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Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies
ACS Pharmacology & Translational Science Pub Date : 2020-11-11 , DOI: 10.1021/acsptsci.0c00144
Shenouda G Eliaa 1 , Ahmed A Al-Karmalawy 2 , Rasha M Saleh 3 , Mohamed F Elshal 1
Affiliation  

Triple-negative breast cancers (TNBCs) comprise 10–15% of all breast cancers but with more resistance affinity against chemotherapeutics. Although doxorubicin (DOX) is the recommended first choice, it has observed cardiotoxicity together with apparent drug resistance. The anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition. In this study, we carried out molecular docking studies which revealed the potential blocking of the calmodulin receptor by EMP through its binding with similar crucial amino acids compared to its cocrystallized inhibitor (AAA) as a proposed mechanism of action. Moreover, combination of DOX with EMP showed a slightly lower cytotoxic activity against the MDA-MB-231 cell line (IC50 = 1.700 ± 0.121) compared to DOX alone (IC50 = 1.230 ± 0.131), but it achieved a more characteristic arrest in the growth of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in comparison to the control as determined by cell cycle analysis, and at the same time reached an increase in the total apoptosis percentage from 27.05- to 29.22-fold, compared to DOX alone as indicated by Annexin V-FITC apoptosis assay. Briefly, the aforementioned in vitro studies in addition to PCR of pro- and antiapoptotic genes (mTOR, p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of EMP combination with DOX which can reduce the required therapeutic dose of DOX in TNBC and eventually will decrease its toxic side effects (especially cardiotoxicity), along with decreasing the chemoresistance of TNBC cells to DOX treatment.

中文翻译:

Empagliflozin 和多柔比星通过干扰 mTOR 通路和抑制钙调蛋白协同抑制三阴性乳腺癌细胞的存活:体外和分子对接研究

三阴性乳腺癌 (TNBC) 占所有乳腺癌的 10-15%,但对化疗药物的耐药性更高。尽管多柔比星 (DOX) 是推荐的首选,但它已观察到心脏毒性和明显的耐药性。最近表明抗高血糖药物恩格列净 (EMP)在体外具有抗癌潜力及其先前报道的与钙调素抑制相关的心脏保护特性。在这项研究中,我们进行了分子对接研究,揭示了 EMP 通过与其共结晶抑制剂 (AAA) 相比与其类似的关键氨基酸结合作为拟议的作用机制,从而潜在地阻断了钙调蛋白受体。此外,与DOX的EMP组合显示针对MDA-MB-231细胞系稍低的细胞毒性活性(IC 50相比,单独DOX(IC = 1.700±0.121)50= 1.230 ± 0.131),但与细胞周期分析确定的对照相比,它在细胞生长方面实现了更具特征性的停滞,比单独使用 DOX 多 4.67 倍(仅 3.27 倍),同时如膜联蛋白 V-FITC 细胞凋亡测定所示,与单独的 DOX 相比,总细胞凋亡百分比从 27.05 增加到 29.22 倍。简而言之,除了对促凋亡和抗凋亡基因(mTOR、p21、JNK、Bcl2 和 MDR1)进行 PCR 外,上述体外研究表明 EMP 与 DOX 组合的化学增敏作用可以降低 TNBC 中所需的 DOX 治疗剂量和最终将减少其毒副作用(尤其是心脏毒性),同时降低 TNBC 细胞对 DOX 治疗的化学抗性。
更新日期:2020-12-12
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