Gedunin, A Novel HSP90 Inhibitor, Decreases Cellular Growth and Induces Apoptosis In Glioblastoma Cell Lines

Abstract

Glioblastoma multiforme (GBM) is an aggressive neoplasm characterized by an elevated, aberrant, proliferative capacity accompanied by diffuse patterns of brain invasion. It has been estimated that in 2018 there were 17,000 deaths out of 24,000 newly diagnosed cases of GBM. The average life expectancy of patients with GBM is only slightly over one year. Current guideline-recommended therapy consisting of tumor resection followed by chemotherapy with temozolomide and radiation has shown limited efficacy due to resistance and high recurrence rates. There is a critical need for the development of new drugs and combination treatment modalities that will considerably increase patient survival and improve the poor prognosis of the disease. Natural products have long served as a source of chemotherapeutic agents. Gedunin is a naturally occurring molecule with clinical potential as an HSP90 inhibitor. Gedunin was isolated from the neem tree, Azadirachta indica A. Juss. (Meliaceae). A. Indica, traditionally used for the treatment of malaria, has been shown to possess some anticancer activity. Our primary objective was to determine the antiproliferative and apoptotic effects of gedunin in glioblastoma cell lines, with the goal of also determining the key signaling pathways affected by gedunin. The antiproliferative effects of gedunin were assessed using the MTT and LDH assays. Protein immunoblots were carried out to test the effects of gedunin on survival signaling pathways such as Akt, mTOR, NF kappa B, and apoptotic markers such as PARP, caspases, and Bcl-xL. Differences between the treated and the untreated groups were analyzed using a one-way ANOVA followed by a Bonferroni post-hoc test. Our data revealed that gedunin (0-20 µM) induced a concentration-dependent and time-dependent decrease in glioma cell proliferation. In addition, gedunin attenuated signaling of downstream targets such as Akt/mTOR and NF kappa B. These protein expressions were downregulated in the presence of gedunin. Furthermore, gedunin induced both PARP and caspase cleavages and decreased the expression of Bcl-xL, an antiapoptotic protein. In conclusion, gedunin decreases cell proliferation and induces apoptosis in glioma cell lines by attenuating key survival signaling pathways and could serve as a therapeutic molecule in the management of gliomas.