3076 - Development of Honokiol Prodrug in Alleviating Myocardial Mitochondrial Dysfunction and Restrictive Cardiomyopathy after Irradiation
Presenter(s)
W. S. Jahng1, S. Melemenidis2, Y. Zhou1, X. Cao1, E. Hu1, J. S. Achter3, S. Rhee1, S. Cho1, A. Lundby3, B. W. Loo Jr4, and J. Wu1; 1Stanford Cardiovascular Institute, Stanford, CA, 2Department of Radiation Oncology, Stanford University, Palo Alto, CA, 3University of Copenhagen, Copenhagen, Denmark, 4Stanford University, Palo Alto, CA
Purpose/Objective(s): Radiation therapy (RT) is a cornerstone in cancer treatment. However, it often causes severe cardiotoxicity, significantly increasing morbidity and mortality among thoracic cancer patients with locally advanced non-small-cell lung cancer or esophageal cancer. The current study aimed to elucidate the mechanisms underlying RT-induced cardiac dysfunction, focusing on myocardial mitochondrial respiratory dysfunction, and to evaluate the radioprotective potential of honokiol (HKL) in mitigating consequential cardiac adverse effects post irradiation.
Materials/Methods: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from three healthy donors were used to assess mitochondrial respiratory function following acute X-ray irradiation at various doses (0–10 Gy) at 1, 3, 7, and 14 days post-irradiation. HKL’s radioprotective effects were evaluated by analyzing functional and transcriptomic changes in iPSC-CMs at 3 and 7 days post-irradiation with HKL treatment. To overcome HKL’s pharmacological limitations, we used a honokiol prodrug (HKLp) with enhanced pharmacokinetic properties. The in vivo therapeutic efficacy of HKL was further assessed using thoracic irradiation mouse models subjected to a single acute 40 Gy partial heart-lung irradiation protocol.
Results: In vitro studies revealed that RT-induced mitochondrial respiratory dysfunction and subsequent immunogenicity are key contributors to cardiac dysfunction. HKL treatment effectively restored mitochondrial function and mitigated radiation-induced immunogenicity. In vivo, a one-week administration of HKLp at 20 mg/kg established a therapeutic HKL circulation range that alleviated transient systolic dysfunction and prevented restrictive cardiac remodeling with beneficial effects persisting for up to 24 weeks post-irradiation.
Conclusion: Targeting mitochondrial dysfunction with HKL and its derivatives shows promise in mitigating RT-induced normal tissue damage. Given the prevalence of mitochondrial respiratory defects reported across various tissues post irradiation, further exploration of HKL-based strategies for reducing normal tissue toxicity is warranted.