A Similar Metabolic Profile Between the Failing Myocardium and Tumor Could Provide Alternative Therapeutic Targets in Chemotherapy-Induced Cardiotoxicity

摘要

Chemotherapy-induced cardiotoxicity (CIC) is an emerging clinical problem with significant healthcare costs and no preventative therapies (1, 2). Identifying selective therapeutic targets in CIC is difficult, in part, because the mechanisms of drug toxicity vary between chemotherapeutics. For example, cardiotoxicity can be acute or chronic, transient or permanent, and can affect myocardial contractility, cardiomyocyte conduction or the myocardial vascular system (3). Thus, candidate CIC therapies would need to target many features involved in cardiac dysfunction, and additionally should not prevent chemotherapy-mediated tumor regression. Although most would agree that investing in new therapies that specifically target the tumor, while not affecting other normal tissues, including the heart would be ideal, this approach is currently impractical, as even the most selective cancer therapies have been associated with cardiotoxicity (1). For example, Bcr-Abl kinase is a specific gene fusion that causes chronic myeologenous leukemia (CML) (4), and although Bcr-Abl kinase inhibitors, including imatinib mesylate are effective in treating CML (5), they are also associated with cardiotoxicity in pre-clinical animal studies and patients (6), suggesting that alternative adjuvant therapies that can prevent, limit or improve CIC need to be developed. The most commonly used preventative therapy for CIC is dexrazoxane (7), and although dexrazoxane has shown some benefit in preventing CIC (7), it has also been associated with prevention of chemotherapy-induced tumor regression (8), and increased incidence in the development of certain types of cancer in pediatric patients (9, 10). In addition, current treatment guidelines for patients diagnosed with CIC often result in discontinuation of the chemotherapy (regardless of the tumor responsiveness) and initiation into standard heart failure treatment regimes (which include β-blockers and angiotensin inhibitors) (11). In both options, for either prevention or treatment of CIC, the myocardium appears to have precedence over the tumor, with patients receiving suboptimal care for their cancer. Rather than separating our treatment regime to focus either on heart failure or cancer, an ideal approach would look for common pathways identified in both tissues, with the aim to limit or improve chemotherapy-induced heart failure, but not prevent (or even enhance) chemotherapy-induced tumor regression. In this opinion article, we will discuss metabolic pathways that appear to be induced in both the failing heart and tumor, suggesting that metabolic therapies could provide an alternative approach for treating CIC, without hindering or potentially even improving chemotherapy-induced tumor regression.