Datan Emmanuel, Minn Il, Xu Peng, He Qing-Li, Ahn Hye-Hyun, Yu Biao, Pomper Martin G, Liu Jun O
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
iScience. 2020 Sep 5;23(9):101536. doi: 10.1016/j.isci.2020.101536. eCollection 2020 Sep 25.
A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity and . Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.
癌症治疗中的一个主要障碍是肿瘤微环境所特有的缺氧诱导的化学抗性。雷公藤内酯醇是一种有效的真核转录抑制剂，具有强大的抗肿瘤活性。然而，其临床应用潜力受到毒性和水溶性的限制。为了解决雷公藤内酯醇的这些局限性，我们设计并合成了葡萄糖-雷公藤内酯醇缀合物（葡雷醇），并证明了它们的抗肿瘤活性。在此，我们鉴定出一种先导物，即具有改变的连接子结构的葡雷醇-2。葡雷醇-2在人血清中具有更高的稳定性，对癌细胞的选择性高于正常细胞，并且对癌细胞的效力增强。葡雷醇-2表现出持续的抗肿瘤活性，可延长前列腺癌转移动物模型的生存期。重要的是，我们发现葡雷醇-2在缺氧条件下对癌细胞的效力比在常氧条件下更强。总之，这项工作提供了一种有吸引力的葡雷醇药物先导物，并提出了一种通过将细胞毒性剂与葡萄糖缀合来克服化学抗性的可行策略。
