Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFκB dependent manner

• Shh inhibitor SANT-1 failed to induce glioma cell death.
• SANT-1 sensitized glioma cells to Ras/NFκB inhibitor Guggulsterone via Caspase 9 activation.
• Functional inactivation of Ras/NFκB axis sensitized glioma cells to SANT-1.
• SANT-1 inhibits the proliferation of glioma stem-like cells.

Since Shh pathway effector, Gli1, is overexpressed in gliomas, we investigated the effect of novel Shh inhibitor SANT-1 on glioma cell viability. Though SANT-1 failed to induce apoptosis, it reduced proliferation of glioma stem-like cells. Apart from canonical Shh cascade, Gli1 is also induced by non-canonical pathways including NFκB. Therefore, a combinatorial strategy with Ras/NFκB inhibitor, Guggulsterone, was employed to enhance effectiveness of SANT-1. Guggulsterone inhibited Ras and NFκB activity and sensitized cells to SANT-1 induced apoptosis via intrinsic apoptotic mechanism. Inhibition of either Ras or NFκB activity was sufficient to sensitize cells to SANT-1. Guggulsterone induced ERK activation also contributed to Caspase-9 activation. Since SANT-1 and Guggulsterone differentially target stem-like and non-stem glioma cells respectively, this combination warrants investigation as an effective anti-glioma therapy.