Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

Abstract

Peroxisomeproliferator-activated receptor gamma (PPARc) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARc fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARc, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARc agonist (RS5444) that is dependent upon PPARc for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC 50 for growth inhibition is B0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited threeto fourfold in nude mice. siRNA against PPARc and a pharmacological antagonist demonstrated that functional PPARc was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21 WAF1/CIP1 . Silencing p21 WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARc is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor γ and Calcium Signaling in Human Colorectal Cancer Cells

“…RS5444 is a high affinity PPAR␥ agonist that has been shown to regulate growth and motility of intestinal epithelial as well as thyroid cancer cells (14,52,53). Rosiglitazone (49653, Invitrogen) was purchased from ChemPacific.…”

“…Because PPAR␥ is a transcription factor, it is likely that the tumor-suppressive effects of this receptor are because of changes in gene expression and that the mechanism of action of PPAR␥ might be inferred from a functional genomic study of the effects of thiazolidinediones on early stage colon cancer cells. The observations described below result from such a study in which we used the high affinity PPAR␥ agonist RS5444 (14,(51)(52)(53) to activate PPAR␥ in MOSER cells. These cells have sustained an APC loss-of-function mutation followed by loss of heterozygosity of the wildtype APC allele; however, MOSER cells retain TGF␤ sensitivity (54,55) and have wild-type K-Ras, indicating that they represent a late adenoma or early adenocarcinoma stage.…”

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

“…Accordingly, specific PPARG agonists have been shown to induce growth arrest in thyroid carcinomas expressing PAX8/PPARG (77), pleading for the investigation of the in vivo relevance of these findings. Similarly, rare fusions involving the PML gene were identified in B-cell acute lymphoblastic leukemia (78).…”

Marked regression of liver metastasis by combined therapy of ultrasound‐mediated NFkB‐decoy transfer and transportal injection of paclitaxel, in mouse

“…These molecules have recently been reported to show synergistic effects with platinum-based or other chemotherapeutic agent, such as taxol, on the inhibition of cancer progression. [22][23][24][25][26] In addition, novel anti-NFkB agents, including proteasome inhibitors such as bortezomib 27,28 and selective small-molecule inhibitors of the IKK complex, such as AS602868 compound, may also sensitize cancer cells, enhancing the response to chemotherapeutic agents 29 and induce drug-induced apoptosis. In this study, we found that inhibition of NFkB activity by treatment with NFkB-decoy significantly increased the susceptibility of cancer cells to paclitaxel, consequently inducing apoptosis; almost 90% of cells treated with NFkB-decoy transfer underwent apoptosis upon incubation with 0.1 lM paclitaxel, whereas less than 60% of cells without such pretreatment underwent apoptosis.…”