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Synergistic anti‐tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21
Author(s) -
Mei Liufeng,
Chen Yicheng,
Wang Zhimeng,
Wang Jian,
Wan Jiali,
Yu Chunrong,
Liu Xin,
Li Wenhua
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13045
Subject(s) - tetrandrine , apoptosis , autophagy , chloroquine , pharmacology , cancer cell , cell culture , reactive oxygen species , protein kinase b , cancer research , biology , cancer , chemistry , immunology , biochemistry , genetics , malaria
Background and Purpose Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the C hinese medicinal herb S tephaniae tetrandrae , has a long history in C hinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. Experimental Approach Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT‐PCR assays were also used along with fluorescence microscopy and histochemical techniques.Key Results Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase‐3 but independent of Akt activity. Blockade of tetrandrine‐induced autophagy with 3‐methyladenine or bafilomycin‐A1 induced apoptosis in cancer cells. Lack of p21 protein (p21 −/− HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth.Conclusions and Implications The combinations of tetrandrine and chloroquine exhibited synergistic anti‐tumour activity, in vitro and in vivo . Our results suggest a novel therapeutic strategy for tumour treatment.