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

机译：双击代谢调制器LDCA协同增强促进的多柔比星，以选择性地打击癌症相关的标志

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摘要

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：常规化疗引起显著的毒性，导致严重的副作用;因此，为了应对这种有效的策略是使用的是有动作的耐药性无关机制药物的组合。多柔比星，一种广泛使用的化学治疗药物，具有不利的副作用;因此，它是降低其毒性，提高其治疗方案是至关重要的。癌细胞从极其正常细胞不同相对于它们的代谢和代谢使用调节剂的预期近侧补偿癌症的各种表现形式。在这项研究中，联合使用阿霉素与双命中代谢调节剂，LDCA，与公设，这一巧妙的癌细胞靶向将发挥有力的治疗效果。结果表明，该组合协同增强的生长抑制和通过募集胱天蛋白酶级联，限制迁移，并消除黑色素瘤细胞的克隆形成潜力生长诱导线粒体介导的细胞凋亡。有趣的是，组合特别挫伤黑素瘤细胞生存力，但是幸免正常人群;这表明其毒性低轮廓。此外，在小鼠黑色素瘤的临床前模型中，联合治疗肿瘤挫败生长动力学抑制致癌进展，从而加剧存活。全面，我们已经证明，在联合疗法的扩大章阿霉素和LDCA的组合有前途的治疗潜力。

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  • 来源
    《RSC Advances》 |2017年第84期|共12页
  • 作者

    Saha Suchandrima; Ghosh Monisankar; Dutta Samir Kumar;

  • 作者单位

    CSIR Indian Inst Chem Biol Drug Dev Diagnost &

    Biotechnol 4 Raja SC Mullick Rd Kolkata 700032 W Bengal India;

    CSIR Indian Inst Chem Biol Drug Dev Diagnost &

    Biotechnol 4 Raja SC Mullick Rd Kolkata 700032 W Bengal India;

    CSIR Indian Inst Chem Biol Drug Dev Diagnost &

    Biotechnol 4 Raja SC Mullick Rd Kolkata 700032 W Bengal India;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;
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