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Cancer‐selective death of human breast cancer cells by leelamine is mediated by bax and bak activation
Author(s) -
Sehrawat Anuradha,
Kim SuHyeong,
Hahm EunRyeong,
Arlotti Julie A.,
Eiseman Julie,
Shiva Sruti S.,
Rigatti Lora H.,
Singh Shivendra V.
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22497
Subject(s) - biology , cancer research , programmed cell death , apoptosis , cancer , cancer cell , cancer stem cell , breast cancer , pharmacology , biochemistry , genetics
The present study is the first to report inhibition of breast cancer cell growth in vitro and in vivo and suppression of self‐renewal of breast cancer stem cells (bCSC) by a pine bark component (leelamine). Except for a few recent publications in melanoma, anticancer pharmacology of this interesting phytochemical is largely elusive. Leelamine (LLM) dose‐dependently inhibited viability of MDA‐MB‐231 (triple‐negative), MCF‐7 (estrogen receptor‐positive), and SUM159 (triple‐negative) human breast cancer cells in association with apoptotic cell death induction. To the contrary, a normal mammary epithelial cell line derived from fibrocystic breast disease and spontaneously immortalized (MCF‐10A) was fully resistant to LLM‐mediated cell growth inhibition and apoptosis induction. LLM also inhibited self‐renewal of breast cancer stem cells. Apoptosis induction by LLM in breast cancer cells was accompanied by a modest increase in reactive oxygen species production, which was not due to inhibition of mitochondrial electron transport chain complexes. Nevertheless, ectopic expression of manganese superoxide dismutase conferred partial protection against LLM‐induced cell death but only at a lower yet pharmacologically relevant concentration. Exposure of breast cancer cells to LLM resulted in (a) induction and/or activation of multidomain proapoptotic proteins Bax and Bak, (b) caspase‐9 activation, and (c) cytosolic release of cytochrome c . Bax and Bak deficiency in immortalized fibroblasts conferred significant protection against cell death by LLM. Intraperitoneal administration of LLM (7.5 mg/kg; 5 times/wk) suppressed the growth of orthotopic SUM159 xenografts in mice without any toxicity. In conclusion, the present study provides critical preclinical data to warrant further investigation of LLM. © 2016 Wiley Periodicals, Inc.