Comparative Study of Cytotoxic and Membranotropic Properties of Betulinic Acid-F16 Conjugate on Breast Adenocarcinoma Cells (MCF-7) and Primary Human Fibroblasts
Konstantin N. Belosludtsev,
Anna I. Ilzorkina,
Natalia V. Belosludtseva,
Vyacheslav A. Sharapov,
Nikita V. Penkov,
Dmitriy A. Serov,
Maxim N. Karagyaur,
Darya A. Nedopekina,
Eldar V. Davletshin,
Marina E. Solovieva,
Anna Yu Spivak,
Ulyana Sh. Kuzmina,
Yulia V. Vakhitova,
Vladimir S. Akatov,
Mikhail V. Dubinin
Affiliations
Konstantin N. Belosludtsev
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Anna I. Ilzorkina
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Natalia V. Belosludtseva
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Vyacheslav A. Sharapov
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
Nikita V. Penkov
Federal Research Center, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute of Cell Biophysics of the Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Dmitriy A. Serov
Federal Research Center, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute of Cell Biophysics of the Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Maxim N. Karagyaur
Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27/10, Lomonosovsky Ave., 119192 Moscow, Russia
Darya A. Nedopekina
Institute of Petrochemistry and Catalysis, Ufa Federal Research Center, Russian Academy of Sciences, Prospekt Oktyabrya 141, 450075 Ufa, Russia
Eldar V. Davletshin
Institute of Petrochemistry and Catalysis, Ufa Federal Research Center, Russian Academy of Sciences, Prospekt Oktyabrya 141, 450075 Ufa, Russia
Marina E. Solovieva
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Anna Yu Spivak
Institute of Petrochemistry and Catalysis, Ufa Federal Research Center, Russian Academy of Sciences, Prospekt Oktyabrya 141, 450075 Ufa, Russia
Ulyana Sh. Kuzmina
Institute of Biochemistry and Genetics, Ufa Federal Research Center, Russian Academy of Sciences, Prospekt Oktyabrya 71, 450054 Ufa, Russia
Yulia V. Vakhitova
Institute of Biochemistry and Genetics, Ufa Federal Research Center, Russian Academy of Sciences, Prospekt Oktyabrya 71, 450054 Ufa, Russia
Vladimir S. Akatov
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Mikhail V. Dubinin
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia
The present study evaluates the cytotoxicity of a previously synthesized conjugate of betulinic acid (BA) with the penetrating cation F16 on breast adenocarcinoma (MCF-7) and human fibroblast (HF) cell lines, and also shows the mechanism underlying its membranotropic action. It was confirmed that the conjugate exhibits higher cytotoxicity compared to native BA at low doses also blocking the proliferation of both cell lines and causing cell cycle arrest in the G0/G1 phase. We show that the conjugate indeed has a high potential for accumulation in mitochondria, being visualized in these organelles, which is most pronounced in cancer cells. The effect of the conjugate was observed to be accompanied by ROS hyperproduction in both cancerous and healthy cells, despite the lower base level of ROS in the latter. Along with this, using artificial liposomes, we determined that the conjugate is able to influence the phase state of lipid membranes, make them more fluid, and induce nonspecific permeabilization contributing to the overall cytotoxicity of the tested agent. We conclude that the studied BA–F16 conjugate does not have significant selective cytotoxicity, at least against the studied breast cancer cell line MCF-7.