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The dual-hit metabolic modulator LDCA synergistically potentiates doxorubicin to selectively combat cancer-associated hallmarks

机译：双重打击的代谢调节剂LDCA协同增强阿霉素以选择性地对抗癌症相关标志

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Conventional chemotherapy induces significant toxicity, leading to serious side effects; thus, an effective strategy to counter this would be to use a combination of drugs that have unrelated mechanisms of action and drug resistance. Doxorubicin, a widely used chemotherapeutic drug, has adverse side effects; thus, it is crucial to reduce its toxicity to improve its therapeutic regimen. Cancer cells vitally differ from normal cells with respect to their metabolism, and the use of metabolic modulators is expected to proximally compensate the various manifestations of cancer. In this study, doxorubicin was used in combination with a dual-hit metabolic modulator, LDCA, with the postulation that this adroit targeting of cancer cells would exert potent therapeutic effects. The results demonstrated that this combination synergistically enhanced the growth inhibition and induced mitochondria-mediated apoptosis by recruiting the caspase cascade, restricting migration, and obviating the clonogenic outgrowth potential of melanoma cells. Interestingly, the combination specifically dampened melanoma cell viability, but spared the normal population; this suggested its low toxicity profile. Furthermore, in the preclinical model of murine melanoma, combination treatment thwarted tumor growth kinetics to restrain oncogenic progression, thus accentuating survival. Comprehensively, we have demonstrated the promising therapeutic potential of the combination of doxorubicin and LDCA in the expanding chapter of combinatorial therapy.
机译：常规化学疗法会产生明显的毒性，导致严重的副作用。因此，针对此问题的有效策略将是使用作用机制和耐药性无关的药物组合。阿霉素是一种广泛使用的化疗药物，具有不良副作用。因此，降低其毒性以改善其治疗方案至关重要。癌细胞在新陈代谢方面与正常细胞完全不同，因此预期使用代谢调节剂可以在近端补偿癌症的各种表现。在这项研究中，阿霉素与双重打击的代谢调节剂LDCA结合使用，假定这种针对癌细胞的机敏将发挥有效的治疗作用。结果表明，该组合通过募集半胱天冬酶级联反应，限制迁移并消除了黑色素瘤细胞的克隆形成增生潜能，从而协同增强了生长抑制并诱导了线粒体介导的凋亡。有趣的是，该组合特别抑制了黑色素瘤细胞的活力，但幸免了正常人群。这表明其毒性较低。此外，在鼠类黑色素瘤的临床前模型中，联合治疗阻碍了肿瘤的生长动力学，以抑制致癌进展，从而提高了生存率。综上所述，我们已经在组合疗法的扩展篇章中证明了阿霉素和LDCA组合的有希望的治疗潜力。

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