Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor
Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor
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天然产物川楝素作为新型 PI3K 抑制剂逆转人乳腺癌细胞对阿霉素的耐药性
DOI：
10.1016/j.bcp.2018.03.022
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发表时间：
2018-06-01
影响因子：
5.8
通讯作者：
Chen Yan
中科院分区：
文献类型：
--
作者：
Wang Kai;Shan Yating;Chen Yan
阿霉素（ADM）是临床治疗乳腺癌的常用药物。然而，某些乳腺癌类型或反复接触阿霉素的乳腺癌会对阿霉素产生强烈的耐药性，从而限制了其临床疗效。在本研究中，我们首次发现川楝素（TSN），一种从传统中药川楝子中提取的三萜类化合物，可以成功逆转人乳腺癌细胞的阿霉素耐药性。免疫荧光和高效液相色谱分析表明，TSN促进阿霉素在乳腺癌细胞中的积累，尤其是在细胞核中。TSN可显著降低ABCB 1的表达。然后我们发现TSN能够抑制阿霉素诱导的Akt磷酸化，这可能是由于PI 3 K催化亚基P110 α和P110 β的下调以及DNA-PKcs的抑制。重要的是，TSN对PI 3 K P110 α和P110 β表达的抑制作用在乳腺癌细胞中特异性观察到，但在正常人细胞中未观察到。TSN能显著增强ADM对4 T1乳腺癌模型的抑瘤作用，抑瘤率接近90%。因此，TSN可用作新型PI 3 K抑制剂来逆转乳腺癌耐药性。ADM和TSN的联合应用可能代表了一种有用的人类乳腺癌治疗策略。
Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus. Furthermore, TSN could significantly reduce ABCB1 expression. We then found that TSN was capable of suppressing adriamycin-induced Akt phosphorylation, probably due to downregulation of the PI3K catalytic subunits P110 alpha and P110 beta, and inhibition of DNA-PKcs. Importantly, the inhibitory effect of TSN on PI3K P110 alpha and P110 beta expression was specifically observed in breast cancer cells but not in normal human cells. Moreover, TSN significantly potentiated the anti-cancer effect of ADM in the 4T1 breast cancer model and its inhibition rate was nearly 90%. Thus, TSN could be used as a novel PI3K inhibitor to reverse breast cancer resistance. The combination of ADM and TSN may represent a useful strategy for human breast cancer therapy.