Bicalutamide failure in prostate cancer treatment: involvement of Multi Drug Resistance proteins.
Prolonged bicalutamide treatment induced pathology regression although relapses with a more aggressive form of prostate cancer have been observed. This failure could be due to androgen receptor mutation. In the present work we hypothesized an alternative mechanism responsible for bicalutamide failure involving activity of ATP-binding cassette (ABC) pumps such as P-glycoprotein, Breast Cancer Receptor Protein (BCRP), and Multi Resistant Proteins (MRPs) that extrude the androgen antagonist from the cell membrane. As experimental models androgen-dependent (LnCap) and androgen-independent (PC-3) prostate cancer cell lines have been employed. Bicalutamide has been tested in the cell lines mentioned above in the absence and in the presence of MC18, our potent P-glycoprotein/BCRP/MRP1 inhibitor. The results displayed that bicalutamide antiproliferative effect at 72 h was ameliorated in LnCap cells (EC(50) from 51.9+/-6.1 microM to 17.8+/-2.6 microM in the absence and in the presence of MC18, respectively) and restored in PC-3 cells (EC(50) from 150+/-2.4 microM to 60+/-3.5 microM in the absence and in the presence of MC18, respectively). Moreover, we established the contribution of each transporter employing stable transfected cells (MDCK) overexpressing P-glycoprotein or BCRP or MRP1 pump. The results displayed that P-glycoprotein and BCRP were involved in bicalutamide efflux while MRP1 was unable to bind the antiandrogen drug.
Colabufo
Nicola Antonio
NA
Dipartimento Farmacochimico, Universita' degli Studi di Bari, via Orabona 4, 70125, Bari, Italy. colabufo@farmchim.uniba.it
Pagliarulo
Vincenzo
V
Berardi
Francesco
F
Contino
Marialessandra
M
Inglese
Carmela
C
Niso
Mauro
M
Ancona
Patrizia
P
Albo
Giancarlo
G
Pagliarulo
Arcangelo
A
Perrone
Roberto
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009570:Nitriles; D014105:Tosyl Compounds; C116614:ABCG2 protein, human; C053541:bicalutamide; C421109:multidrug resistance-associated protein 1