>>Clinical Cancer Research Vol. 10, 1508-1520, February 2004
Experimental Therapeutics, Preclinical Pharmacology
RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor- 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 Kumagai1, Takayuki Ikezoe1, Dorina Gui2, James O’Kelly1, Xiang-Jun Tong1, Fredric J. Cohen3, Jonathan W. Said2 and H. Phillip Koeffler1
Division of Hematology/Oncology, Departments of1 Medicine and 2 Pathology, Center of Health of Science, University of California at Los Angeles School of Medicine, Los Angeles, California, and 3 Global Clinical Research, Johnson and Johnson Pharmaceutical Research and Development, La Jolla, California
Purpose: RWJ-241947 (MCC-555) is a novel peroxisome proliferator-activated receptor- 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 p21WAF1, 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- 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 (As2O3), 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 As2O3 against myeloma cells. Small, well-defined clinical studies using RWJ-241947 are in order for these cancers. <<
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