In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth.
Malignant pleural mesothelioma (MPM), an aggressive and refractory tumor type, is increasing in frequency throughout the world. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists have anticancer activity against several cancer cell lines in vitro and in vivo. However, there have been no reports that PPAR-γ agonists induce growth inhibition of MPM cell lines. In this study, we investigated the inhibitory effect of a PPAR-γ agonist in combination with an anticancer agent on MPM cell growth in vitro and in vivo. We examined the therapeutic efficacy of the PPAR-γ agonist troglitazone (TGZ) in combination with cisplatin against a human MPM cell line, both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. Troglitazone (TGZ) alone inhibited MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. The combination of TGZ and cisplatin showed an additive inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with 500 mg/kg or 1000 mg/kg TGZ effectively inhibited the production of thoracic tumors and pleural effusion in EHMES-10 cell-bearing SCID mice. Moreover, treatment with 500 mg/kg TGZ in combination with 3 mg/kg cisplatin more effectively prolonged survival compared to treatment with either individual drug. These results suggest that TGZ in combination with cisplatin may become a novel therapy for MPM.
Hamaguchi
Naohiko
N
Department of Integrated Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
Hamada
Hironobu
H
Miyoshi
Seigo
S
Irifune
Kazunori
K
Ito
Ryoji
R
Miyazaki
Tatsuhiko
T
Higaki
Jitsuo
J
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D000077288:Troglitazone; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002839:Chromans; D019394:Ki-67 Antigen; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077288:Troglitazone; D002945:Cisplatin