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1. Toxicol In Vitro. 2012 Jan 17. [Epub ahead of print]

P-glycoprotein depresses cisplatin sensitivity in L1210 cells by inhibiting
cisplatin-induced caspase-3 activation.

Gibalová L, Sereš M, Rusnák A, Ditte P, Labudova M, Uhrík B, Pastorek J, Sedlák
J, Breier A, Sulová Z.

Institute of Molecular Physiology and Genetics, Centre of Excellence of the
Slovak Research and Development Agency "BIOMEMBRANES2008", Slovak Academy of
Sciences, 83334 Bratislava, Slovak Republic.

Multidrug resistance (MDR) is a phenomenon in which cells become resistant to
cytostatic drugs and other substances with diverse chemical structures and
cytotoxicity mechanisms. The most often observed molecular mechanism for MDR
includes high levels of P-glycoprotein (P-gp) - an ABCB1 member of the ABC drug
transporter family. Overexpression of P-gp in neoplastic tissue is an obstacle to
chemotherapeutic treatment. Herein, we were focused on differences in apoptosis
induced by cisplatin (no substrate for P-gp) between P-gp-positive and
P-gp-negative L1210 cells. P-gp-positive cells were obtained by either L1210 cell
adaptation to vincristine (R) or L1210 cell transfection with the human gene for
P-gp (T) and compared with parental L1210 cells (S). R and T cells were more
resistant to CisPt than S cells. R and T cell resistance to CisPt-induced
apoptosis could not be reversed by verapamil (a well-known P-gp inhibitor), which
excludes P-gp transport activity as a cause of CisPt resistance. CisPt induced a
more pronounced entry into apoptosis in S than R and T cells, which was measured
using the annexin-V/propidium iodide apoptosis kit. CisPt induced more pronounced
caspase-3 activation in S than R and T cells. CisPt did not induce changes in the
P-gp protein level for R and T cells. While similar levels of Bax and Bcl-2
proteins were observed in P-gp-negative and P-gp-positive cells, CisPt induced a
more significant decrease in Bcl-2 levels for S cells than P-gp-positive cells.
Expression of p53 and its molecular chaperone Hsp90 were more pronounced in R and
T than S cells. Moreover, CisPt enhanced the upregulation of p53 and Hsp90 in R
and T cells to a higher degree than S cells. Apoptosis was shown to be the
prevalent mode of cell death in S, R and T cells by the typical DNA fragmentation
and cell ultrastructure changes. All of the above findings indicate that P-gp,
independent of its drug efflux activity, induced changes in cell regulatory
pathways that confer a partial loss of cisplatin sensitivity.

Copyright © 2012. Published by Elsevier Ltd.

PMID: 22269388 [PubMed - as supplied by publisher]