Mitigation of Doxorubicin-Induced Cardiotoxicity by Phytochemicals in Micelles - PROJECT SUMMARY/ABSTRACT
Doxorubicin (DOX) is a potent chemotherapeutic agent reserved for second line therapy, such as recurrent
ovarian cancer, due to its cardiotoxicity and drug resistance issues. With a cumulative lifetime dose limit of
450-550 mg/m2 patients who have benefited from its use before may be barred from further use in any
relapses. One promising solution to DOX's cardiotoxicity and chemoresistance is through the use of
phytochemicals such as resveratrol (RES), curcumin (CUR), or quercetin (QUE). Although these
phytochemicals have been shown to be cardioprotective and can overcome tumor resistance through
chemosensitization, they require long pre-treatment times and have short biologic half-lives, restricting their
value in addressing DOX's limitations. However, our preliminary in vitro and in vivo research suggests that
these phytochemicals, when dosed concurrently in specific combinations in polymeric micelles with existing
DOX formulations, are both cardioprotective and chemosensitizing while delivering clinically relevant
concentrations of the molecules. The proposed project will extend our preliminary work through two specific
aims. Specific Aim 1 will establish preclinical safety and pharmacokinetic profiles for the micellar
phytochemicals for use with DOX. Specific Aim 2 will validate the efficacy of the complementary therapeutic
approach, i.e., cardioprotection with chemosensitization, in ovarian cancer xenograft mouse models.
The significance of the work lies in developing a complementary therapeutic strategy using phytochemicals as
a cost-effective strategy to mitigate DOX-induced cardiotoxicity and to chemosensitize resistant cells. By
effecting these changes, the cumulative lifetime dose limit of DOX will be increased, making it available for
wider applications, including recurrent relapses. Further, these effects will be accomplished without changing
the current dosing schedule, increasing the likelihood of patient compliance. The impact of this proposal lies in
addressing both mechanisms of DOX-induced cardiotoxicity, ROS and TOPIIβ inhibition, without compromising
DOX efficacy or resulting in additional side effects associated with the complementary approach. The global
impact of this project lies in addressing the under-utilization of DOX use through a complementary approach,
thus increasing the range of treatment options and ultimately the quality of care for patients. In addition, this
approach to developing micellar phytochemicals has significant potential for use with other chemotherapeutic
agents for which drug resistance is a concern. This R15 application offers excellent research training
opportunities for undergraduate, graduate, and pharmacy students and will make significant contributions to
the enhancement of the Pacific University research infrastructure while strengthening Oregon State
University's biomedical research.
