Honokiol in cancer: Roles in enhancing combination therapy efficacy and preventing post-transplant malignancies

Therapeutic resistance remains a significant challenge in cancer treatment, often resulting in relapse and poor outcomes. Conventional chemotherapies, such as cisplatin and paclitaxel, are frequently undermined by the development of chemoresistance and systemic toxicity. Targeted therapies, such as receptor tyrosine kinase (RTKs) inhibitors and monoclonal antibodies (mAbs), offer better specificity but face resistance over time. Combination therapies are being explored to improve efficacy and mitigate resistance. Honokiol, a biphenolic natural compound derived from Magnolia species, has emerged as a potential adjunct in combination therapies due to its anti-cancer, anti-inflammatory, and immunomodulatory properties. It enhances the efficacy of chemotherapies, such as cisplatin and paclitaxel, RTK inhibitors, such as cabozantinib and erlotinib, and mAbs, such as cetuximab. Notably, honokiol combined with mAbs has shown promise in pre-clinical studies by reactivating the immune system and reducing tumor growth in resistant models. In addition, honokiol aids in post-transplant cancer prevention by modulating immune responses, reducing tumor progression, and lowering the required dose of immunosuppressants, such as cyclosporine A and rapamycin. Pre-clinical studies in renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer emphasize its potential to overcome resistance. Despite promising evidence, further clinical studies are needed to validate honokiol as a viable adjunct in combination therapies. While several reviews have focused on the effects of honokiol alone, there is a lack of comprehensive studies examining its potential in combination with other therapies. This review aims to fill this gap by offering critical insights into the role of honokiol as a candidate for combination therapy.