p53 at the Crossroads between Doxorubicin-Induced Cardiotoxicity and Resistance: A Nutritional Balancing Act

Abstract

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.

Comparative Studies of Resveratrol, Oxyresveratrol and Dihydrooxyresveratrol on Doxorubicin-Treated Lung Cancer Cells

“…However, many metastases still contain high levels of E-cadherin. E-cadherin expression can contribute to either tumor-suppressing or tumor-promoting processes [47][48][49]. In this study, DOX decreased E-cadherin expression in dose-dependent manner.…”

“…DOX induced apoptosis in H9c2 cells. DOX induced apoptosis of cardiomyocytes, H9c2 cells, via p53 upregulated modulator of apoptosis [47,48]. In Figure 3, compared to a DOX alone or simultaneous RES (or RES analogue) exposure, p53 expression was significantly increased in DOX + RES group and the highest increase was found in DOX + Oxy-RES group.…”

Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations

“…While Dox is designed to tarnish cellular replication and prompt p53's pro-apoptotic action in the neoplastic cell population, in DIC, Dox-treated cardiac tissues demonstrate impaired vital gene expression, DNA damage, and dysregulated p53, among other complications [21,22]. In this notion, genetic and pharmacologic inhibition of p53 have been shown to attenuate acute DIC [23][24][25][26][27]; however, disrupted p53 activity has been associated with exacerbated cardiac dysfunction in animal models [22] and is also a feature of Dox-resistant tumor cells [28], suggesting a selectivity challenge for p53 targeting therapeutic strategies.…”

“…In addition, activated ATM and ATR interact with the CHK proteins to stabilize p53, which upregulates cell cycle inhibitors and checkpoint activators. If DSBs are not repaired, p53's continuous activity will eventually upregulate the molecular trigger of apoptosis-BAX; BAM; and PUMA (28). The DDR package devotes two separate repair mechanisms for DSBs.…”

A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines

“…It has been found that p53 is overexpressed in cardiomyocytes and can promote apoptosis through transcriptional activation into the nucleus ( Wang et al, 2013 ). Conversely, inhibition of p53 activity promotes apoptosis in cardiomyocytes at the later stages of Dox treatment ( Guo et al, 2023 ). The expression and regulation of Bcl-2 family genes have a decisive influence on the occurrence of apoptosis, among which Bax and Bcl-2 have an important role in the regulation of mitochondrial apoptosis ( Qi et al, 2022 ).…”