Investigating the role of ketogenic diet and high-dose vitamin C in modulating doxorubicin toxicity in a murine breast cancer model

Abstract

In this study, we investigated the effectiveness of combining the ketogenic diet (KD) with high-dose vitamin C (VitC) as adjuvant nutritional therapy to mitigate doxorubicin (DOX) toxicity, with a focus on cardiotoxicity, while enhancing DOX's anti-cancer efficacy. Syngrafts were generated by implanting EMT6 cells into BALB/c mice. Once tumors had become palpable, the mice were divided into five experimental groups. One group received DOX alone (15 mg/kg cumulative dose), while the others received DOX with KD, high-dose VitC (4 g/kg), or a combination of both. The treatment regimens lasted 14 days, involving three DOX cycles. Co-administration of KD, high-dose VitC, and their combination did not enhance DOX-mediated tumor volume reduction, but DOX efficacy was preserved. DOX treatment induced acute cardiac injury and fibrosis, evidenced by higher cardiac severity scores and collagen deposition. KD tended to exacerbate DOX-induced cardiac injury, while high-dose VitC showed a trend towards mitigation, though neither alleviated cardiac fibrosis. DOX increased cardiac troponin I (cTnI) levels and decreased cardiac catalase activity, without affecting malondialdehyde (MDA) levels or superoxide dismutase (SOD) activity compared to controls. However, co-administration of KD with DOX resulted in a significant reduction in MDA levels and an increase in SOD activity compared to both the control and DOX groups. High-dose VitC tended to lower cTnI levels and significantly increased catalase activity. Cardiac topoisomerase IIβ (Top2β) levels decreased with DOX monotherapy and tended to decrease further with KD, but peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) levels were unaffected. DOX induced weight loss and decreased food intake, exacerbated by KD. Relative heart and spleen weights were adversely affected by DOX, with KD further reducing relative spleen weight but increasing relative kidney weight and plasma creatinine levels. Histological examination revealed pathological changes in kidney, liver, and spleen tissues, not prevented by KD, high-dose VitC, or their combination. In conclusion, while KD and high-dose VitC may offer some benefits in mitigating specific aspects of DOX-induced toxicity, their use as adjuvant therapies requires further exploration to ensure safety and optimize treatment regimens for patients receiving DOX-based chemotherapy.

Keywords: Cancer; Cardiotoxicity; Complementary and alternative medicine; Doxorubicin; Ketogenic diet; Vitamin C.