RWJ-241947 (MCC-555), a Unique Peroxisome Proliferator-Activated Receptor-γ Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide

Takashi Kumagai, Takayuki Ikezoe, Dorina Gui, James O'Kelly, Xiang Jun Tong, Fredric J. Cohen, Jonathan W. Said, H. Phillip Koeffler

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Purpose: RWJ-241947 (MCC-555) is a novel peroxisome proliferator-activated receptor-γ ligand of the thiazolidinedione class that was recently developed as an antidiabetic drug with unique properties. Some thiazolidinediones have anticancer activity against solid and hematological malignancies; the anticancer potency of RWJ-241947 has not been examined. We, therefore, investigated these effects in vitro and in vivo either alone or in combination with other compounds. Experimental Design: Tumor growth was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, soft agar colony assay in vitro, and xenografts in nude mice. Its effects on cell cycle, differentiation, and apoptosis were examined. Results: In vitro studies using various solid and hematological tumor cell lines showed that RWJ-241947 had antiproliferative activity against prostate cancer cells, with the strongest effect against the androgen-independent PC-3 prostate cancer cells. It increased expression of cyclin-dependent kinase inhibitor p21 WAF1, deceased cyclin E, and induced apoptosis in PC-3 cells. It increased E-cadherin and lowered protein expression of prostate-specific antigen without down-regulating the androgen receptor in androgen-dependent LNCaP prostate cancer cells. Reporter gene assays showed that this peroxisome proliferator-activated receptor-γ ligand inhibited androgen activation of the androgen receptor response elements of the prostate-specific antigen gene. Remarkably, in vivo treatment of male beige/nude/X-linked immunodeficient (BNX) mice with RWJ-241947 profoundly suppressed growth of PC-3 prostate cancer xenografts with prominent apoptosis, as well as fibrosis, including inflammatory and giant cell reaction in the remaining tumor tissue. Notably, the experimented mice had a significantly decreased cholesterol. In addition, we studied the combination of arsenic trioxide (As203), which is used in the treatment of multiple myeloma, and RWJ-241947; these two reagents together prominently inhibited proliferation and caused apoptosis of multiple myeloma cells. Conclusions: RWJ-241947 has surprisingly potent antiproliferative effects against prostate cancer cells in vivo, and it enhances the antitumor activity of As203 against myeloma cells. Small, well-defined clinical studies using RWJ-241947 are in order for these cancers.

Original languageEnglish (US)
Pages (from-to)1508-1520
Number of pages13
JournalClinical Cancer Research
Volume10
Issue number4
DOIs
StatePublished - Feb 15 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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