title: Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme.
abstract: 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.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Bhattacharya
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Bag
authors.affiliation: Cell Death and Differentiation Research, National Institute of Immunology New Delhi, India.
authors.forename: Rakshamani
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Suman K
authors.initials: SK
authors.lastname: Samanta
authors.affiliation: National Institute of Pharmaceutical Education and Research Kolkata, India.
authors.forename: Bikas C
authors.initials: BC
authors.lastname: Pal
authors.affiliation: Cell Death and Differentiation Research, National Institute of Immunology New Delhi, India.
authors.forename: Chandrima
authors.initials: C
authors.lastname: Shaha
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Mandal
keywords: DNA damage response; G0/G1 arrest; ROS; glioblastoma multiforme; mahanine; mitochondrial ETC