Synergistic Antitumor Effect of the Activated PPARγ and Retinoid Receptors on Human Osteosarcoma

Purpose: Osteosarcoma is the most common primary malignancy of bone. The long-term survival of osteosarcoma patients hinges on our ability to prevent and/or treat recurrent and metastatic lesions. Here, we investigated the activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) and retinoid receptors as a means of differentiation therapy for human osteosarcoma. Experimental Design: We examined the endogenous expression of PPAR gamma and retinoid receptors in a panel of osteosarcoma cells. Ligands or adenovirus-mediated overexpression of these receptors were tested to inhibit proliferation and induce apoptosis of osteosarcoma cells. Osteosarcoma cells overexpressing the receptors were introduced into an orthotopic tumor model. The effect of these ligands on osteoblastic differentiation was further investigated. Results: Endogenous expression of PPAR gamma and isotypes of retinoic acid receptor (RAR) and retinoid X receptor (RXR) is detected in most osteosarcoma cells. Troglitazone, 9-cis retinoic acid (RA), and all-trans RA, as well as overexpression of PPAR gamma, RAR alpha, and RXR alpha, inhibit osteosarcoma cell proliferation and induce apoptosis. A synergistic inhibitory effect on osteosarcoma cell proliferation is observed between troglitazone and retinoids, as well as with the overexpression pairs of PPAR gamma/RAR alpha, or PPAR gamma/RXR alpha. Overexpression of PPAR gamma, RAR alpha, RXR alpha, or in combinations inhibits osteosarcoma tumor growth and cell proliferation in vivo. Retinoids (and to a lesser extent, troglitazone) are shown to promote osteogenic differentiation of osteosarcoma cells and mesenchymal stem cells. Conclusions: Activation of PPAR gamma, RAR alpha, and RXR alpha may act synergistically on inhibiting osteosarcoma cell proliferation and tumor growth, which is at least partially mediated by promoting osteoblastic differentiation of osteosarcoma cells. Clin Cancer Res; 16(8); 2235-45. (C) 2010 AACR.