Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells

Gao, Sumei; Li, Xiaoyan; Ding, Xia; Qi, Wenwen; Yang, Qifeng

doi:10.1111/j.1349-7006.2005.00057.x

Cited by 1,705 publications

(38 citation statements)

References 27 publications

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“…3I) suggests that, as an amphiphilic cation, it may directly enter the lysosomes and modulate pH, an effect similar to that seen with lysosomotropic agents [41]. This possibility has been proposed previously [42]. The dysfunction of lysosomal acidification and an increase in the organelle size is not likely due to the inhibition of NPC1 as another NPC1 inhibitor itraconazole did not change lysosomal size or pH in endothelial cells (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 63%

“…It has been proposed that CEP is a membrane interacting and stabilizing agent, and this effect may modulate the function of membrane proteins such as V-type ATPase on the lysosomes [55]. In support of this notion, CEP inhibited lysosome acidification in cancer cells and potentiated the effects of weak-base chemotherapy drugs by preventing sequestration of the drugs in the lysosomes [42]. In addition to its anticancer potentiating activity, CEP also showed several beneficial effects on cancer management.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu

Yang

Head³

et al. 2017

Cancer Letters

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Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Lyu

Yang

Head³

et al. 2017

Cancer Letters

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“…Cepharanthine is known as a membrane-interacting agent with membranestabilizing activity, and is widely used in Japan for the treatment of snake venom-induced hemolysis, nasal allergy, leukopenia induced by anticancer drugs and radiation therapy (6). We previously reported that cotreatment of cepharanthine with doxorubicin and vincristine resulted in the enhancement of cytotoxicity the anti-cancer drugs and the apoptosis induced in K562 cells (15). Cepharanthine also reversed paclitaxel resistance in MRP7-transfected cells (7).…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Ikeda

Vermeulen²,

Lau³

et al. 2011

Int J Oncol

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Abstract.Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabineresistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/GR cells were resistant to gemcitabine as well as paclitaxel and docetaxel but not carboplatin and irinotecan. The expression level of multidrug resistance protein 7 (MRP7) in A549/GR cells was higher than that in A549 cells, and the inhibitor of MRP7 by cepharanthine increased the sensitivity to gemcitabine in A549/GR cells. These findings indicate that cepharanthine reversed gemcitabine resistance. To determine predictive molecular markers of gemcitabine resistance for more effective treatment of these tumors, we performed PCR array. We identified that CDKN1A/p21, CYP3A5, microsomal epoxide hyrolase 1 (EPHX1) and ABCC6 (MRP6) were up-regulated >5-fold in A549/GR cells. Gemcitabine also induced the expression of p21 and CYP3A5 in A549 cells. A better understanding of the characterization and mechanism of the resistance to gemcitabine in A549/GR cells may help identify agents that reverse clinical gemcitabine resistance in NSCLC.

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“…Cepharanthine 89 showed that cepharanthine is an effective agent for the reversal of resistance in human chronic myelogenous leukemia cell line (K562). It has also enhanced the sensitivity to doxorubicin and VCR, and enhanced apoptosis induced by doxorubicin and VCR in K562 cells.…”

mentioning

confidence: 99%

Advances in plant-based inhibitors of P-glycoprotein

Zhou

James

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression of multidrug efflux pumps. P-glycoprotein (P-gp) belongs to the family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds out of the cell. An attractive therapeutic strategy for overcoming MDR is to inhibit the transport function of P-gp and thus, increase intracellular concentration of drugs. Recently, various types of P-gp inhibitors have been found and used in experiments. However, none of them has passed clinical trials due to their high side-effects. Hence, the search for alternatives, such as plant-based P-gp inhibitors have gained attention recently. Therefore, we give an overview of the source, function, structure and mechanism of plant-based P-gp inhibitors and give more attention to cancer-related studies. These products could be the future potential drug candidates for further research as P-gp inhibitors.

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Cepharanthine potently enhances the sensitivity of anticancer agents in K562 cells

Cited by 1,705 publications

References 27 publications

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Advances in plant-based inhibitors of P-glycoprotein

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