The Blocking of Drug Resistance Channels by Selected Hydrophobic Statins in Chemoresistance Human Melanoma
Wojciech Placha,
Piotr Suder,
Agnieszka Panek,
Patrycja Bronowicka-Adamska,
Marta Zarzycka,
Małgorzata Szczygieł,
Jacek Zagajewski,
Monika Weronika Piwowar
Affiliations
Wojciech Placha
Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7b St., 31-034 Krakow, Poland
Piotr Suder
Department of Analytical Chemistry and Biochemistry, Faculty of Materials Science and Ceramics, AGH University of Science and Technology, 31-007 Krakow, Poland
Agnieszka Panek
Institute of Nuclear Physics Polish Academy of Sciences, 31-342 Krakow, Poland
Patrycja Bronowicka-Adamska
Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7b St., 31-034 Krakow, Poland
Marta Zarzycka
Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7b St., 31-034 Krakow, Poland
Małgorzata Szczygieł
Department of Biophysics and Cancer Biology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, 31-007 Krakow, Poland
Jacek Zagajewski
Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7b St., 31-034 Krakow, Poland
Monika Weronika Piwowar
Department of Bioinformatics and Telemedicine, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7e St., 31-034 Krakow, Poland
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model (Mus musculus SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity.
