Antitumor efficacy of two novel non-thiazolidinedione compounds as peroxisome proliferator-activated receptor-gamma agonists in human osteosarcoma cells in vitro.
BACKGROUND
Due to chemotherapy resistance in osteosarcoma subgroups, the prognosis of these patients is still poor, and the development of new agents is of utmost importance. The aim of our study was to test the antitumor effects of two novel alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives as peroxisome proliferator-activated receptor (PPAR) gamma agonists, together with rosiglitazone, a well-known thiazolidinedione (TZD) acting on several osteosarcoma cell lines.


RESULTS
The MTT assay revealed that cell viability was inhibited in a dose-dependent manner with IC(50) 6.2-15.8 microM for the two novel compounds and rosiglitazone (48.4-83.5 microM). Exposure to DG8 and DH9 at low micromolar concentrations induced a dose-dependent block of DNA synthesis and colony formation. In these antitumor assays, DG8 and DH9 were more effective than rosiglitazone, although the PPARgamma agonistic activity of rosiglitazone is much higher. The SiRNA approach to downregulate specifically PPARgamma in U-2OS cells did not affect the cytotoxic efficiency of either the two novel compounds or rosiglitazone.


CONCLUSIONS
These observations suggest that non-TZDs with less PPARgamma agonistic activity might show more potent antitumor efficacy independent of PPARgamma in human osteosarcoma cells, which supports the possibility that they could be beneficial in the treatment of osteosarcoma patients.
Fu
Lili
L
Nephrology Institute of PLA, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, PR China.
Xiong
Xishan
X
Wang
Li
L
Gao
Xiang
X
Ye
Yangliang
Y
Jia
Jieshuang
J
Hu
Huimin
H
Li
Lin
L
Shen
Jianhua
J
Mei
Changlin
C
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology
D000970:Antineoplastic Agents; D047495:PPAR gamma; D010666:Phenylpropionates; D045162:Thiazolidinediones; C470568:alpha-methylhydrocinnamic acid; D000077154:Rosiglitazone