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An autophagy-dependent cell death of MDA-MB-231 cells triggered by a novel Rhein derivative 4F

Liu, Yunfenga,*; Zhong, Yanpinga,*; Tian, Weib; Lan, Fub; Kang, Jiankanga; Pang, Huifenga; Hou, Huaxinb; Li, Danronga

doi: 10.1097/CAD.0000000000000820
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Triple negative breast cancer (TNBC) has very poor prognosis and no efficacious therapeutic options due to the absence of a validated molecular target. Therefore, novel therapeutic strategies against TNBC are urgently needed. Our team synthesized and screened a series of compounds derived from Rhein, of which 4F was selected for further analysis based on its ability to produce the vacuolated appearance of cells. Using Cell counting kit-8 assay, colony-formation assay, cell apoptosis and cell cycle assay, we compared the antitumor effects of 4F, Rhein and Cisplatin on a TNBC cell line MDA-MB-231 in vitro. The vacuoles in MDA-MB-231 cells were observed and analyzed by hematoxylin–eosin staining and transmission electron microscopy. Autophagy and apoptosis-related proteins including p62, Microtubule Light Chain 3 (LC3), Beclin-1 and Caspase-3 were determined by western blot. The tandem mRFP-GFP-LC3 Lentivirus was used for monitoring the maturation step of autophagosomes. Our data revealed that 4F had lower cytotoxicity to normal breast cell line MCF-10A as compared with positive drug Doxorubicin. Although 4F had better cytotoxicity than Rhein, it had no influence on cells apoptosis in 4F-treated cells. Accumulation of autolysosomes and autophagosomes was observed in 4F-treated MDA-MB-231 cells, accompanied by increased level of Beclin-1 protein. Enhanced autophagic flux was verified by higher ratio of LC3-II/LC3-I, the degradation of p62 protein and alteration in red and green fluorescence puncta. These findings suggested that the process of MDA-MB-231 cell death induced by 4F seemed rely mainly on autophagy rather than apoptosis. 4F may be an alternative drug candidate against TNBC and merits more exploration.

aLife Sciences Institute

bCollege of Pharmacy, Guangxi Medical University, Nanning, China

* Yunfeng Liu and Yanping Zhong contributed equally to this work.

Received 11 January 2019 Revised form accepted 23 May 2019

Correspondence to Huaxin Hou, Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China, Tel: +86 0771 5358131; fax: +86 0771 5350975; e-mail: houhuaxin@163.com

Correspondence to Danrong Li, Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China, Tel: +86 0771 5358131; fax: +86 0771 5350975; e-mail: danrongli@163.com

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