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 language | English (US) |
|---|---|
| Pages (from-to) | 1508-1520 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 10 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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. / Kumagai, Takashi; Ikezoe, Takayuki; Gui, Dorina; O'Kelly, James; Tong, Xiang Jun; Cohen, Fredric J.; Said, Jonathan W.; Koeffler, H. Phillip.
In: Clinical Cancer Research, Vol. 10, No. 4, 15.02.2004, p. 1508-1520.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Kumagai, Takashi
AU - Ikezoe, Takayuki
AU - Gui, Dorina
AU - O'Kelly, James
AU - Tong, Xiang Jun
AU - Cohen, Fredric J.
AU - Said, Jonathan W.
AU - Koeffler, H. Phillip
PY - 2004/2/15
Y1 - 2004/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=1642343741&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642343741&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-0476-03
DO - 10.1158/1078-0432.CCR-0476-03
M3 - Article
C2 - 14977855
AN - SCOPUS:1642343741
VL - 10
SP - 1508
EP - 1520
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 4
ER -