Cancer-selective death of human breast cancer cells by leelamine is mediated by bax and bak activation.
Cancer-selective death of human breast cancer cells by leelamine is mediated by bax and bak activation.
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DOI：
10.1002/mc.22497
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发表时间：
2017-02
影响因子：
4.6
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
--
作者：
Sehrawat, Anuradha;Kim, Su-Hyeong;Hahm, Eun-Ryeong;Arlotti, Julie A.;Eiseman, Julie;Shiva, Sruti S.;Rigatti, Lora H.;Singh, Shivendra V.
本研究首次报道了松树皮成分（leelamine）在体外和体内抑制乳腺癌细胞生长以及抑制乳腺癌干细胞（bCSC）的自我更新。除了最近发表的几篇关于黑色素瘤的文章外，这种有趣的植物化学物质的抗癌药理学在很大程度上是难以捉摸的。 Leelamine (LLM) 剂量依赖性地抑制 MDA-MB-231（三阴性）、MCF-7（雌激素受体阳性）和 SUM159（三阴性）人乳腺癌细胞的活力，并与细胞凋亡诱导相关。相反，源自纤维囊性乳腺疾病并自发永生化的正常乳腺上皮细胞系（MCF-10A）完全抵抗LLM介导的细胞生长抑制和凋亡诱导。 LLM 还抑制乳腺癌干细胞的自我更新。 LLM 在乳腺癌细胞中诱导细胞凋亡伴随着活性氧产生的适度增加，这并不是由于线粒体电子传递链复合物的抑制所致。然而，锰超氧化物歧化酶的异位表达对 LLM 诱导的细胞死亡提供了部分保护，但仅限于较低但药理学相关的浓度。将乳腺癌细胞暴露于 LLM 会导致 (a) 多域促凋亡蛋白 Bax 和 Bak 的诱导和/或激活，(b) caspase-9 激活，以及 (c) 细胞色素 c 的胞质释放。 Bax and Bak deficiency in immortalized fibroblasts conferred significant protection against cell death by LLM. Intraperitoneal administration of LLM (7.5 mg/kg; five times/week) 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.
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; five times/week) 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.
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影响因子：
3.8
作者：
Chandra-Kuntal, Kumar;Lee, Joomin;Singh, Shivendra V.
通讯作者：
Singh, Shivendra V.
影响因子：
--
作者：
Renault TT;Chipuk JE
通讯作者：
Chipuk JE
影响因子：
11.2
作者：
Choi, S;Singh, SV
通讯作者：
Singh, SV
DOI：
10.1073/pnas.0932692100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Sorlie, T;Tibshirani, R;Botstein, D
通讯作者：
Botstein, D
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Ward, Elizabeth
通讯作者：
Ward, Elizabeth