Probable Mechanisms of Doxorubicin Antitumor Activity Enhancement by Ginsenoside Rh2
Alexander Popov,
Anna Klimovich,
Olga Styshova,
Alexander Tsybulsky,
Dmitry Hushpulian,
Andrey Osipyants,
Anna Khristichenko,
Sergey Kazakov,
Manuj Ahuja,
Navneet Kaidery,
Bobby Thomas,
Vladimir Tishkov,
Abraham Brown,
Irina Gazaryan,
Andrey Poloznikov
Affiliations
Alexander Popov
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 Prospect 100-Years of Vladivostok, 690022 Vladivostok, Russia
Anna Klimovich
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 Prospect 100-Years of Vladivostok, 690022 Vladivostok, Russia
Olga Styshova
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159 Prospect 100-Years of Vladivostok, 690022 Vladivostok, Russia
Alexander Tsybulsky
Department of Biochemistry, Microbiology and Biotechnology, Institute of the World Ocean, Far Eastern Federal University, Campus L, Island Russian, 690920 Vladivostok, Russia
Dmitry Hushpulian
Department of Biochemistry, Microbiology and Biotechnology, Institute of the World Ocean, Far Eastern Federal University, Campus L, Island Russian, 690920 Vladivostok, Russia
Andrey Osipyants
Department of Biochemistry, Microbiology and Biotechnology, Institute of the World Ocean, Far Eastern Federal University, Campus L, Island Russian, 690920 Vladivostok, Russia
Anna Khristichenko
Moscow Institute of Physics and Technology, 9 Institutskiy lane, Dolgoprudny, 141701 Moscow, Russia
Sergey Kazakov
Department of Chemistry and Physical Sciences, Dyson College of Art and Sciences, Pace University, 861 Bedford Road, Pleasantville, NJ 10570, USA
Manuj Ahuja
Departments of Pediatrics, Darby Research Institute, Neurosciencec, Drug Discovery, Medical University of South Carolina, Charleston, SC 29425, USA
Navneet Kaidery
Departments of Pediatrics, Darby Research Institute, Neurosciencec, Drug Discovery, Medical University of South Carolina, Charleston, SC 29425, USA
Bobby Thomas
Departments of Pediatrics, Darby Research Institute, Neurosciencec, Drug Discovery, Medical University of South Carolina, Charleston, SC 29425, USA
Vladimir Tishkov
Innovation and High Technologies MSU Ltd., Tsymlyanskaya 16, 109599 Moscow, Russia
Abraham Brown
Department of Anatomy Cell Biology, New York Medical College, 15 Dana Road, Valhalla, NY 10595, USA
Irina Gazaryan
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, 13-4 Myasnitskaya Street, 117997 Moscow, Russia
Andrey Poloznikov
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, 13-4 Myasnitskaya Street, 117997 Moscow, Russia
Ginsenoside Rh2 increases the efficacy of doxorubicin (DOX) treatment in murine models of solid and ascites Ehrlich’s adenocarcinoma. In a solid tumor model (treatment commencing 7 days after inoculation), DOX + Rh2 co-treatment was significantly more efficacious than DOX alone. If treatment was started 24 h after inoculation, the inhibition of tumor growth of a solid tumor for the DOX + Rh2 co-treatment group was complete. Furthermore, survival in the ascites model was dramatically higher for the DOX + Rh2 co-treatment group than for DOX alone. Mechanisms underlying the combined DOX and Rh2 effects were studied in primary Ehrlich’s adenocarcinoma-derived cells and healthy mice’s splenocytes. Despite the previously established Rh2 pro-oxidant activity, DOX + Rh2 co-treatment revealed no increase in ROS compared to DOX treatment alone. However, DOX + Rh2 treatment was more effective in suppressing Ehrlich adenocarcinoma cell adhesion than either treatment alone. We hypothesize that the benefits of DOX + Rh2 combination treatment are due to the suppression of tumor cell attachment/invasion that might be effective in preventing metastatic spread of tumor cells. Ginsenoside Rh2 was found to be a modest activator in a Neh2-luc reporter assay, suggesting that Rh2 can activate the Nrf2-driven antioxidant program. Rh2-induced direct activation of Nrf2 might provide additional benefits by minimizing DOX toxicity towards non-cancerous cells.
