Cytotoxic effects induced by a combination of cydopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells

Murielle Mimeault, Erik Moore, Nicolas Moniaux, Jean Pierre Hénichart, Patrick Depreux, Ming-Fong Lin, Surinder Kumar Batra

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Although the blockade of the hedgehog cascade by using cyclopamine has been reported to inhibit the growth of some cancer cell types, few studies on the mechanism by which this drug alone or in combination with other cytotoxic agents induces its cytotoxic effect have been reported. In our study, we evaluate, for the first time, the antiproliferative and cytotoxic effects induced by a combination of selective SMO inhibitor, cyclopamine and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib on metastatic prostate cancer (PC) cells. The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog- (SHH), epidermal growth factor- (EGF) and serum-stimulated androgen-sensitive LNCaP-C33 and LNCaP-LN3 and androgen-independent LNCaP-C81, DU145 and PC3 cells. The antiproliferative effect of cyclopamine and gefitinib, alone or in combination, was mediated via a blockade of the PC3 cells in the G1 phase of the cell cycle. Importantly, the combined cyclopamine and gefitinib also caused a higher rate of apoptotic death of PC cells compared to single agents. The cytotoxic effect induced by these drugs in PC3 cells appears to be mediated at least, in part, via the mitochondrial pathway through the depolarization of the mitochondrial membrane and the release of cytochrome c and reactive oxygen species into the cytosol. This was also accompanied by the activation of caspase cascades, PARP cleavage and DNA fragmentation. Additionally, the combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone. These findings indicate that the simultaneous blockade of SHH-GLI-1 and EGF-EGFR signaling, which results in the growth arrest and massive rate of apoptotic cell death, represents a promising strategy for a more effective treatment of metastatic PC forms.

Original languageEnglish (US)
Pages (from-to)1022-1031
Number of pages10
JournalInternational Journal of Cancer
Volume118
Issue number4
DOIs
StatePublished - Feb 15 2006

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Epidermal Growth Factor Receptor
Prostatic Neoplasms
Epidermal Growth Factor
Androgens
Growth
Pharmaceutical Preparations
Cytotoxins
G1 Phase
Mitochondrial Membranes
DNA Fragmentation
Caspases
Cytochromes c
gefitinib
Cytosol
Protein-Tyrosine Kinases
cyclopamine
Reactive Oxygen Species
Cell Cycle
Cell Death
Mortality

Keywords

  • Apoptotic death
  • Cyclopamine
  • EGFR
  • Growth inhibition
  • Hedgehog signaling
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cytotoxic effects induced by a combination of cydopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. / Mimeault, Murielle; Moore, Erik; Moniaux, Nicolas; Hénichart, Jean Pierre; Depreux, Patrick; Lin, Ming-Fong; Batra, Surinder Kumar.

In: International Journal of Cancer, Vol. 118, No. 4, 15.02.2006, p. 1022-1031.

Research output: Contribution to journalArticle

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AU - Lin, Ming-Fong

AU - Batra, Surinder Kumar

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