A synergistic anti-cancer effect of troglitazone and lovastatin in a human anaplastic thyroid cancer cell line and in a mouse xenograft model

Wen Bin Zhong, Yuan Chin Tsai, Li Han Chin, Jen Ho Tseng, Li Wen Tang, Steve Horng, Yu Ching Fan, Sung Po Hsu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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, PPARγ), 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, p21cip and p27kip, 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.

Original languageEnglish
Article number1834
JournalInternational Journal of Molecular Sciences
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

Fingerprint

troglitazone
Lovastatin
cultured cells
Heterografts
mice
lipid metabolism
cancer
Cells
Coenzymes
Lipid Metabolism
Cell Line
Retinoblastoma Protein
Cyclin-Dependent Kinases
PPAR gamma
Thyrotropin
Iodine
Cell culture
Pharmaceutical Preparations
inhibitors
Toxicity

Keywords

  • Anaplastic thyroid cancer
  • HMGCR
  • Lovastatin
  • P21
  • P27
  • PPARγ
  • RB
  • Troglitazone

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

A synergistic anti-cancer effect of troglitazone and lovastatin in a human anaplastic thyroid cancer cell line and in a mouse xenograft model. / Zhong, Wen Bin; Tsai, Yuan Chin; Chin, Li Han; Tseng, Jen Ho; Tang, Li Wen; Horng, Steve; Fan, Yu Ching; Hsu, Sung Po.

In: International Journal of Molecular Sciences, Vol. 19, No. 7, 1834, 01.07.2018.

Research output: Contribution to journalArticle

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abstract = "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, PPARγ), 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, p21cip and p27kip, 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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