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.