In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth

Our plain-English summary of In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth, by N. Hamaguchi, H. Hamada, S. Miyoshi, et al (Cancer Science, 2010).

The study

• Authors: N. Hamaguchi, H. Hamada, S. Miyoshi, K. Irifune, R. Ito, T. Miyazaki, J. Higaki
• Journal: Cancer Science
• Published: 2010;101(9):1955-64
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2010 Japanese Cancer Association.

In plain English

This laboratory study tested troglitazone, alone and with cisplatin, against human malignant pleural mesothelioma (MPM) cells. It did not study asbestos exposure or patients. The authors used two mesothelioma cell lines and mice injected in the chest with one line (EHMES-10). In dishes, troglitazone slowed growth more at higher doses. It held more cells in the G1 cell-cycle phase and, at high doses, caused cell death. Combined with cisplatin, the effect was nearly additive. In mice, cisplatin and the combination significantly reduced tumor weight and chest fluid. At 1000 mg/kg, troglitazone significantly reduced tumor weight; the table does not mark its fluid reduction significant, though the text does. At 500 mg/kg, these only tended to be lower. Troglitazone at 500 or 1000 mg/kg and cisplatin at 3 mg/kg each lengthened survival over controls. The combination lengthened survival more than either drug alone. The authors concluded that troglitazone, alone or with cisplatin, may benefit patients with MPM. They noted its clinical use is limited by liver toxicity in earlier reports and poor fluid control; this study's mouse liver and kidney tests showed no abnormalities.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiment: in vitro cell-line study plus animal experiment (orthotopic mouse model)
• Who was studied: Two human malignant pleural mesothelioma cell lines: EHMES-10, established from a patient's pleural effusion at the authors' institution in Japan, and MSTO-211H, purchased from the American Type Culture Collection. Male severe combined immunodeficient (SCID) mice aged 6 to 8 weeks, given EHMES-10 cells in the thoracic cavity. The methods state seven groups of 7 mice each; Table 1 reports results out of 5 per group.
• Exposure: No asbestos exposure was studied. The exposures were drug treatments. In cells: troglitazone, ciglitazone, rosiglitazone and 15d-PGJ2 (0 to 200 micromolar), cisplatin (0 to 80 micromolar), and cisplatin followed by troglitazone. In mice: troglitazone 250, 500 or 1000 mg/kg per day by gavage; cisplatin 3 or 6 mg/kg per week by intraperitoneal injection; or troglitazone 500 mg/kg plus cisplatin 3 mg/kg. All started 1 week after tumor cell injection.
• Main results:
  • All four PPAR-gamma agonists inhibited growth of EHMES-10 and MSTO-211H cells in a dose-dependent manner. Troglitazone had the most potent effect.
  • In EHMES-10 cells, 58.03% were in the G1 phase after 48 h with vehicle alone, compared with 83.24% after 48 h of troglitazone treatment.
  • High doses of troglitazone induced apoptosis of EHMES-10 cells in a dose-dependent manner, with similar results in MSTO-211H cells.
  • Troglitazone increased p21waf1/cip1 and PPAR-gamma protein and decreased cyclin D1 protein in EHMES-10 cells.
  • In EHMES-10 cells, the IC50 was 124.81 micromolar for troglitazone and 6.19 micromolar for cisplatin. The averaged combination index for the two drugs together was 0.924, which the authors interpreted as a nearly additive effect.
  • In mice (Table 1), the median thoracic tumor weight was 390 mg in controls. It was 153 mg with 1000 mg/kg troglitazone (P less than 0.05), 89 mg with 3 mg/kg cisplatin, 16 mg with 6 mg/kg cisplatin, and 82 mg with the combination (each P less than 0.01).
  • Pleural effusion was present in 5/5 control mice (median 450 microliters), 2/5 with 500 mg/kg troglitazone, 3/5 with 1000 mg/kg troglitazone (median 40 microliters), and 0/5 in the cisplatin and combination groups. Table 1 marks the effusion reductions as significant (P less than 0.01) for the cisplatin and combination groups but not for 1000 mg/kg troglitazone, although the results text calls that reduction significant too.
  • With 500 mg/kg troglitazone, tumor weight and pleural effusion only tended to be lower than in controls.
  • Troglitazone at 500 or 1000 mg/kg and cisplatin at 3 mg/kg significantly prolonged survival of the mice compared with controls. The combination significantly prolonged survival compared with either drug alone. No survival times were given in the text.
  • Mean blood troglitazone concentrations were 0.546 (n = 4), 0.685 (n = 3) and 0.566 (n = 5) micrograms per mL in the 500 mg/kg, 1000 mg/kg and combination groups. No abnormal liver or kidney function test results were observed.
  • In the mouse tumors, Ki-67-positive (dividing) cells decreased significantly only in the cisplatin group. TUNEL-positive (dying) cells increased significantly in the cisplatin and combination groups. Changes with troglitazone alone were only trends.
• The authors' conclusion: The authors concluded that troglitazone inhibited EHMES-10 cell growth through cell cycle arrest and apoptosis. They concluded that troglitazone, alone or with cisplatin, may provide therapeutic benefit to patients with MPM.
• Limitations the authors state:
  • The authors stated that clinical use of high-dose troglitazone is limited by increased liver toxicity, citing earlier reports, and by unsatisfactory control of pleural effusion. In their own mice, liver and kidney function tests showed no abnormal findings.
  • The authors stated that it was not clarified how troglitazone induced p21waf1/cip1 but not p27kip1.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Apoptosis, Pleural Effusion.

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