A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model

被引:25
作者
Zhong, Wen-Bin [1 ,2 ]
Tsai, Yuan-Chin [3 ]
Chin, Li-Han [2 ]
Tseng, Jen-Ho [4 ]
Tang, Li-Wen [2 ]
Horng, Steve [3 ]
Fan, Yu-Ching [3 ]
Hsu, Sung-Po [1 ,2 ]
机构
[1] Taipei Med Univ, Sch Med, Dept Physiol, Coll Med, Taipei 110, Taiwan
[2] Taipei Med Univ, Grad Inst Med Sci, Coll Med, Taipei 110, Taiwan
[3] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Coll Med Sci & Technol, Taipei 110, Taiwan
[4] Taipei City Hosp, Renai Branch, Dept Neurosurg, Taipei 106, Taiwan
关键词
anaplastic thyroid cancer; HMGCR; lovastatin; PPAR gamma; p21(cip); p27(cip); RB; troglitazone; ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; SINGLE-INSTITUTION; UP-REGULATION; CARCINOMA; STATINS; PROTEIN; EXPRESSION; APOPTOSIS; THERAPY;
D O I
10.3390/ijms19071834
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPAR gamma), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21(cip) and p27(kip), and the reduction of hyperphosphorylated retinoblastoma protein (pp-Rb)-E2F1 signaling. Therefore, targeting two pathways involved in lipid metabolism may provide a new direction for treating ATC.
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页数:13
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