Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease; Department of Respiration, First Affiliated Hospital, Bengbu Medical College , Bengbu, Anhui Province, China.
Department of Medical Oncology, First Affiliated Hospital, Bengbu Medical College , Bengbu, Anhui Province, China.
Cancer Biol Ther. 2020 Aug 2;21(8):698-708. doi: 10.1080/15384047.2020.1763147. Epub 2020 Jun 3.
Non-small cell lung cancer (NSCLC) remains recalcitrant to effective treatment due to tumor relapse and acquired resistance. Cancer stem cells (CSCs) are believed to be one mechanism for relapse and resistance and are consequently considered promising drug targets. We report that chetomin, an active component of , blocks heat shock protein 90/hypoxia-inducible factor 1 alpha (Hsp90/HIF1α) pathway activity. Chetomin also attenuated sphere-forming, a stem cell-like characteristic, of NSCLC CSCs (at ~ nM range) and the proliferation of non-CSCs NSCLC cultures and chemoresistant sublines (at ~ μM range). At these concentrations, chetomin exerted a marginal influence on noncancerous cells originating from several organs. Chetomin markedly decreased tumor formation in a spontaneous lung cancer model, flank xenograft models, and a tumor propagation flank implanted model at doses that did not produce an observable toxicity to the animals. Chetomin blocked Hsp90/HIF1α pathway activity via inhibiting the Hsp90-HIF1α binding interaction without affecting Hsp90 or Hsp70 protein levels. This study advocates chetomin as a Hsp90/HIF1α pathway inhibitor and a potent, nontoxic NSCLC CSC-targeting molecule.
非小细胞肺癌（NSCLC）由于肿瘤复发和获得性耐药，仍然难以有效治疗。癌症干细胞（CSCs）被认为是复发和耐药的一种机制，因此被认为是有前途的药物靶点。我们报告称，雪胆素甲是 的一种活性成分，可阻断热休克蛋白 90/缺氧诱导因子 1α（Hsp90/HIF1α）通路活性。雪胆素甲还能减弱 NSCLC CSCs 的球体形成能力（在 nM 范围内）和非 CSCs NSCLC 培养物和耐药亚系的增殖（在 μM 范围内）。在这些浓度下，雪胆素甲对来自几个器官的非癌细胞的影响微不足道。雪胆素甲在自发性肺癌模型、侧翼异种移植模型和肿瘤传播侧翼植入模型中，以不产生明显毒性的剂量显著减少肿瘤形成，在这些剂量下，雪胆素甲不会影响 Hsp90 或 Hsp70 蛋白水平。这项研究主张雪胆素甲作为 Hsp90/HIF1α 通路抑制剂和一种有效、无毒的 NSCLC CSC 靶向分子。
