PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Abstract

BACKGROUND: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. METHODS: We used global PDE10A KO (knockout) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. RESULTS: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA- (protein kinase A) and cGMP/PKG-dependent signaling. CONCLUSIONS: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations

“…Since renal inflammation can arise from CP-induced oxidative stress and apoptosis, PDE emergence as a nephrotoxic mediator further rationalizes PV's protective effects, given precedents of PDE inhibition managing inflammatory diseases including COPD, IBD, psoriasis, and CNS inflammation [38,39]. It has been reported that inhibitors of PDE10 have potential therapeutic effects in several diseases, including neurological diseases [14] and cardiotoxicity [40].…”

Recent progress in the role of endogenous metal ions in doxorubicin-induced cardiotoxicity

“…Similarly, DIC can be alleviated by activating some classical signaling pathways such as cAMP/PKA/SIRT1 (Hu et al, 2020), or AKT/SIRT3/SOD2 (Liu et al, 2022). Recently, some potential DIC therapeutic targets have been newly discovered, such as PDE10A (Chen et al, 2023), Sestrin 2 (Wang et al, 2022a), FAM134B (Qu et al, 2022), TFEB (Chen et al, 2022), etc., which play a cardioprotective role in reducing apoptosis, improving cardiac function, reducing oxidative stress and endoplasmic reticulum stress, and promoting autophagy.…”

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

“…PDE10A deficiency or inhibition reduces the apoptosis, malfunction, and atrophy caused by DOX. Recent findings suggest that inhibiting PDE10A attenuates DOX-induced cardiotoxicity and prevents cancer growth, and thus could be a promising strategy in cancer therapy [157,158].…”