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.

PMID:37232184 | DOI:10.1161/CIRCRESAHA.122.322264

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PubMed articles on: Cardio-Oncology

Cardiotoxicity of targeted therapies in children with haematological malignancies and solid tumors

Anticancer Agents Med Chem. 2023 May 25. doi: 10.2174/1871520623666230525162147. Online ahead of print.

ABSTRACT

Cardiotoxicity represents an important acute or chronic adverse event of treatment modalities for childhood cancer. In the last two decades the emergence of novel cancer therapies has aimed to increase unaided or mostly in combination with conventional chemotherapy for the survival rates of pediatric cancer especially for those patients with relapsed and/or refractory disease. The use of emerging targeted therapies in combination with conventional chemotherapy is related to cardiovascular adverse events mostly reported in adults. The aim of our short review was to investigate the cardiotoxic side effects of targeted chemotherapeutic agents as monoclonal antibodies and small molecules in pediatric cancer patients.

PMID:37231721 | DOI:10.2174/1871520623666230525162147

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PubMed articles on: Cardio-Oncology

Corrigendum: D-dimer trends elaborate the heterogeneity of risk in hospitalized patients with COVID-19: a multi-national case series from different waves

Front Med (Lausanne). 2023 May 10;10:1205719. doi: 10.3389/fmed.2023.1205719. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fmed.2023.1103842.].

PMID:37234241 | PMC:PMC10208720 | DOI:10.3389/fmed.2023.1205719

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PubMed articles on: Cardio-Oncology

Preoptimisation in patients with acute obstructive colon cancer (PREOCC) - a prospective registration study protocol

BMC Gastroenterol. 2023 May 25;23(1):186. doi: 10.1186/s12876-023