Novel combination therapy against metastatic and androgen-independent prostate cancer by using gefitinib, tamoxifen and etoposide.
In this study, we evaluated, for the first time, the antiproliferative and cytotoxic effects induced by a combination of a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, with other chemotherapeutic drugs including estrogen receptor-beta (ER-beta) antagonist (tamoxifen) and topoisomerase II inhibitor (etoposide) on some metastatic prostate cancer (PC) cell lines. Immunohistochemial analyses revealed that EGFR expression was enhanced in 38% of primary prostatic adenocarcinomas (Gleason scores 4-10) as compared to the corresponding normal tissues of the same prostate gland from 32 PC patients. The RT-PCR and Western blot data have also indicated the higher expression levels of EGFR and ER-beta transcripts and proteins in metastatic LNCaP, DU145 and PC3 cells relative to nonmalignant normal prostate cells. Moreover, the results from MTT and FACS analyses revealed that the drugs, alone or in combination at lower concentrations, inhibited the growth of 17beta-estradiol (E2) plus EGF and serum-stimulated androgen-responsive LNCaP-C33 and androgen-independent LNCaP-C81, DU145 and PC3 cells. Importantly, the combined gefitinib, tamoxifen and etoposide also caused a higher rate of apoptotic death of PC cells as compared to single agents. The cytotoxic effects induced by these drugs in PC3 cells appear to be mediated through the accumulation of cellular ceramide and activation of caspase cascades via a mitochondrial pathway. These findings indicate that the combined use of inhibitors of EGF-EGFR and E2-ER-beta signaling with etoposide, which act by increasing the cellular ceramide levels and caspase activity, represents a promising strategy for a more effective treatment of metastatic PC forms.
Mimeault
Murielle
M
Department of Biochemistry and Molecular Biology, University of Nebraska College of Medicine, 985870 Medical Center, Omaha, Nebraska 68198, USA.
Venkatraman
Ganesh
G
Johansson
Sonny L
SL
Moore
Erik
E
Henichart
Jean-Pierre
JP
Depreux
Patrick
P
Lin
Ming-Fong
MF
Batra
Surinder K
SK
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005047:Etoposide / Q000008:administration & dosage; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000008:administration & dosage
D002518:Ceramides; D011799:Quinazolines; D012333:RNA, Messenger; D013629:Tamoxifen; D004815:Epidermal Growth Factor; D005047:Etoposide; D045304:Cytochromes c; D066246:ErbB Receptors; D020169:Caspases; D000077156:Gefitinib