Conjugation of Triterpenic Acids of Ursane and Oleanane Types with Mitochondria-Targeting Cation F16 Synergistically Enhanced Their Cytotoxicity against Tumor Cells
Mikhail V. Dubinin,
Darya A. Nedopekina,
Anna I. Ilzorkina,
Alena A. Semenova,
Vyacheslav A. Sharapov,
Eldar V. Davletshin,
Natalia V. Mikina,
Yuri P. Belsky,
Anna Yu. Spivak,
Vladimir S. Akatov,
Natalia V. Belosludtseva,
Jiankang Liu,
Konstantin N. Belosludtsev
Affiliations
Mikhail V. Dubinin
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
Darya A. Nedopekina
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Prospekt Oktyabrya 141, Ufa 450075, Russia
Anna I. Ilzorkina
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, Russia
Alena A. Semenova
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
Vyacheslav A. Sharapov
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
Eldar V. Davletshin
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Prospekt Oktyabrya 141, Ufa 450075, Russia
Natalia V. Mikina
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
Yuri P. Belsky
Centre of Preclinical Translational Research, Almazov National Medical Research Centre, St. Petersburg 197371, Russia
Anna Yu. Spivak
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Prospekt Oktyabrya 141, Ufa 450075, Russia
Vladimir S. Akatov
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, Russia
Natalia V. Belosludtseva
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
Jiankang Liu
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, China
Konstantin N. Belosludtsev
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, Russia
The present work shows the cytotoxic effects of novel conjugates of ursolic, oleanolic, maslinic, and corosolic acids with the penetrating cation F16 on cancer cells (lung adenocarcinoma A549 and H1299, breast cancer cell lines MCF-7 and BT474) and non-tumor human fibroblasts. It has been established that the conjugates have a significantly enhanced toxicity against tumor-derived cells compared to native acids and also demonstrate selectivity to some cancer cells. The toxic effect of the conjugates is shown to be due to ROS hyperproduction in cells, induced by the effect on mitochondria. The conjugates caused dysfunction of isolated rat liver mitochondria and, in particular, a decrease in the efficiency of oxidative phosphorylation, a decrease in the membrane potential, and also an overproduction of ROS by organelles. The paper discusses how the membranotropic- and mitochondria-targeted effects of the conjugates may be related to their toxic effects.
