İnvestigation on the effects of selective RXR ligand Bexarotene on Thyroid cancer cell lines

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. It has been one of the most rapidly increasing cancer type in recent years. Effective therapies are urgently needed. Retinoids are biological derivatives of vitamin A and they have regulatory effects on cell proliferation, differentiation and apoptosis. Retinoids bind to their inner cell receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Selective RXR ligand, Bexarotene (LGD1069) was shown to increase the clinical responses of cutaneous T-cell lymphoma (CTCL) patients refractory to treatment by 50% with minimum toxicity. Bexarotene was also demonstrated to decrease migration, invasion and metastasis of solid tumors. It was approved by FDA in the treatment of CTCL in January 2000. In this study, the human papillary thyroid carcinoma (BCPAP), human follicular thyroid carcinoma originated from sternal metastasis (CGTH-W-1), human undifferentiated-anaplastic thyroid carcinoma (8505C) and human anaplastic thyroid carcinoma (CAL-62) cell lines were studied. We aimed to investigate the effects of bexarotene on cell viability, cell cycle, apoptosis and necrosis on these differentiated and undifferentiated thyroid cancer cell lines. The cell lines were cultured and grown as recommended. The cells were treated with different concentrations of of bexarotene. The concentration of bexarotene inhibiting 50% of the cell viability (IC50) was determined by using CCK-8 assay. IC50 values are 34 µM in BCPAP cell line, 50 µM in CGTH-W-1 cell line, 48 µM in 8505C cell line and 46 µM in CAL-62 cell line. The cells were treated with IC50 values of bexarotene and the ratio of the cells that undergo apoptosis and arrested in different phases of cell cycle were analysed by flow cytometry. After 48-hour treatment of bexarotene, our results showed that the cell ratio arrested in S phase was significantly reduced in 8505C cell line while the cell ratio arrested in Sub-G1 phase was considerably increased when compared to the control group in 8505C and CAL-62 cell lines (p<0,05). The results of apoptosis analysis demonstrated that bexarotene increased the apoptotic and necrotic cell death significantly in these cell lines (p<0,05). In conclusion, our in vitro study suggests that bexarotene has the ability to decrease cell viability, arrest cell cycle in Sub-G1 phase, trigger cells to apoptotic and necrotic cell death in differentiated and undifferentiated thyroid cancer cell lines. The present work will provide new insights into the future in vivo studies. Keywords: Apoptosis, Bexarotene, Cell Cycle, Chemoprevention, Rexinoid, Thyroid Cancer Cell Line