Synergistic Effects of Epirubicin-Vorinostat-Pimozide Drug Cocktail on Proliferation, Stemness, Invasiveness, and Fatty Acid Metabolism in Breast Cancer Cells

IF 3.7 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
IUBMB Life Pub Date : 2025-04-30 DOI:10.1002/iub.70020
Thirukumaran Kandasamy, Shilpi Sarkar, Azar Zochedh, Thandavarayan Kathiresan, Siddhartha Sankar Ghosh
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Abstract

Chemotherapeutic treatments for breast cancer are often associated with severe toxicity due to the requirement of high concentrations of the drugs for efficacy. The combination of chemotherapy drugs along with repurposed drugs offers a promising strategy to enhance efficacy while reducing toxicity. However, the effectiveness of such combinations is likely to be hindered by improper metabolism of the drugs due to the sharing of the same metabolizing enzymes. In this study, we explored a novel approach to enhance the efficacy of Pimozide (repurposed drug) by combining it with chemotherapeutic drugs that utilize different metabolizing enzymes than Pimozide, thereby reducing metabolic load and toxicity. The Epirubicin-SAHA(Vorinostat)-Pimozide (ESP) combination emerged as highly synergistic, reducing the IC50 of Pimozide from 16.54 to 0.57 μM in MCF-7 cells and from 17.5 to 3.35 μM in MDA-MB-231 cells, representing a significant enhancement in efficacy. Mechanistic studies revealed increased intracellular reactive oxygen species (ROS) generation and activation of the intrinsic apoptosis pathway, as indicated by a 10-fold increase in the cleaved PARP levels. In MDA-MB-231 cells, there was also a 2-fold increase in p53 and a 10-fold increase in p21 expression, with a concomitant reduction in AKT signaling. Furthermore, the ESP combination reduced cancer stemness, invasiveness, fatty acid uptake, and lipid droplet accumulation, pointing to its broad impact on cancer cell survival and metabolism. These findings suggest that the ESP combination holds promise as an effective therapeutic strategy for breast cancer, with reduced toxicity and enhanced efficacy.

表柔比星-伏立诺他特-匹莫齐混合药物对乳腺癌细胞增殖、干性、侵袭性和脂肪酸代谢的协同作用
乳腺癌的化疗治疗往往伴随着严重的毒性,因为需要高浓度的药物才能有效。化疗药物与重新利用的药物联合使用提供了一种有希望的策略,以提高疗效,同时降低毒性。然而,由于共享相同的代谢酶,这种组合的有效性可能会受到药物代谢不当的阻碍。在本研究中,我们探索了一种新的方法,通过将其与使用不同代谢酶的化疗药物联合使用,从而降低代谢负荷和毒性,从而提高匹莫齐(再用途药物)的疗效。表柔比星- saha (Vorinostat)-Pimozide (ESP)联合用药具有高度协同作用,Pimozide在MCF-7细胞中的IC50从16.54 μM降低到0.57 μM,在MDA-MB-231细胞中的IC50从17.5 μM降低到3.35 μM,显著增强了疗效。机制研究表明,细胞内活性氧(ROS)的产生增加,内在凋亡途径的激活,如裂解PARP水平增加10倍所示。在MDA-MB-231细胞中,p53表达增加2倍,p21表达增加10倍,同时AKT信号传导减少。此外,ESP联合使用可降低肿瘤的干性、侵袭性、脂肪酸摄取和脂滴积聚,表明其对癌细胞存活和代谢有广泛的影响。这些发现表明,ESP联合治疗有望成为一种有效的乳腺癌治疗策略,具有降低毒性和提高疗效的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
IUBMB Life
IUBMB Life 生物-生化与分子生物学
CiteScore
10.60
自引率
0.00%
发文量
109
审稿时长
4-8 weeks
期刊介绍: IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant original research articles, reviews, and hypotheses in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.
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