Rawan W. Hadi

Background: This study evaluated the effects of black seed oil (BSO), a simulated ketogenic metabolic condition consisting of a low-glucose medium supplemented with 5 mM β-hydroxybutyrate (BHB), and their combination in EMT6/P and EMT6/DOX cells. The in vivo effects of a ketogenic diet, BSO, and their combination were also investigated in tumor-bearing mice. Methods: Cytotoxicity of black seed oil (BSO), a simulated ketogenic metabolic condition consisting of low-glucose medium supplemented with 5 mM β-hydroxybutyrate (BHB), their combination, and doxorubicin (DOX) was evaluated in EMT6/P and EMT6/DOX cells using the MTT assay. Combination index (CI) analysis was used to determine the interaction between BSO and the simulated ketogenic metabolic condition. Caspase-3 activity, vascular endothelial growth factor VEGF expression, and P-glycoprotein (P-gp) expression were evaluated in EMT6/DOX cells. In vivo, mice bearing EMT6/P and EMT6/DOX tumors received a ketogenic diet, BSO, their combination, DOX, and control treatment, and tumor growth, tumor weight, tumor-free rate, and serum biochemical parameters were assessed. Results: BSO half-maximal inhibitory concentration IC50 was 14.5-fold higher in EMT6/DOX than in EMT6/P, and DOX IC50 was 39.5-fold higher. The simulated ketogenic metabolic condition consisting of a low-glucose medium supplemented with 5 mM BHB + BSO combination gave a CI of 0.1244 in EMT6/P and 0.0239 in EMT6/DOX, indicating synergism in both lines. The combination produced the highest caspase-3 activity (1.54-fold vs. control), the lowest VEGF level (268.34 pg/mL vs. 953.34 pg/mL in control), and the lowest P-gp level (1.6 ng/mL vs. 3.7 ng/mL in control) among the treatments tested. In vivo, the combination reduced tumor volume by 87.15% in EMT6/P and 58.12% in EMT6/DOX, and gave a tumor-free rate of 66.6% in EMT6/P and 50% in EMT6/DOX. No consistent treatment-related change was observed in liver enzymes, renal markers, or lipid profile compared with healthy controls. Conclusions: The combination of a simulated ketogenic metabolic condition and BSO showed synergistic cytotoxic activity in vitro, while the ketogenic diet and BSO combination produced enhanced antitumor activity in vivo. These effects were associated with increased caspase-3 activity and reduced VEGF and P-gp expression in EMT6/DOX cells, without evidence of hepatic, renal, or metabolic toxicity. These findings support further investigation of this combination in doxorubicin-resistant breast cancer.

Cancer is one of the leading causes of death globally. Conventional treatments such as surgery, radiotherapy, and chemotherapy are associated with several side effects, including chemoresistance and cancer relapse. As a result, there is a critical demand for new therapeutic agents to support the current therapeutic options. Recently, research started to focus on the possible positive interaction(s) between melatonin and many phytochemicals as a combination therapy to target altered metabolism in cancer. Such a combination has many advantages, including low toxicity, the possibility of having multiple synergistic anticancer effects, and low cost. This review comprehensively examines the current literature regarding combining melatonin with phytochemicals as a potential strategy to target cancer metabolism. It aims to contribute to the evolving landscape of cancer therapeutics by highlighting the potential benefits and future directions of melatonin–phytochemical combinations as an area of active research.

Cancer remains a major global health challenge, requiring new adjunctive therapies. Integrative oncology, which combines conventional treatments with complementary agents, has gained attention for improving patient outcomes. Melatonin, a potent antioxidant and immunomodulator, has shown promise in cancer therapy. Recent evidence suggests that combining melatonin with vitamins—particularly vitamin D, vitamin C, and vitamin E—may enhance its anticancer effects through synergistic mechanisms. Melatonin exerts anticancer effects by regulating oxidative stress, apoptosis, and immune responses. Vitamin D enhances immune modulation, while vitamins C and E provide antioxidant and cytoprotective benefits. Their combined action may improve tumor suppression and reduce treatment-induced toxicity. However, despite promising preclinical data, clinical studies on melatonin–vitamins synergy remain limited. This review explores the molecular interactions, current evidence, and research gaps in melatonin–vitamin combinations for cancer therapy. Future studies should focus on mechanistic insights, optimal dosing, and clinical trials to establish their role in integrative oncology. Unlocking this potential could enhance existing cancer treatment strategies and improve patient outcomes.

Epigallocatechin gallate (EGCG) is a catechin, which is a type of flavonoid found in high concentrations in green tea. EGCG has been studied extensively for its potential health benefits, particularly in cancer. EGCG has been found to exhibit anti-proliferative, anti-angiogenic, and pro-apoptotic effects in numerous cancer cell lines and animal models. EGCG has demonstrated the ability to interrupt various signaling pathways associated with cellular proliferation and division in different cancer types. EGCG anticancer activity is mediated by interfering with various cancer hallmarks. This article summarize and highlight the effects of EGCG on cancer hallmarks and focused on the impacts of EGCG on these cancer-related hallmarks. The studies discussed in this review enrich the understanding of EGCG’s potential as a therapeutic tool against cancer, offering a substantial foundation for scientists and medical experts to advance scientific and clinical investigations regarding EGCG’s possibility as a potential anticancer treatment.