Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

Mei, Liufeng; Chen, Yi-Cheng; Wang, Zhimeng; Wang, Jian; Wan, Jianfeng; Yu, Chunrong; Liu, Xin; Li, Wenhua

doi:10.1111/bph.13045

Cited by 54 publications

(36 citation statements)

References 61 publications

(82 reference statements)

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“…This may explain why DU145 cells exhibited the highest sensitivity towards Tet in all of the 11 cell lines tested (1). It has been reported that CQ enhances the anti-tumor effects in cancer cells (19). The results of the present study indicated that lysosomal pH is able to affect Tet-induced cell death.…”

Section: Discussionsupporting

confidence: 57%

Tetrandrine triggers an alternative autophagy in DU145 cells

2017

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Abstract. Tetrandrine (Tet), a potent lysosomal inhibitor, blocks autophagic flux and induces cancer cell death. Previously, the present authors identified the prostate cancer cell line DU145 to exhibit high sensitivity towards Tet in 11 cancer cell lines. In the present study, autophagy in Tet-treated DU145 cells was investigated. Similar to other cell lines, such as PC-3 and 786-O cells, Tet neutralized the acidity of lysosome and blocked autophagy in DU145 cells. However, Tet failed to induce microtubule-associated protein 1 light chain 3 (LC3) conversion in DU145 cells. By contrast, it was observed by transmission electron microscopy that Tet induced an accumulation of autophagosomes in the cytoplasm. These contrasting results indicated that Tet triggered an LC3-independent autophagy in DU145 cells. Alkalizing lysosome with chloroquine enhanced Tet-induced cell death. The results of the present study indicated that detection of autophagy in tumor cells may assist in selecting lysosome inhibitors for chemotherapy treatment in prostate cancer. Introduction Tetrandrine (Tet), a natural product isolated fromStephania tetrandra, has been reported to be an anti-tumor and anti-inflammatory drug (1-8). Previously, the present authors have demonstrated that Tet induces cell death in 11 cancer cell lines (1). Tet directly neutralizes the lysosomal acidity, blocks the autophagic flux in the degradation step and causes energetic impairment, which eventually results in cell death (1). By contrast, Tet also acts as an autophagy agonist by inducing the synthesis of reactive oxygen species (3,4,9-11), indicating that Tet may function as a multi-target drug to regulate autophagy in cancer cells. Regardless of the Tet target, the present authors and other groups have previously consistently observed that Tet increases the number of autophagosomes, levels of microtubule-associated protein 1 light chain 3, type II (LC3-II) and the number of enhanced green fluorescent protein-LC3 puncta in cancer cells (1,3,9). DU145, a commonly used prostate cancer cell line for research, is different from PC-3 and LNCaP cells in terms of autophagy regulation (12). As alternative transcripts of autophagy related 5 (ATG5) lack one or two exons in DU145 cells, and this causes the autophagy pathway to be genetically impaired (12). By contrast, DU145 cells exhibited the highest sensitivity to Tet in all of the 11 cancer cell lines that were previously tested by the authors of the present study (1), implying that impairment in autophagy may increase Tet-induced cell death. In order to investigate the role of autophagy on Tet-induced cell death in DU145 cells, the ultrastructural changes following Tet treatment were observed by transmission electron microscopy (TEM). Notably, Tet treatment triggered an accumulation of autophagosomes in this cell line, indicating that alternative autophagy was involved. Materials and methodsTetrandrine and other reagents. Tet (Santa Cr uz Biotechnology, Inc., Dallas, TX, USA) was dissolved as previously described (1)....

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Section: Discussionsupporting

confidence: 57%

Tetrandrine triggers an alternative autophagy in DU145 cells

2017

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“…STOCK1N-35874 is a cytotoxic quinoline alkaloid that inhibits the DNA enzyme topoisomerase, which is isolated from the bark and stem of Camptotheca acuminata (39). STOCK1N-35874 showed marked anticancer activity in preliminary clinical trials, and its analogues have been used in cancer chemotherapy (40,41). 5182598 is considered to be an important anticancer drug from the group of benzylisoquinoline alkaloids (42).…”

Section: Discussionmentioning

confidence: 99%

Genomic profiling screens small molecules of metastatic prostate carcinoma

Xu¹,

Sun²

2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the pathogenesis of metastatic prostate carcinoma, to find the metabolic pathways changed in the disease and to screen out the potential therapeutic drugs. GSE38241 was downloaded from Gene Expression Omnibus; the Geoquery package was applied to preprocessed expression profiling, and the differentially-expressed genes (DEGs) were selected with limma (linear regression model packages). Next, WikiPathways cluster analysis was performed for DEGs on a Gene Set Analysis Toolkit V2 platform, and DEGs with hypergeometric algorithms were calculated through gene set enrichment analysis. A total of 1,126 DEGs were identified between the normal prostate and metastatic prostate carcinoma. In addition, KPNA4, SYT1, PLCB1, SPRED1, MBNL2, RNF165, MEF2C, MBNL1, ZFP36L1 and CELF2, were found to be likely to play significant roles in the process of metastatic prostate carcinoma. The small molecules STOCK1N-35874 and 5182598 could simulate the state of normal cells well, while the small molecules MS-275 and quinostatin could simulate the state of metastatic prostate carcinoma cells. In conclusions, the small molecules STOCK1N-35874 and 5182598 were identified to be good potential therapeutic drugs for the treatment of metastatic prostate carcinoma, while the two small molecules MS-275 and quinostatin could cause metastatic prostate carcinoma.

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“…A number of studies have suggested that CQ can inhibit autophagy through the prevention of lysosome acidification, and subsequently, the inhibition of autophagosome-lysosome fusion, to block the degradation of autolysosomes at the last step of autophagy (8,9). Previous studies have indicated that CQ exhibited an antitumor effect on several types of cancer, including glioblastoma (10,11), hepatocellular carcinoma (12), breast cancer (13), prostate cancer (14) and pancreatic cancer (15), which prompts us to hypothesize that CQ may be able to influence the growth of esophageal carcinoma through the modulation of autophagy. Therefore, the aim of the present study is to explore the antitumor effect of CQ on the esophageal squamous carcinoma cell line EC109, and the potential mechanism for this effect.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells inï¿½vitro

Cai

et al. 2017

Oncol Lett

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Abstract. Esophageal carcinoma is a malignancy that severely threatens human health, with a high incidence rate and a low 5-year survival rate. Resistance to chemotherapy frequently emerges during its treatment, partly due to the induction of autophagy. Therefore, targeting autophagy may be a promising therapeutic approach for the treatment of esophageal carcinoma. In the present study, it was investigated how chloroquine (CQ) can influence the growth ability and biological behaviors of EC109 esophageal squamous carcinoma cells in vitro, as well as the potential molecular mechanisms behind its activity. It was demonstrated that CQ could suppress the growth and proliferation of EC109 cells in a time-and dose-dependent manner; migration and colony formation abilities were also inhibited by CQ. Furthermore, subsequent to the exposure to CQ, the number of autophagosomes was clearly increased in EC109 cells overexpressing green fluorescent protein tagged-light chain (LC)3 when observed by fluorescence microscopy. Protein expression of the endogenous autophagy markers LC3-II and p62 was elevated subsequent to CQ treatment, whereas the expression of proteins from the protein kinase B/mechanistic target of rapamycin target of rapamycin pathway was inhibited. This suggested that CQ could induce the formation of autophagosomes in the initiation of autophagy, but inhibit the degradation of autophagosomes in a later stage of autophagy. The overall effect was that autophagic cell death was activated by CQ, as confirmed by flow cytometry. Overall, the anticancer effect of chloroquine on EC109 was revealed to be mediated through modulating autophagy, and this may produce promising therapeutic benefits for esophageal carcinoma.

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Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

Cited by 54 publications

References 61 publications

Tetrandrine triggers an alternative autophagy in DU145 cells

Tetrandrine triggers an alternative autophagy in DU145 cells

Genomic profiling screens small molecules of metastatic prostate carcinoma

Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells inï¿½vitro

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