60 vs 11.05 μM). FITC-loaded PLV/DXR NPs were prepared to investigate cellular uptake: both cell lines showed a time-dependent uptake of NPs, but the number of NPs entering MDA-MB-231 cells was greater than that entering the MDA-MB-453 cells. Pullulan-based NP co-delivery of LV and DXR could efficiently inhibit TNBC cells, which may help in designing a powerful drug delivery system for treating TNBC. [ABSTRACT FROM AUTHOR]

CircRNAs represent a new class of non‐coding RNAs which show aberrant expression in diverse cancers, such as gastric cancer (GC). circSTRBP, for instance, is suggested to be overexpressed in GC cells and tissues. However, the biological role of circSTRBP in the progression of GC and the potential mechanisms have not been investigated. circSTRBP levels within GC cells and tissues were measured by RT‐qPCR. The stability of circSTRBP was assessed by actinomycin D and Ribonuclease R treatment. Cell proliferation, migration, invasion and in vitro angiogenic abilities after circSTRBP knockdown were analysed through CCK‐8 assay, transwell culture system and the tube formation assay. The interaction of circSTRBP with the predicted target microRNA (miRNA) was examined by RNA immunoprecipitation and luciferase reporter assays. Xenograft tumour model was established to evaluate the role of exosomal circSTRBP in the tumour formation of GC cells. circSTRBP was upregulated in GC cells and tissues, and there was an increased level of circSTRBP in GC‐derived exosomes. circSTRBP in the exosomes enhanced GC cell growth and migration in vitro, which modulates E2F Transcription Factor 2 (E2F2) expression through targeting miR‐1294 and miR‐593‐3p. Additionally, exosomal circSTRBP promoted the tumour growth of GC cells in the xenograft model. Exosomal circSTRBP is implicated in the progression of GC by modulating the activity of miR‐1294/miR‐593‐3p/E2F2 axis. [ABSTRACT FROM AUTHOR]

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound. [ABSTRACT FROM AUTHOR]

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Abstract: Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), namely, gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. About 50% of this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as the one corresponding to T790M. In our previous study, we found that combined treatment with fulvestrant and gefitinib decreases the proliferation of H1975 NSCLC cells, compared to treatment with either fulvestrant or gefitinib alone; however, the molecular mechanism for the improved effects of the combination treatment are still unknown. In this study, we confirmed that fulvestrant increases the gefitinib sensitivity of H1975 cells and found that let-7c was most upregulated in the fulvestrant-treated cells. Our data revealed that let-7c increases gefitinib sensitivity by repressing RAS and inactivating the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. Taken together, our findings suggest that let-7c plays an important role in fulvestrant-induced upregulation of gefitinib sensitivity in H1975 cells. [Copyright &y& Elsevier]

Non‐coding RNA 886 (nc886/VTRNA2‐1) is a Pol III transcript and an atypical imprinted gene. Its exact function as a negative regulator of protein kinase R establishes its connection with innate immunity. Studies have shown that nc886 silencing is closely associated with prostate cancer progression. Previous work has constructed a cell model of stable nc886 overexpression ("mimic" or "nc886+") in PC‐3M‐1E8 cell lines (1E8), which are highly bone‐metastatic human prostate cancer cells with low expression of nc886, and cells expressing the mimic were validated to have lower invasive and metastatic abilities than cells expressing the scramble transcript in vitro and in vivo. In this study, we directly injected mimic or scramble cells into the left ventricle of C57BL/C mice, an immunocompetent animal model, to elucidate the immune mechanisms of tumor‐host interactions. Interestingly, we found that tumor cells induced the inflammation of many important organs due to xenogeneic antigen rejection; this inflammation was ultimately repaired by tissue fibrosis after 28 days, except for in the spleen. The reason is that mimic cells, as heterogeneous antigens, are mostly directly recognized by macrophages or T cells in blood, and few mimic cells enter the spleen compared with scramble cells. The induction of splenic macrophage polarization to M2 macrophages by scramble cells is a critical factor in maintaining chronic splenic inflammation. In addition, we recognize that nc886 broadly decreases the expression of some human leukocyte antigen molecules and antigen transporters. This evidence reveals the interesting role of nc886 in regulating tumor cell antigens. [ABSTRACT FROM AUTHOR]

Trophoblast cell surface antigen 2 (Trop2) has emerged as a potential target for effective cancer therapy. In this study, we report a novel anti-Trop2 antibody IMB1636, developed using hybridoma technology. It exhibited high affinity and specificity (K D = 0.483 nM) in binding both antigens and cancer cells, as well as human tumor tissues. hIMB1636 could induce endocytosis, and enabled targeted delivery to the tumor site with an in vivo retention time of 264 h. The humanized antibody hIMB1636, acquired using CDR grafting, exhibited the potential to directly inhibit cancer cell proliferation and migration, and to induce ADCC effects. Moreover, hIMB1636 significantly inhibited the growth of MDA-MB-468 xenograft tumors in vivo. Mechanistically, hIMB1636 induced cell cycle arrest and apoptosis by regulating cyclin-related proteins and the caspase cascade. In comparison to commercialized sacituzumab, hIMB1636 recognized a conformational epitope instead of a linear one, bound to antigen and cancer cells with similar binding affinity, induced significantly more potent ADCC effects against cancer cells, and displayed superior antitumor activities both in vitro and in vivo. The data presented in this study highlights the potential of hIMB1636 as a carrier for the formulation of antibody-based conjugates, or as a promising candidate for anticancer therapy. • A novel anti-Trop2 humanized antibody hIMB1636 with high affinity and specificity was produced. • hIMB1636 can induce endocytosis, and enables targeted delivery to the tumor site in vivo. • hIMB1636 shows similar affinity, stronger ADCC and antitumor effects in contrast with sacituzumab. • hIMB1636 can serve as a carrier for conjugates, or potentially be utilized as a promising drugs. [ABSTRACT FROM AUTHOR]

Large tumor suppressor 2 (LATS2), an important mediator of the cell apoptotic response pathway, has been linked to the progression of several cancers. Here, we described the molecular feature of LATS2 as a novel antitumor factor in liver cancer cells in vitro. Western blotting was used to detect the expression of LATS2 and its downstream factors. ELISA, immunofluorescence, and flow cytometry were used to evaluate the alterations of mitochondrial function in response to LATS2 overexpression. Adenovirus-loaded LATS2 and siRNA against DRP1 were transfected into liver cancer cells to overexpress LATS2 and knockdown DRP1 expression, respectively. The results of the present study demonstrated that overexpression of LATS2 was closely associated with more liver cancer cell death. Mechanistically, LATS2 overexpression increased the expression of DRP1, and DRP1 elevated mitochondrial division, an effect that was accompanied by mitochondrial dysfunction, including mitochondrial membrane potential reduction, mitochondrial respiratory complex downregulation, mitochondrial cyt-c release into the nucleus and mitochondrial oxidative injury. Moreover, LATS2 overexpression also initiated mitochondrial apoptosis, and this process was highly dependent on DRP1-related mitochondrial division. Molecular investigations demonstrated that LATS2 modulated DRP1 expression via the Wnt/β-catenin pathway. Inhibition of the Wnt/β-catenin pathway pregented LATS2-mediated DRP1 upregulation, ultimately sustaining mitochondrial function and cell viability in the presence of LATS2 overexpression. Altogether, the above data identify LATS2-Wnt/β-catenin/DRP1/mitochondrial division as a novel anticancer signaling pathway promoting cancer cell death, which might be an attractive therapeutic target for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Recently, PtIV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated PtIV prodrug that is among the most cytotoxic PtIV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC50 values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC50 values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective PtIV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes. [ABSTRACT FROM AUTHOR]

Abstract: The development of acquired EGFR‐TKI therapeutic resistance is still a serious clinical problem in the management of lung adenocarcinoma. Peroxisome proliferator activated receptor gamma (PPARγ) agonists may exhibit anti‐tumor activity by transactivating genes which are closely associated with cell proliferation, apoptosis, and differentiation. However, it remains not clear whether efatutazone has similar roles in lung adenocarcinoma cells of gefitinib resistant such as HCC827‐GR and PC9‐GR. It has been demonstrated by us that efatutazone prominently increased the mRNA and protein expression of PPARγ, liver X receptor alpha (LXRα),as well as ATP binding cassette subfamily A member 1 (ABCA1). In the presence of GW9662 (a specific antagonist of PPARγ) or GGPP (a specific antagonist of LXRα), efatutazone (40 μmol/L) restored the proliferation of both HCC827‐GR and PC9‐GR cells and obviously inhibited the increased protein and mRNA expression of PPAR‐gamma, LXR‐alpha, and ABCA1 induced by efatutazone. LXRα knockdown by siRNA (si‐LXRα) significantly promoted the HCC827‐GR and PC9‐GR cells proliferation, whereas incubation efatutazone with si‐LXRα restored the proliferation ability compared with the control group. In addition, combination of efatutazone and LXRα agonist T0901317 showed a synergistic therapeutic effect on lung adenocarcinoma cell proliferation and PPAR gamma, LXR A and ABCA1 protein expression. These results indicate that efatutazone could inhibit the cells proliferation of HCC827‐GR and PC9‐GR through PPARγ/LXRα/ABCA1 pathway, and synergistic therapeutic effect is achieved when combined with T0901317. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins. It has been thought as a promising target for many diseases, particularly cancer. Despite the potential applications of PRMT5 inhibitors in cancer treatment, very few of PRMT5i have been publicly reported. In this investigation, virtual screening and structure-activity relationship studies were carried out to discover novel PRMT5i, which finally led to the identification of a number of new PRMT5i. The most active compound, P5i-6, exhibited a considerable inhibitory potency against PRMT5 with an IC50 value of 0.57 μ m, and a high selectivity for PRMT5 against other tested PRMTs. It displayed a very good antiviability activity against two colorectal cancer cell lines, HT-29 and DLD-1, and one hepatic cancer cell line, HepG2, in a sensitivity assay against 36 different cancer cell lines. Western blot assays indicated that P5i-6 selectively inhibited the symmetric dimethylations of H4R3 and H3R8 in DLD-1 cells. Overall, P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract: Reaction‐diffusion (RD) is the most important inherent feature of living organisms, but it has yet to be used for developing biofunctional nanoparticles (NPs). Here we show the use of chirality to control the RD of NPs for selective inhibition of cancer cells. We observe that l‐phosphotyrosine ( l‐pY)‐decorated NPs (NP@ l‐pYs) are innocuous to cells, but d‐pY‐decorated ones (NP@ d‐pYs) selectively inhibit cancer cells. Our study shows that phosphatases, present in the culture and overexpressed on the cancer cells, dephosphorylate NP@ l‐pYs much faster than NP@ d‐pYs. Such a rate difference allows the NP@ d‐pYs to be mainly dephosphorylated on cell surface, and thus adhere selectively on the cancer cells, resulting in poly(ADP‐ribose)polymerase (PARP)‐hyperactivation‐mediated cell death. Without phosphate groups or with premature dephosphorylation before reaching cancer cells (as in the case of NP@ l‐pYs), the NPs are innocuous to cells. Moreover, NP@ d‐pYs exhibit even more potent activity than cisplatin for inhibiting platinum‐resistant ovarian cancer cells (e.g., A2780‐cis). As the first example of chirality controlling a RD process of NPs for inhibiting cancer cells, this work illustrates a fundamentally new way to develop nanomedicine based on RD processes and nanoparticles. [ABSTRACT FROM AUTHOR]

Highlights: [•] We demonstrated that irradiation induced MET overexpression and activation. [•] The aberrant MET signal mediated by HGF induced proliferation and radioresistance of NPC cells. [•] MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. [•] PHA-665752 suppressed the three downstream pathway of HGF/MET signal in a dose-dependent manner. [Copyright &y& Elsevier]

Activation of the Wnt signaling pathway has been implicated in the pathogenesis of many tumors as well as in leukemia. However, its role in myelodysplastic syndrome (MDS) is unknown. In this study, we employed methylation-specific PCR to examine the methylation status of six Wnt antagonist genes in 144 MDS patients and in the MDS cell line SKM-1. We also used real-time PCR to examine the expression of Wnt antagonist genes and Wnt pathway genes in the SKM-1 cell line after treatment with 5-aza-2′-deoxycytidine. We found that methylation of the gene promoters of each of the six genes were observed in MDS patients at the following methylation frequencies: 41 % for sFRP1, 89.6 % for sFRP2, 43.1 % for sFRP4, 50.7 % for sFRP5, 44.4 % for DKK-1, and 69.4 % for DKK-3. In the SKM-1 cell line, the gene promoters sFRP1, sFRP2, sFRP5, DKK-1, and DKK-3 were methylated, while sFRP4 was not methylated. Treatment of the SKM-1 cell line with 5-aza-2′-deoxycytidine induced re-expression of methylated Wnt antagonists and inactivation of the Wnt pathway. Survival analysis showed that methylation status of sFRP1, sFRP4, and sFRP5 was associated with worse survival in MDS and sFRP5 methylation also predicted a high risk of leukemia evolution ( P = 0.018). Our results indicate that epigenetic regulation of the Wnt pathway in MDS cell line, and the methylation status of Wnt antagonists predicts prognoses of MDS patients. [ABSTRACT FROM AUTHOR]

Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apcmin/+ mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apcmin/+/TR3−/− mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy. [ABSTRACT FROM PUBLISHER]

• Benzimidazole derivatives Rh-1 – Rh-3 were synthesized and characterized. • Rh-1 – Rh-3 are more selective for A549/DDP cells versus HL-7702 cells. • Rh-1 – Rh-3 show high antitumor activity. • Rh-1 – Rh-3 induce apoptosis via mitochondrial dysfunction pathway. Three new non-cisplatin analogs [Rh(BID1)(CH 3 OH)]·CH 3 OH (Rh-1), [Rh(BID2)(CH 3 OH)]·CH 3 OH (Rh-2) and [Rh(BID3)(CH 3 OH)]·2CH 3 OH (Rh-3) bearing benzimidazole derivatives (BID1–BID-3) were first prepared as potential anti-tumor compounds. The Rh-3 complex with 8-fluoro group in BID-3 ligand exhibited potential antiproliferative activity against multidrug-resistant human lung adenocarcinoma A549/DDP and cisplatin-resistant human ovarian cancer SK-OV-3/DDP cells, at most 5.0 fold more potent than Rh-1 , Rh-2 and cisplatin under the same conditions. Importantly, Rh-1 – Rh-3 are more selective for A549/DDP cells versus human normal liver HL-7702 cells. The Rh-2 and Rh-3 caused mitochondrial dysfunction was in the following order: Rh-3 > Rh-2. The different biological behavior of Rh-1 – Rh-3 may correlate with different 8-substituted groups in benzimidazole derivatives. [ABSTRACT FROM AUTHOR]

miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy. [ABSTRACT FROM AUTHOR]