A combination of a ketogenic diet and high-dose vitamin C did not prove superior in enhancing doxorubicin efficiency in vivo

Background Recent advancements in cancer therapy still lack complementary treatments that substantially enhance the effectiveness of existing anti-cancer agents. A promising emerging strategy is the fine-tuning of nutrients, with a combinatory approach likely achieving superior results. Objective Here, the study aimed to evaluate the efficacy of a novel nutritional regimen that combines the ketogenic diet (KD) and high-dose vitamin C (VitC) as an adjuvant cancer therapy. Methods Syngrafts were established using triple-negative breast cancer EMT-6 cells in BALB/c mice. Five experimental groups were created: one received doxorubicin (DOX) alone, while the others received DOX with KD, high-dose VitC, or both. Treatments were administered over 14 days. Results Both KD and high-dose VitC individually enhanced the response to DOX, as reflected by favorable changes in cancer-associated markers, while their combination did not provide additional benefit. Specifically, KD positively influenced tumor proliferative signaling, angiogenesis, hypoxic response, anti-tumor immunity, and glucose metabolism, evidenced by reductions in insulin-like growth factor-1, vascular endothelial growth factor, hypoxia-inducible factor-1α, and programmed death-ligand 1, as well as decreased activity of pyruvate kinase and glyceraldehyde-3-phosphate dehydrogenase. High-dose VitC primarily targeted tumor replicative potential by reducing telomerase reverse transcriptase levels and may have inhibited metastasis by increasing tumor collagen content. However, neither the individual use of KD and high-dose VitC nor their combination enhanced DOX efficacy in reducing tumor volume or weight. Conclusion The combined nutritional approach, comprising KD and high-dose VitC, did not show significant advantages over the individual use of each in enhancing the tumor-inhibitory effects of DOX or modulating the tested cancer-associated markers. These findings highlight the need for further research to optimize dosing, treatment schedules, and mechanistic understanding of the combined therapy.