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

21:28

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

21:28

PubMed articles on: Cardio-Oncology

Radiation Therapy-Induced Cardiac Toxicity

2023 May 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.

ABSTRACT

Radiation therapy is an important component in the treatment of cancer. It may play a role as an adjuvant, neoadjuvant, palliative, or definitive therapy, with or without concurrent chemotherapy. Radiation is most commonly delivered as a local/regional treatment by an external beam consisting of photons, electrons, protons, or heavy particles but may also be delivered via brachytherapy (where a sealed radiation source is placed adjacent to the target) or systemically via unsealed sources. The side effects of radiation therapy are a function of the tissues included in the radiation field. Treatment of diseases within the thoracic region, such as Hodgkin lymphoma, lung, and breast cancer, carries the risk of radiation-induced cardiovascular toxicity (RICT).

Side effects of therapeutic radiation to the heart and coronary vessels include pericarditis, coronary artery disease (CAD), arrhythmias, cardiomyopathy, valvular dysfunction, and heart failure. Pericarditis and pericardial effusions are potential short-term toxicities that may occur during or within the weeks following treatment. Long-term side effects may present in the months to years after radiation therapy, possibly as late as 20 years or more post-treatment. Late toxicities include CAD, valvular heart disease, and heart failure.

Major risk factors that increase the likelihood of RICT include higher radiation doses, adjuvant treatment with cardiotoxic chemotherapy, irradiation of the left side of the thorax, and the presence of pre-existing cardiovascular disease. Studies have correlated the mean dose of radiation received by various heart sub-structures to the incidence of major adverse cardiac events (MACE), such as hospitalization for heart failure, myocardial infarction, and even cardiac death. Given the importance of radiation therapy in treating cancer and the high prevalence of cardiovascular disease in Western populations, numerous preventive measures have been suggested and used in clinical practice, such as dose limitation, proton and particle therapy, conformal radiation therapy, and deep-inspiration breath-hold technique.

PMID:32119340 | Bookshelf:NBK554453

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PubMed articles on: Cardio-Oncology

The impact of tumor characteristics on cardiovascular disease death in breast cancer patients with CT or RT: a population-based study

Front Cardiovasc Med. 2023 May 9;10:1149633. doi: 10.3389/fcvm.2023.1149633. eCollection 2023.