Combination of Anti-Cancer Therapy with Natural Products and Inorganic Pharmaceuticals: Old and New Developments Against Cancer

Combination therapy integrating transition metal complexes with natural products (NPs) has emerged as a transformative strategy to enhance anticancer efficacy while mitigating drug resistance and systemic toxicity. This review comprehensively examines historical milestones and modern advancements (up to September 2025) in the synergistic application of inorganic pharmaceuticals and natural compounds in oncology. Transition metal complexes, particularly vanadium(IV/V), ruthenium(II), rhenium(I), palladium(II), platinum(II/IV), and gold(I), exhibit unique mechanisms of action, including DNA intercalation, the generation of reactive oxygen species (ROS), and the induction of apoptosis. However, clinical utility has been limited by dose-limiting toxicity, resistance, and impaired DNA repair pathways. Promising natural products such as flavonoids, alkaloids, saponins, and polyphenols (e.g., curcumin), enhance metal-based therapies by fine-tuning oxidative stress, suppressing pro-survival pathways, and enhancing tumor selectivity. Platinum(IV) prodrugs conjugated with flavonoids exhibited dual-action cytotoxicity, while ruthenium-polypyridyl complexes combined with doxorubicin amplified DNA damage in resistant carcinomas. Recent innovations include multi-metallic, binuclear ruthenium(II) complexes that optimize pharmacokinetics and reduce off-target effects. Preclinical and clinical studies highlight synergies such as vanadium-flavonoid hybrids overcoming cisplatin resistance in breast cancer, and palladium complexes with plant extracts enhancing apoptosis in vitro. Despite promising outcomes, challenges persist in pharmacokinetic synchronization to align drug metabolism and biodistribution of the metal complex and natural product, as well as limitations in real-world scalability. This review, organized according to the periodic table, underscores the necessity for mechanistic elucidation of co-treatment methods, standardized synergy assays, and clinical validation to harness the full potential of metal-natural product combinations as next-generation anticancer agents.