Osteosarcoma is a common type of malignant bone tumor with features of osteoid formation or osteolytic lesions of bone. New therapeutic approaches are urgently needed since it lacks response to chemotherapeutic treatments. Saurolactam, a natural compound isolated from the aerial portions of Saururus chinensis, was reported to have an anti-inflammatory activity. Here, we demonstrate that saurolactam shows anti-cancer activity against human osteosarcoma cells. Saurolactam treatment inhibited proliferation of human osteosarcoma cell lines MG-63 and HOS and decreased colony formation in soft agar in a dose-dependent manner. Intraperitoneal administration of saurolactam at 25 mg/kg of body weight for 21 days dramatically inhibited the growth of MG-63 xenografts in nude mice. Flow cytometric analysis indicated that saurolactam treatment (20 μM) led to G1 cell cycle arrest and induced apoptosis in these two cell lines. Western analysis suggested that saurolactam treatment resulted in a reduction of Akt/PKB, phospho-Ser473-Akt, c-Myc, and S-phase kinase-associated protein 2 (Skp2) in MG-63 and HOS osteosarcoma cells. Akt overexpression significantly abolished saurolactam-induced decrease in protein and phosphorylation levels of Akt, c-Myc, and Skp2 protein levels, implying that Akt inactivation was a causal mediator of saurolactam-induced inhibition of c-Myc and Skp2. Moreover, Skp2 overexpression in MG-63 cells partly abolished the growth inhibition induced by saurolactam. Saurolactam treatment repressed migration and invasion ability, and Skp2 overexpression significantly blocked these inhibitory effects of saurolactam in MG-63 Cells. The present study indicates that saurolactam might represent a new promising agent to improve osteosarcoma treatment.
Keywords: Cell proliferation; Osteosarcoma; S-phase kinase-associated protein 2 (Skp2); Saurolactam; Tumor xenografts.