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

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.

Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells

“…We confirmed that the growth-inhibitory effect of statins in OSCC cells is associated with the suppression of cell cycle progression. Similar to our results, statins have been reported to arrest cancer cells such as G 0 /G 1 phase arrest in glioma, hypopharyngeal cancer [ 9 ], anaplastic thyroid cancer [ 10 ], liver cancer [ 11 ], and bladder cancer [ 12 ]; G 1 phase in HeLa cells [ 13 ], anaplastic thyroid cancer [ 14 ], and nasopharyngeal [ 15 ]; G 1 S in hepatocellular carcinoma [ 16 ] and colon cancer [ 17 ]; and S phase in prostate cancer [ 18 ]. Moreover, statins upregulated the p21 mRNA and protein expression and downregulated the expression of CDK2, CDK4, and CDK6 in OSCC cells.…”

“…These results suggest that the functions of kinases have been inhibited by p21 upregulation. Similar to our results, statins have been reported to upregulate p21 expression in glioma, hypopharyngeal cancer [ 9 ], anaplastic thyroid cancer [ 10 , 14 ], liver cancer [ 11 ], HeLa cells [ 13 ], colon cancer [ 17 ], oral cancer [ 29 ], and melanoma [ 30 ]. p21 also negatively regulates the cell cycle by binding to proliferating cell nuclear antigen (PCNA) through its carboxyl-terminal domain, thus blocking DNA replication [ 31 ].…”

“…Statins have shown chemoprevention and anticancer effects in a wide range of cancers, such as anaplastic thyroid cancer, liver cancer, bladder cancer, nasopharyngeal cancer, colon cancer, prostate cancer, oral cancer, ovarian cancer, breast cancer, brain cancer, lung cancer, and leukemia. The pleiotropic effects of statins have been observed in several cellular processes, such as cell cycle arrest [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], apoptosis [ 14 , 16 , 18 , 19 , 20 , 21 ], autophagy [ 22 ], migration [ 18 , 23 ], invasion [ 24 ], stemness, and metastasis [ 25 ]. In addition, the mevalonate pathway (MVP) has been demonstrated as playing an important role in modulating cancer development, because it controls the biosynthesis of cholesterol that is an essential component of cell membranes and as well as other precursors and metabolites [ 26 , 27 , 28 ].…”

“…Statins have been reported to inhibit cell proliferation mainly by negative regulation on cell cycle in several cancers. The suppression of cell cycle progression was achieved through the upregulation of cyclin-dependent kinase (CDK) inhibitors, mostly p21 and p27 [ 9 , 10 , 11 , 13 , 14 , 15 , 17 , 29 , 30 ]. These cell cycle-related tumor suppressor genes (TSGs) bind to cyclin-CDKs complexes and inhibit kinase activity, which leads to the cell cycle arrest [ 31 ].…”

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

“…Several agents have been identified to inhibit the expression of Skp2 in human cancer. For example, troglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was identified to downregulate the expression levels of Skp2 and to induce p27-associated cell cycle arrest in liver cancer cells (33,34). EB1089 induced Skp2-dependent p27 accumulation, resulting in inhibition of cell growth and cell cycle G1 phase arrest in hepatoma cells (35).…”