Recent studies have suggested that the lipid-lowering agent simvastatin holds great promise as a cancer therapeutic; it inhibits the growth of multiple tumors, including triple-negative breast cancer. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca²⁺ signaling, but the underlying mechanisms remain incompletely understood. Here we identify how Ca²⁺ signaling regulates the breast tumor cell response to doxorubicin and simvastatin. These two drugs inhibit cell survival while increasing apoptosis in two human breast cancer cell lines and five primary breast tumor specimens through the modulation of Ca²⁺ signaling. Signal transduction and functional studies revealed that both simvastatin and doxorubicin trigger persistent cytosolic Ca²⁺ release, thereby stimulating the proapoptotic BIM pathway and mitochondrial Ca²⁺ overload, which are responsible for metabolic dysfunction and apoptosis induction. Simvastatin and doxorubicin suppress the prosurvival ERK1/2 pathway in a Ca²⁺-independent and Ca²⁺-dependent manner, respectively. In addition, reduction of the Ca²⁺ signal by chelation or pharmacological inhibition significantly prevents drug-mediated anticancer signaling. Unexpectedly, a scratch-wound assay indicated that these two drugs induce rapid cell migration, while inhibiting cell invasion and colony formation in a Ca²⁺-dependent manner. Further, the in vivo data for MDA-MB-231 xenografts demonstrate that upon chelation of Ca²⁺, the ability of both drugs to reduce the tumor burden was significantly reduced via caspase-3 deactivation. Our results establish a calcium-based mechanism as crucial for executing the cell death process triggered by simvastatin and doxorubicin, and suggest that combining simvastatin with doxorubicin may be an effective regimen for the treatment of breast cancer.

中文翻译：

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Ca2 +信号传导的整合调节了乳腺肿瘤细胞对辛伐他汀和阿霉素的反应。

最近的研究表明，降脂药辛伐他汀作为癌症治疗剂具有广阔的前景。它抑制多种肿瘤的生长，包括三阴性乳腺癌。阿霉素和辛伐他汀诱导的细胞毒性与Ca ²⁺信号传导的调节有关，但其潜在机制仍不完全清楚。在这里，我们确定了Ca ²⁺信号传导如何调节乳腺肿瘤细胞对阿霉素和辛伐他汀的反应。这两种药物通过调节Ca ^2+，抑制细胞存活，同时增加了两个人类乳腺癌细胞系和五个原发性乳腺癌肿瘤标本的凋亡。信号。信号转导和功能研究表明，辛伐他汀和阿霉素都触发持续的胞质Ca ²⁺释放，从而刺激促凋亡的BIM途径和线粒体Ca ²⁺超负荷，这是代谢功能障碍和细胞凋亡诱导的原因。辛伐他汀和多柔比星抑制在钙的促存活ERK1 / 2途径²⁺非依赖性和Ca ²⁺依赖性的方式，分别。另外，Ca ^2+的还原通过螯合或药理学抑制作用的信号显着阻止了药物介导的抗癌信号传导。出乎意料的是，刮伤试验表明这两种药物诱导快速的细胞迁移，同时以Ca ²⁺依赖性方式抑制细胞侵袭和集落形成。此外，MDA-MB-231异种移植物的体内数据表明，Ca ²⁺螯合后，两种药物通过降低caspase-3的活性来降低肿瘤负荷的能力均显着降低。我们的研究结果建立了一种基于钙的机制，该机制对于执行辛伐他汀和阿霉素触发的细胞死亡过程至关重要，并表明将辛伐他汀与阿霉素联用可能是治疗乳腺癌的有效方案。