Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells
Journal
Biochemical Pharmacology
Journal Volume
71
Journal Issue
6
Pages
751-760
Date Issued
2006
Author(s)
Hsieh M.-W.
Wang C.-W.
Liu G.-Y.
Guan J.-Y.
Lin S.-R.
Hour T.-C.
Abstract
Recent data showed that epidermal growth factor receptor (EGFR) inhibitors, such as ZD1839, alone or in combination with chemotherapeutic agents for androgen-independent prostate cancer (AIPC) did not produce promising results in clinical settings. More effective regimens involving novel stronger inhibitor of EGFR and better combinations are needed. The anti-tumor activity of PD168393, an irreversible EGFR inhibitor, with or without chemotherapeutic agents for the treatment of AIPC was investigated in vitro. In results, both the androgen-independent cell lines PC-3 and DU145 expressed higher levels of EGFR than the androgen-dependent MDA PCa 2b and androgen-responsive LNCaP cells by Western blotting. DU145 was much more sensitive to PD168393 and ZD1839 than MDA PCa 2b. PD168393, but not ZD1839, significantly potentiated paclitaxel cytotoxicity against DU145 by MTT assay and median-effect analysis. The combination of PD168393 or ZD1839 with other cytotoxic agents including docetaxel and 5-fluorouracil, however, was either additive or antagonistic. Compared to paclitaxel alone, PD168393 significantly enhanced paclitaxel-induced DNA fragmentation, sub-G1 fraction accumulation, mitochondrial membrane dysfunction, cytochrome C release, caspase-3 activation and eventually apoptosis. These molecular events were accompanied by Bad up-regulation, p53 and p21Waf1/Cip1 induction, ERK1/2 inactivation and inhibition of EGFR phosphorylation in the presence of PD168393. These effects did not involve significant alteration in the Akt1/2 and STAT3 signaling pathway. In conclusion, the combination of paclitaxel and PD168393 produced a profound synergistic growth inhibition of AIPC cells. Combining PD168393 with paclitaxel may have clinical benefits and warrants further investigation. ? 2005 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
androgen; antineoplastic agent; caspase 3; cyclin dependent kinase inhibitor 1; cytochrome c; DNA fragment; docetaxel; epidermal growth factor receptor; epidermal growth factor receptor kinase inhibitor; fluorouracil; gefitinib; mitogen activated protein kinase 1; mitogen activated protein kinase 3; n [4 (3 bromoanilino) 6 quinazolinyl]acrylamide; paclitaxel; protein BAD; protein kinase B; protein kinase B beta; protein p53; STAT3 protein; antineoplastic activity; apoptosis; article; cancer cell; cancer cell culture; controlled study; cytotoxicity; drug effect; drug potentiation; enzyme activation; enzyme inactivation; enzyme inhibition; human; human cell; in vitro study; mitochondrial membrane; priority journal; prostate cancer; protein expression; protein induction; protein phosphorylation; upregulation; Western blotting; Adenocarcinoma; Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Male; Paclitaxel; Prostatic Neoplasms; Quinazolines; Receptor, Epidermal Growth Factor
Type
journal article