Hinokitiol as a Promising Anticancer Agent: Mechanisms of Action, Potential in Combination Therapy, and Overcoming Chemoresistance

Abstract

Cancer remains a major global health challenge, with conventional treatments such as chemotherapy and radiotherapy often lacking specificity and causing significant side effects. Hinokitiol, a natural tropolone derivative from the Cupressaceae family, has emerged as a promising anticancer agent due to its broadspectrum activity. This review provides a comprehensive overview of hinokitiol's anticancer properties, mechanisms of action, and safety profile. Hinokitiol has demonstrated potent effects across various cancer types, including breast, lung, prostate, colorectal, and melanoma. Its mechanisms include apoptosis induction, cell cycle arrest at the G1/S and G2/M checkpoints, inhibition of Epithelial-Mesenchymal Transition (EMT), suppression of metastasis, and iron chelation. Additionally, it may enhance chemosensitivity in cancer cells that are resistant to treatment. Importantly, this review identifies and discusses key research gaps limiting hinokitiol's clinical translation. These include the absence of human clinical trials, limited pharmacokinetic and pharmacodynamic data, insufficient toxicity profiling, and context-dependent effects on cellular pathways such as ferroptosis and autophagy. We also highlight its unexplored potential in combination therapies aimed at overcoming multidrug resistance. By synthesizing current preclinical findings and outlining future research directions such as optimizing delivery systems, clarifying mechanisms in specific cancer contexts, and initiating clinical evaluation, this review contributes a critical perspective on the steps needed to develop hinokitiol as a viable anticancer therapeutic. Addressing these gaps could significantly enhance its therapeutic utility and integration into modern oncology.