SMBA1 (small-molecule Bax agonists 1), a small molecular activator of Bax, is a potential anti-tumour agent. In the present study, we investigated the biological effects of SMBA1 on glioblastoma (GBM) cells. SMBA1 reduced the viabilities of U87MG, U251 and T98G cells in a time- and dose-dependent manner. Moreover, treatment with SMBA1 induced cell cycle arrest at the G2/M phase transition, accompanied by the downregulation of Cdc25c and cyclin B1 and the upregulation of p21. SMBA1 also induced apoptosis of GBM cells in a dose-dependent manner. Mechanistically, SMBA1 induced apoptosis via the intrinsic pathway. Silencing of Bax or ectopic expression of Bcl-2 significantly inhibited SMBA1-induced apoptosis. Moreover, SMBA1 inhibited the growth of U87MG xenograft tumours in vivo. Overall, SMBA1 shows anti-proliferative effects against GBM cells through activation of the intrinsic apoptosis pathway.

Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review.
. 2013 Nov;310(17):1842–50.
Alifieris C, Trafalis DT. Glioblastoma multiforme: pathogenesis and treatment.
Pharmacol Ther
. 2015 Aug;152:63–82.
Xin M, Li R, Xie M, Park D, Owonikoko TK, Sica GL, et al. Small-molecule Bax agonists for cancer therapy.
Nat Commun
. 2014 Sep;5(1):4935.
Yu R, Yu BX, Chen JF, Lv XY, Yan ZJ, Cheng Y, et al. Anti-tumor effects of Atractylenolide I on bladder cancer cells.
J Exp Clin Cancer Res
. 2016 Mar;35(1):40.
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
. 1997 Feb;275(5303):1132–6.
Adrain C, Creagh EM, Martin SJ. Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2.
. 2001 Dec;20(23):6627–36.
Cory S, Adams JM. Killing cancer cells by flipping the Bcl-2/Bax switch.
Cancer Cell
. 2005 Jul;8(1):5–6.
Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, et al. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment.
Cancer Biol Ther
. 2008 Aug;7(8):1243–9.
Liu E, Wu J, Cao W, Zhang J, Liu W, Jiang X, et al. Curcumin induces G2/M cell cycle arrest in a p53-dependent manner and upregulates ING4 expression in human glioma.
J Neurooncol
. 2007 Dec;85(3):263–70.
Schmidt F, Knobbe CB, Frank B, Wolburg H, Weller M. The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines.
Oncol Rep
. 2008 Apr;19(4):1061–6.
Gupta S, Afaq F, Mukhtar H. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells.
. 2002 May;21(23):3727–38.
Chen QM, Liu J, Merrett JB. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts.
Biochem J
. 2000 Apr;347(Pt 2):543–51.
Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, et al. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells.
Cancer Res
. 2000 Mar;60(5):1426–33.
McArthur K, Kile BT. Apoptotic Caspases: Multiple or Mistaken Identities?
Trends Cell Biol
. 2018 Jun;28(6):475–93.
Zamaraev AV, Kopeina GS, Prokhorova EA, Zhivotovsky B, Lavrik IN. Post-translational Modification of Caspases: The Other Side of Apoptosis Regulation.
Trends Cell Biol
. 2017 May;27(5):322–39.
Ashkenazi A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions.
J Clin Invest
. 2015 Feb;125(2):487–9.
Fulda S. Targeting extrinsic apoptosis in cancer: challenges and opportunities.
Semin Cell Dev Biol
. 2015 Mar;39:20–5.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.
. 1997 Nov;91(4):479–89.
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
. 2000 Jul;102(1):33–42.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
. 2001 Apr;292(5517):727–30.
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death.
Nat Rev Mol Cell Biol
. 2008 Jan;9(1):47–59.
Zhao G, Zhu Y, Eno CO, Liu Y, Deleeuw L, Burlison JA, et al. Activation of the proapoptotic Bcl-2 protein Bax by a small molecule induces tumor cell apoptosis.
Mol Cell Biol
. 2014 Apr;34(7):1198–207.
Reyna DE, Garner TP, Lopez A, Kopp F, Choudhary GS, Sridharan A, et a. Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia.
Cancer Cell
. 2017 Oct;32:490–505.e10.
Stornaiuolo M, La Regina G, Passacantilli S, Grassia G, Coluccia A, La Pietra V, et al. Structure-based lead optimization and biological evaluation of BAX direct activators as novel potential anticancer agents.
J Med Chem
. 2015 Mar;58(5):2135–48.
Li R, Ding C, Zhang J, Xie M, Park D, Ding Y, et al. Modulation of Bax and mTOR for Cancer Therapeutics.
Cancer Res
. 2017 Jun;77(11):3001–12.
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