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Sulforaphane attenuates doxorubicin-induced cardiotoxicity without inhibiting anticancer activity Mecit Kaplan1, Vetriselvan Manavalan1, Martin Hauer-Jensen2, Marjan Boerma2, Sharda P. Singh1, 1 Department of Pharmacology and Toxicology and 2Department of Pharmaceutical Sciences at UAMS, Background: Doxorubicin (DOX) is a clinically important anti‐cancer drug but has serious cardiotoxic side-effects. We used a preclinical animal model to test whether sulforaphane (SFN), an activator of the Nrf2 transcription factor pathway, may protect the heart from DOX toxicity without compromising the ability of DOX to kill cancer cells. Methods: Control and breast tumor (~5-6 mm3) bearing female rats were treated with vehicle, SFN (40 mg/kg oral; 5 days/week), DOX (total of 20 mg/kg, i.p. for 4 weeks) and SFN+DOX. At the end of the regimens cardiac function, tumor growth, Nrf2 activation, transcription level of antioxidant/anti-electrophile genes and metabolizing enzyme activities were measured. Results: SFN improved cardiac function and tumor regression during DOX-therapy in tumor bearing rats. Cox regression analysis indicated that SFN reduced the hazard of death from DOXtoxicity. Nrf2 and its target anti-oxidant/anti-electrophile genes and metabolizing enzyme were upregulated in the hearts of SFN- and SFN+DOX-treated rats, but not in their tumors. Discussion & Conclusions: Our initial results suggest that DOX and SFN act synergistically in tumor regression, which may improve the therapeutic index of DOX in cancer-therapy. SFN activates Nrf2 to induce protective gene expression which protects the heart against DOX-toxicity but not the tumor cells. Taken together, we have demonstrated preclinical proof of principle for SFN/DOX co-therapy in the treatment of breast cancer.
