Project

Identification of Molecular Mechanisms of Action of the Cardioprotective Compound Arjunolic Acid

Anthracyclines are among the most effective anti-cancer treatments ever developed, but their clinical use is limited by their cumulative dose-related cardio-toxicity which may ultimately lead to a severe form of cardiomyopathy. A classical example is Doxorubicin (DOX) that is used for the treatment of a wide variety of cancers, including lymphoma, leukemia, and solid tumors. DOX-induced cardio-toxicity is a complex multi-factorial process, the mechanisms of which are not completely understood. Studies to date suggest that DOX induces cardio-toxicity through redox cycling and reactive oxygen species (ROS) generation. Exposure of cardiomyocytes to DOX induces ROS generation that causes mitochondrial structural and functional alterations. The increase in oxidative stress and depletion of endogenous antioxidants triggers the intrinsic mitochondria dependent apoptotic pathway in cardiomyocytes. Numerous signal molecules, such as Cytochrome c, Superoxide Dismutase, Bcl-2, and Bax, have been indicated in the reactive oxygen species-induced apoptotic pathways of cardiomyocytes. Since Natural Products are a repository of new chemical entities, they could potentially serve as a good alternative antidote against the doxorubicin-induced cardio-toxicity. The focus of the study is to identify such active small molecules to be utilized in combination with Doxorubicin, to alleviate its limitation of cardio-toxicity. Herbal plants with antioxidant properties are widely used in Ayurvedic medicine for cardiac and other problems. Arjunolic acid is one such novel phyto-medicine with multifunctional therapeutic applications. It is a triterpenoid saponin, and is a major component of the extracts of the bark of Terminalia arjuna, Leandra chaetodon, Combretum leprosum and Campsis grandiflora. The current study aims to elucidate the molecular mechanisms of cardio-protection elicited by Arjunolic acid against Doxorubicin induced cardio-toxicity.

Publications

• Kalyanavenkataraman, S., Nanjan, P, Banerji, A, Nair, BG, Kumar, GB, “Discovery of arjunolic acid as a novel non-zinc binding carbonic anhydrase II inhibitor“, Bioorganic Chemistry, 66, 72- 79, (2016).