After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.

中文翻译：

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双重靶向 Mcl-1 和 Bcl-2 以克服宫颈癌和结肠癌的化疗耐药性。

在对化疗产生最初的积极反应后，癌症患者通常会产生耐药性并出现复发。我们之前的研究发现真核翻译起始因子 4E (eIF4E) 是克服化疗耐药性的关键靶点。在这项研究中，我们进一步深入研究了髓系细胞白血病 1 (Mcl-1)（一种 eIF4E 介导的靶标）在化疗耐药中的作用和治疗潜力。我们发现，化疗耐药的宫颈癌细胞中磷和总 eIF4E 以及 Mcl-1 的水平升高，但结肠癌细胞则没有升高。无论 Mcl-1 上调如何，Mcl-1 抑制剂 S64315 都会降低化疗耐药癌细胞中的 Mcl-1 水平，降低化疗耐药癌细胞的活力，并与化疗药物协同作用。与单独抑制任一靶标相比，采用遗传和药理学方法联合抑制 Mcl-1 和 B 细胞淋巴瘤 2 (Bcl-2) 会导致存活率显着更大幅度的下降。S64315 和 Bcl-2 抑制剂的组合可减少化疗耐药宫颈癌和结肠癌模型中的肿瘤生长，且不会对小鼠产生一般毒性。与单独使用 S64315 或 Venetoclax 相比，这种组合还延长了总生存期。我们的研究强调了同时抑制 Mcl-1 和 Bcl-2 在化疗耐药癌症中的治疗潜力，并为启动临床试验研究 S64315 和 Venetoclax 联合治疗晚期结肠癌和宫颈癌提供了理论依据。