Anticancer effects of sclareol and its derivatives in glioblastoma cells

Abstract

Background: Glioblastoma is the most common, aggressive and lethal brain tumor in adults with high proliferation rate, infiltrating nature and presence of multidrug resistance (MDR). Sclareol (SC) is a naturally occurring labdane type diterpene, derived from Salvia sclarea. We examined cell growth inhibition effect of SC and its derivatives (PAS and TNT groups of compounds) - hybrid (chimeric) molecules. Sclareol was covalently bonded to [1,2,4]triazolo[1,5-a]pyrimidin-7-amine scaffold, and different diamines were used as linkers. We also studied SC potential to reverse DOX resistance and its accumulation. The combination of SC with DOX has been earlier described to potentiate DOX cytotoxicity if simultaneously delivered in nanoparticles. Material and Methods: SC in combination with DOX as well as SC derivatives were tested on human glioma cell line U87, and its MDR counterpart - U87-TxR. MTT assay was used to examine inhibition of cell growth. Accumulation of DOX was measured by flow cytometry. Results: Thirteen out of nineteen TNT derivatives and three out of six PAS derivatives showed stronger anti-glioma effect than SC. Simultaneous treatment of SC with DOX demonstrated potential of SC to reverse DOX resistance. Even more, SC significantly increased DOX accumulation in both glioblastoma cell lines. Conclusion: Results obtained in this study showed a considerable synergy of SC and DOX in glioma cells. Better results observed with SC derivatives make them good candidates for further testing.