Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids

Peroxisome proliferator activated receptor gamma (PPAR gamma) plays a centr al role in the process of adipocyte differentiation. This receptor and its heterodimeric partner, retinoid X receptor alpha (RXR alpha), form a DNA-bi nding complex that regulates transcription of adipocyte-specific genes. Tro glitazone, an antidiabetic drug, has recently been identified as a syntheti c ligand for PPAR gamma. We studied the effects of troglitazone on prolifer ation and differentiation of normal and malignant hematopoietic cells. Expr ession of PPAR gamma was easily detectable by Western blot analyses in all five myeloid leukemia cell lines. Troglitazone alone (10(-5) M) did not ind uce differentiation in any of the cell lines; however, this compound suppre ssed the clonal growth (10-75% of inhibition) of all five myeloid leukemia cell lines. Myelomonocytic U937 cells, which were the most responsive to th e growth suppressing effects of troglitazone, were arrested in the G(1) pha se of the cell cycle when cultured with this compound. Simultaneous treatme nt of myeloid leukemia cell lines with both troglitazone and a ligand that specifically binds either RXR (LG100268), or retinoic acid receptors (RAR, ATRA, ALART1550), or both (9-cis RA) resulted in additive suppression of cl onal growth. In summary, our studies showed that troglitazone when combined with a retinoid was a moderately potent inhibitor of clonogenic growth of acute myeloid leukemia cells.