School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China.
Nutrients. 2023 May 10;15(10):2259. doi: 10.3390/nu15102259.
Doxorubicin (DOX) is a highly effective chemotherapeutic drug, but its long-term use can cause cardiotoxicity and drug resistance. Accumulating evidence demonstrates that p53 is directly involved in DOX toxicity and resistance. One of the primary causes for DOX resistance is the mutation or inactivation of p53. Moreover, because the non-specific activation of p53 caused by DOX can kill non-cancerous cells, p53 is a popular target for reducing toxicity. However, the reduction in DOX-induced cardiotoxicity (DIC) via p53 suppression is often at odds with the antitumor advantages of p53 reactivation. Therefore, in order to increase the effectiveness of DOX, there is an urgent need to explore p53-targeted anticancer strategies owing to the complex regulatory network and polymorphisms of the p53 gene. In this review, we summarize the role and potential mechanisms of p53 in DIC and resistance. Furthermore, we focus on the advances and challenges in applying dietary nutrients, natural products, and other pharmacological strategies to overcome DOX-induced chemoresistance and cardiotoxicity. Lastly, we present potential therapeutic strategies to address key issues in order to provide new ideas for increasing the clinical use of DOX and improving its anticancer benefits.
阿霉素（DOX）是一种高效的化疗药物，但长期使用会导致心脏毒性和耐药性。越来越多的证据表明，p53 直接参与 DOX 的毒性和耐药性。DOX 耐药的一个主要原因是 p53 的突变或失活。此外，由于 DOX 引起的 p53 非特异性激活会杀死非癌细胞，因此 p53 是降低毒性的热门靶点。然而，通过抑制 p53 来减少 DOX 诱导的心脏毒性（DIC）往往与 p53 重新激活的抗肿瘤优势相悖。因此，为了提高 DOX 的疗效，由于 p53 基因的复杂调控网络和多态性，迫切需要探索针对 p53 的抗癌策略。在这篇综述中，我们总结了 p53 在 DIC 和耐药性中的作用和潜在机制。此外，我们重点介绍了应用膳食营养素、天然产物和其他药理学策略来克服 DOX 诱导的化疗耐药性和心脏毒性的进展和挑战。最后，我们提出了潜在的治疗策略来解决关键问题，为提高 DOX 的临床应用和改善其抗癌效益提供新的思路。
