Cyclic nucleotide phosphodiesterases (PDEs), through the degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. PDE10A is able to hydrolyze both cAMP and cGMP. Its high expression in medium spiny neurons of the human striatum has led to the development of several PDE10A inhibitors with the intent to treat various psychiatric/neurodegenerative disorders, such as schizophrenia and Huntington's disease. Our previous study has reported the upregulation of PDE10A expression in failing hearts and demonstrated the protective effects of PDE10A deficiency/inhibition against cardiac hypertrophy, fibrosis, and dysfunction in mouse models of heart failure. Doxorubicin (DOX) is an effective chemotherapeutic agent against a variety of cancers. While its therapeutic utility is limited by the development of dose-dependent cardiotoxicity. In the current study, we aim to determine the role of PDE10A in cancer and cardiotoxicity induced by DOX. We found that PDE10A inhibition or deficiency alleviated DOX-induced cardiotoxicity in vivo, as well as cardiac myocyte (CM) death and atrophy in vitro. In ovarian cancer cells, PDE10A inhibition induced cell death and reduced cell proliferation; as well as potentiated the effect of DOX on antagonizing cancer cells. Interestingly, in nude mice with ovarian cancer xenografts, PDE10A inhibition attenuated ovarian tumor growth while protected DOX-induced cardiotoxicity. RNAseq and bioinformatics analysis uncovered a number of PDE10A-regulated signaling pathways and cellular processes involved in DOX-induced cardiotoxicity. Mechanistic studies further revealed that PDE10A regulates CM death and atrophy via different mechanistic actions: regulating CM death via a cGMP-dependent while cAMP-independent mechanism; and regulating CM atrophy via a mechanism dependent on both cGMP and cAMP. Several PDE10A inhibitors have been tested in humans and successfully passed phase I clinical trials for safety. Thus, our findings suggest that PDE10A may be a safe "druggable" target for cancer therapy by simultaneously preventing DOX-induced cardiotoxicity and antagonizing tumor growth.
Keywords: Cardio-oncology; Ventricular remodeling.