治疗癌症中双靶向小分子药物的策略，以克服药物抗性。
Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy.
发表日期：2023 Feb 24
作者：
Jing Ye, Junhao Wu, Bo Liu
来源：
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
摘要：
尽管针对人类癌症的靶向治疗有所进展，但由于药物耐受性出现，治愈癌症仍然是一个巨大的挑战。针对癌症靶向药物的各种潜在耐药机制最近揭示了双靶向治疗策略将是一个有吸引力的途径。与药物组合策略相比，一个同时调节两个可药理作用的靶标的药物通常显示出较少的不良反应和较低的毒性。因此，双靶向小分子已被广泛探索以克服癌症治疗中的耐药性。因此，在本文中，我们重点总结癌细胞的耐药机制，如增强药物外输、细胞死亡失调、DNA损伤修复和表观遗传改变。基于这些耐药机制，我们进一步讨论当前的双靶向小分子治疗策略以克服药物耐受性，这将为未来的癌症治疗开发更为复杂的机制和相关的双靶向药物提供新的思路。版权所有©2023 Elsevier B.V. 发布。
Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated of cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.Copyright © 2023. Published by Elsevier B.V.