5′-methylschweinfurthin G reduces chondrosarcoma tumor growth

Abstract

New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well-differentiated hyaline cartilage-like extracellular matrix (e.g., collagen II and proteoglycan-rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5′-methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate- to high-grade chondrosarcoma model, having a hyaline cartilage-like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC 50 ) of 35 nM MeSG; approximately 300-fold less than freshly isolated rat chondrocytes (IC 50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17-day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult-to-treat intermediate-to high-grade hyaline cartilage-like chondrosarcoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1283–1293, 2018.