Mitochondria Targeted Antioxidants Mitoquinone and SKQ1 Provide Protection against Doxorubicin Induced Cell Damage on H9c2 Myoblast
Authors: Onal Halil , Martorana Rose , Sehgal Amogh , Wastella Catherine , Sacks Brian , Pjetergjoka Adona , Barsotti Robert , Young Lindon , Chen Qian 
Published: April 2020

Doxorubicin (DOX) is a widely used anti‐cancer drug but known to induce severe cardiotoxicity. Its adverse effect is caused by an overproduction of free radicals after its accumulation in mitochondria, particularly in heart which constitute about 30% mitochondria. Common antioxidant treatments have not shown significant protection, possibly due to its lack of accumulation within mitochondria. Mitochondria targeted antioxidants have been developed which can accumulate 100 times in mitochondria due to its lipophilic and positive charge properties. Mitoquinone (10‐(6'‐Ubiquinonyl) decyltriphenylphosphonium bromide; MitQ), a mitochondria targeted antioxidant, has shown protection against DOX induced cardiotoxicity in cells and animal studies. By contrast, SKQ1 (conjugate of decyl‐triphenylphosphonium cation (TPP+) with plastoquinone), another mitochondria targeted antioxidant, has shown better antioxidant capacity than MitQ in aqueous solution and lipid environment but no comparison has been made in cardiac tissue. The aim of this study is to compare the effects of MitQ and SKQ1, in their ability to attenuate DOX induced cell damage in H9c2 myoblast. Cell viability was analyzed using a cell counting kit which measured dehydrogenases activity that directly corresponds to cell viability. We found that DOX (500 nM – 50 μM; n=7) reduced cell viability in a dose dependent manner after 24 hour incubation. DOX (40 μM; n=7) reduced cell viability to 41 ± 3% of control. Cells cotreatment of SKQ1 (0.05 μM – 25 μM; n=7) or MitQ (0.05 μM – 10 μM; n=7) with DOX (40 μM) for 24 hours, showed similar dose dependent cellular protection. SKQ1 (5 μM; n=7) treated cells showed the highest cell protection having 55 ±19% increase in cell viability when compared to DOX. Similarly, MitQ (1μM; n=7) treated cells showed highest cell protection exhibiting 64 ± 7% increase in cell viability compared to DOX. Additionally, cells were also protected after pretreatment of SKQ1 (0.05 μM – 25 μM; n=7) or MitQ (0.05 μM – 10 μM; n=7) for 24 hours followed by washing out drug, then cells were treated with DOX (40μM; n=7). SKQ1 (5μM; n=7) pretreated cells showed the highest cell protection with 56 ± 16% increase in cell viability when compared to DOX. By contrast, MitQ (2.5 μM; n=7) pretreated cells showed highest cell protection with 121± 24% increase in cell viability when compared to DOX. Preliminary data suggest that MitQ and SKQ1 both showed protection against DOX induced cardiac cell damage. Moreover, MitQ is more efficacious than SKQ1 when given as pretreatment. MitQ is also more potent when compared to SKQ1. Further studies will be performed to investigate the mechanism of MitQ and SKQ1 protection against DOX.

Support or Funding Information

This research is supported by the Division of Research, Department of Bio‐Medical Sciences, and the Center for Chronic Disorders of Aging at Philadelphia College of Osteopathic Medicine.