The Electron transport chain (ETC) is responsible for oxidative phosphorylation-mediated mitochondrial respiration. Here we wanted to address the
mahanine-induced targeted pathways in
glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated
mahanine, as a novel mitochondrial
complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by
mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of
mahanine. During G0/G1 arrest, other hallmark
proteins like,
cyclin D1/
cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of
mahanine was also established in in vivo mice model.
Mahanine-induced
complex-III inhibition triggered enhanced ROS in
hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that
mahanine-treated G0/G1 arrested cells were less potent to form xenograft
tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage. Taken together, our results established that
complex-III of ETC is one of the possible potential targets of
mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes.