Improvement of cytotoxic effects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades

Murielle Mimeault, Parmender P Mehta, Ralph Hauke, Jean Pierre Henichart, Patrick Depreux, Ming-Fong Lin, Surinder Kumar Batra

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The results of the present study revealed for the first time the possibility to use a combination of mitoxantrone with gefitinib and cyclopamine for inhibiting the growth of epidermal growth factor (EGF), sonic hedgehog- (SHHNp), and serum-stimulated androgen-sensitive LNCaP-C33 and androgen-independent (AI) LNCaP-C81, DU145 and PC3 prostate cancer (PC) cells. The supra-additive anti-proliferative effects of drugs were mediated via a blockade of the PC3 cells in the G1 and G2M phases of the cell cycle. Importantly, the combination of mitoxantrone plus gefitinib and/or cyclopamine also caused a higher rate of apoptotic death of PC cells including enriched fraction of CD44high PC3 cell subpopulation as compared to the individual agents or bi-combination of drugs. The cytotoxic effects induced by mitoxantrone, gefitinib and cyclopamine on PC3 cells appear to be at least partly mediated through the depolarization of the mitochondrial membrane, release of cytochrome c into the cytosol, hydrogen peroxide production and activation of caspase cascades. These findings indicate that the simultaneous blockade of EGF-EGFR and sonic hedgehog tumorigenic signaling cascades may represent a promising strategy for improving the efficacy of current mitoxantrone-based therapies against incurable AI and metastatic PCs in the clinics.

Original languageEnglish (US)
Pages (from-to)400-416
Number of pages17
JournalGrowth Factors
Volume25
Issue number6
DOIs
StatePublished - Dec 1 2007

Fingerprint

Mitoxantrone
Epidermal Growth Factor Receptor
Refractory materials
Prostatic Neoplasms
Cells
Hormones
Androgens
Epidermal Growth Factor
Depolarization
Drug Combinations
Caspases
Cytochromes c
Hydrogen Peroxide
G1 Phase
Mitochondrial Membranes
Cytosol
Chemical activation
Membranes
Cell Cycle
Pharmaceutical Preparations

Keywords

  • Apoptotic death
  • Combined targeted therapy
  • EGF-EGFR system
  • Mitoxantrone
  • Prostate cancer
  • Sonic hedgehog signaling

ASJC Scopus subject areas

  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Improvement of cytotoxic effects induced by mitoxantrone on hormone-refractory metastatic prostate cancer cells by co-targeting epidermal growth factor receptor and hedgehog signaling cascades. / Mimeault, Murielle; Mehta, Parmender P; Hauke, Ralph; Henichart, Jean Pierre; Depreux, Patrick; Lin, Ming-Fong; Batra, Surinder Kumar.

In: Growth Factors, Vol. 25, No. 6, 01.12.2007, p. 400-416.

Research output: Contribution to journalArticle

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