Abstract P2125: Melatonin As A Strategy To Mitigate Late Doxorubicin-induced Cardiotoxicity

Abstract

There are more than 500,000 childhood cancer survivors in the USA. These patients have an elevated risk of developing life-threatening health problems, cardiovascular disease being the main cause of early mortality in this population. Most of these survivors received anthracyclines. These antitumor agents are the benchmark for treatment in pediatric and adult oncology. Doxorubicin (DOX) is the most used anthracycline due to its high efficacy against solid cancer and hematological malignancies. With the improvements in five-year survival rates and growing survivor population, the long-term wellbeing of these cancer survivors is a primary healthcare concern.The clinical utility of DOX is compromised by its link to cardiac disease development after a long asymptomatic period preceding cardiac dysfunction and irreversible heart failure. A mechanism proposed for this late DOX - i nduced c ardiotoxicity ( DOXIC ) is the accumulation of DOX in cardiac fibroblasts (CFs), a key cell type in cardiac maturation and injury response, which increases mitochondrial oxidative stress, declining heart function over decades. The use of a safe approach against DOXIC without impeding the antitumor activity of DOX is a major clinical challenge.Our study proposes melatonin (aMT) as a strategy against late DOXIC. This mitochondria-targeted antioxidant has been reported to enhance the efficacy of chemotherapy and has been used safely in patients even at high doses. Our in vitro results showed that young primary murine CFs presented higher proliferation and fewer dead cells with continuous exposure to aMT post-DOX treatment (% of death at 24h: 100% in DOX 3uM 3h, 86% DOX + 5uM aMT, 7% DOX + 10uM aMT, 0% DOX + 20uM aMT). Our i n vivo results proved that aMT protected against early DOXIC in young mice, with a fractional shortening (FS) similar to vehicle. Furthermore, aMT was used as a rescue strategy in mature mice with impaired cardiac function. This aMT intervention recovered FS from 28 to 39%, suggesting aMT could counteract late DOXIC. These experiments produce the first data of this kind using aMT as a preventive and rescue strategy to mitigate late DOXIC with an approach that is closely aligned with the cardiac outcomes noted in childhood cancer survivors decades after DOX exposure.