Guggulsterone from Commiphora mukul potentiates anti-glioblastoma efficacy of temozolomide in vitro and in vivo via down-regulating EGFR/PI3K/Akt signaling and NF-κB activation

Abstract

Ethnopharmacological relevanceMyrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. Aim of the studyThe present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. Materials and methodsCell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. ResultsThe results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. ConclusionsThe present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.