NEW terpenoids from marine-derived Penicillium with potent anticancer activity in osteosarcoma models

Osteosarcomas are uncommon bone cancers affecting children and young adults for which no satisfactory treatment is available. During an in vitro screening of marine fungi for new antitumor compounds against osteosarcoma, a marine-derived strain of Penicillium belonging to a new species was selected for further investigation. Bioguided fractionation led to the isolation of four active compounds. Among them, a new chlorinated sesquiterpenoid, ligerin, is related to fumagillin and TNP470, an antiangiogenic MetAP2 inhibitor undergoing clinical trials for treatment of solid tumors.

Time-lapse and flow cytometry analyses of ligerin on osteosarcoma cells showed a clear slow-down of cell division and an increase in both G2M- as well S-phase fractions. On human and murine cell lines, activity of ligerin was higher than those of other analogs synthetized from fumagillin, and was equivalent to doxorubicin and TNP470. Activity of ligerin was also more specific, with a higher activity on osteosarcoma cells than on non-tumor cells. The results of in vivo studies on osteosarcoma murine models showed significant antitumor activity and a lower toxicity of ligerin vs TNP 470at the same daily SC dose.