Date of Award

6-2026

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Qian Chen, Ph.D.

Second Advisor

Robert Barsotti, Ph.D.

Third Advisor

Ruth C. Borghaei, Ph.D.

Fourth Advisor

Dianzheng Zhang, Ph.D.

Abstract

Introduction:

Although Doxorubicin (DOX) is a widely prescribed chemotherapeutic agent, its clinical use is limited by cardiotoxicity (DIC) caused by oxidative stress, mitochondrial dysfunction, and cardiac apoptosis. Dexrazoxane (DEX) is the only FDA-approved cardioprotective agent to prevent DIC. However, DEX may induce secondary malignancy. Mitochondria-targeted antioxidants (MTAs), such as mitoquinone (MitoQ) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1), selectively accumulate within mitochondria to scavenge reactive oxygen species (ROS) at their primary site of production. Our previous findings demonstrated that MitoQ and SKQ1 prevented the reduction in cell viability caused by DOX treatment in H9c2 myoblasts. However, it remains unclear whether MitoQ can selectively protect cardiomyocytes without compromising DOX’s anti-cancer efficacy.

Methods:

We treated H9c2 myoblasts and 22Rv1 prostate cancer cells with DOX, MitoQ, and DEX to determine optimal concentration and exposure times with a cell viability assay (CCK-8). Afterward, CCK-8 was used to evaluate H9c2 and 22Rv1 cell viability after 30 min or 24 h of treatment with MitoQ or DEX, either before DOX (pre-treatment) or simultaneously with DOX (co-treatment). In addition, apoptosis was assessed by Western blot detection of cleaved caspase-3 (CC3).

Results:

DOX (0.5-60 μM, n=5) dose-dependently reduced H9c2 and 22Rv1 cell viability similarly in both cell lines, when compared with nontreated cells. MitoQ (0.5-5 μM, n=3) pre-treatment in H9c2 cells for 24 hours significantly protected H9c2 cells against DOX-induced cell damage (p < 0.05). This protection was greater than that observed with MitoQ when given pre-treatment for 30 min, MitoQ co-treatment for 30 min and 24 h, or DEX (1-500 μM) pre- or co-treatment for 30 min and 24 h. Lastly, a 24 h treatment with MitoQ (1-5 μM) decreased CC3 expression in H9c2 cells but increased it in 22Rv1 cells. By contrast, DOX (1-20 μM) increased CC3 expression in both cell lines.

Conclusion:

DOX produced comparable dose-dependent cytotoxicity in H9c2 myoblast and 22Rv1 prostate cancer cells, possibly by apoptosis. Notably, 24-hour MitoQ pre-treatment significantly protected H9c2 myoblasts from DOX-induced damage while slightly enhancing DOX’s cytotoxicity in prostate cancer cells, which is better than DEX’s effects. The underlying mechanisms of MitoQ-mediated cardioprotection will be further evaluated.

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