Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers.
Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers.
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DOI：
10.1038/cddiscovery.2017.9
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发表时间：
2017
影响因子：
7
通讯作者：
Iyer AK
中科院分区：
文献类型：
--
作者：
Kaushik V;Azad N;Yakisich JS;Iyer AK
乳腺癌是女性中第二常见的癌症，在癌症相关死亡中仅次于肺癌。它是一种异质性疾病，根据激素受体和/或人表皮生长因子受体2（HER 2）的存在或不存在，有几种亚型。激素受体阳性和HER 2富集的癌症可以使用激素和HER 2靶向治疗，如曲妥珠单抗或拉帕替尼。然而，三阴性乳腺癌（TNBC）不表达任何受体，因此对大多数靶向治疗具有抗性，细胞毒性化疗是治疗TNBC的唯一可行选择。最近，强心苷（CG）已成为潜在的抗癌药物，赋予他们的抗增殖作用，通过靶向多个途径。在这项研究中，我们的目的是评估两种天然存在的CG，Convallatoxin（CT）和Peruvoside（PS）对ER+和TNBC细胞的抗癌作用。CT和PS显示对MCF-7细胞的剂量和时间依赖性细胞毒性作用，这进一步得到了药物处理后集落形成丧失的支持。CT和PS将MCF-7细胞阻滞在G 0/G1期，并降低了MCF-7衍生的乳腺球的活力（MTT）。有趣的是，虽然CT和PS以剂量和时间依赖性方式在来自高加索人（MDA-MB-231细胞）和非洲裔美国人（MDA-MB-468细胞）的TNBC细胞中赋予细胞死亡，但与TNBC MDA-MB-231细胞相比，药物在MDA-MB-468中更有效。两种药物均显著抑制MCF-7和MDA-MB-468细胞的迁移和侵袭。对细胞内途径的评估表明，两种药物都能够调节两种细胞类型中的几种关键细胞途径，如EMT、细胞周期、增殖和细胞死亡。我们的数据表明，CG在乳腺癌治疗中特别是在靶向来自非洲裔美国人的TNBC方面具有很好的作用，并为进一步研究这类药物的抗癌潜力提供了动力。
Breast cancer is second most prevalent cancer in women, and the second only to lung cancer in cancer-related deaths. It is a heterogeneous disease and has several subtypes based on the presence or absence of hormone receptors and/or human epidermal growth factor receptor 2 (HER2). Hormone receptor-positive and HER2-enriched cancers can be targeted using hormone and HER2-targeting therapies such as trastuzumab or lapatinib. However, triple-negative breast cancers (TNBCs) do not express any of the receptors and therefore are resistant to most targeted therapies, and cytotoxic chemotherapies are the only viable option available for the treatment of TNBCs. Recently, cardiac glycosides (CGs) have emerged as potential anticancer agents that impart their antiproliferative effect by targeting multiple pathways. In this study our aim was to evaluate anticancer effects of two naturally occurring CGs, Convallatoxin (CT) and Peruvoside (PS), on ER+ and TNBCs cells. CT and PS demonstrated dose- and time-dependent cytotoxic effect on MCF-7 cells, which was further supported by loss of colony formation on drug treatment. CT and PS arrested MCF-7 cells in the G0/G1 phase and reduced the viability of MCF-7-derived mammospheres (MMs). Interestingly, while CT and PS imparted cell death in TNBCs cells from both Caucasians (MDA-MB-231 cells) and African Americans (MDA-MB-468 cells) in a dose- and time-dependent manner, the drugs were much more potent in MDA-MB-468 as compared with TNBC MDA-MB-231 cells. Both drugs significantly inhibited migration and invasion of both MCF-7 and MDA-MB-468 cells. An assessment of intracellular pathways indicated that both drugs were able to modulate several key cellular pathways such as EMT, cell cycle, proliferation and cell death in both cell types. Our data suggest a promising role for CGs in breast cancer treatment specifically in targeting TNBCs derived from African Americans, and provides impetus for further investigation of the anticancer potential of this class of drugs.