Inhibitory effect of AK-7 mediates by apoptosis, increases DNA fragmentation and caspase-3 activity in human glioblastoma multiforme cells

Authors

DOI:

https://doi.org/10.3329/bjp.v17i2.59809

Keywords:

AK-7, Apoptosis, Glioblastoma multiforme, Sirtuin 2, SIRT2 inhibitor, qRT-PCR

Abstract

Sirtuins (SIRTs) which are nicotinamide adenine dinucleotide (NAD+) dependent class III histondeacetylases have a controversial role in cancer. In this study, the effect of pharmacological inhibition of AK-7, a SIRT2 inhibitor, was investigated in U87 glioblastoma multiforme cells. The cytotoxic effect of AK-7 was evaluated by XTT analysis. After AK-7 treatment, colony forming capacity of cells was determined and apoptosis was evaluated. The expression levels of apoptosis-related genes were determined by qRT-PCR. According to the results, AK-7 inhibited cell proliferation in a dose- and time-dependent manner. After AK-7 treatment, the colony forming capacity of U87 cells was suppressed. And, AK-7 increased apoptosis rate, DNA fragmentation, and caspase-3 activity. According to qRT-PCR, a significant increase was observed in expression levels of apoptosis-related genes. This study revealed that AK-7 inhibits cell proliferation and induces apoptosis in glioblastoma multiforme cells and SIRT2 inhibition can be evaluated as a therapeutic approach in glioblastoma multiforme.

Downloads

Download data is not yet available.
Abstract
134
Download
193

References

Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 2008; 19: 325-31.

Aventaggiato M, Vernucci E, Barreca F, Russo MA, Tafani M. Sirtuins' control of autophagy and mitophagy in cancer. Pharmacol Ther. 2021; 221: 107748.

Biella G, Fusco F, Nardo E, Bernocchi O, Colombo A, Lichtenthaler SF, Forloni G, Albani D. Sirtuin 2 inhibition improves cognitive performance and acts on amyloid-β protein precursor processing in two Alzheimer's disease mouse models. J Alzheimer's Dis. 2016; 53: 1193-207.

Chen G, Huang P, Hu C. The role of SIRT2 in cancer: A novel therapeutic target. Int J Cancer. 2020; 147: 3297-304.

Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, Song C, Cheung YS, Lai PB, Cheng SH, Ng MH, Huang A, Ko BC. SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling. Hepato-logy. 2013; 57: 2287-98.

Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, Rauf NA, Wang H, Silverman RB, Ayata C, Maxwell MM, Steegborn C, Schwarzschild MA, Outeiro TF, Kazantsev AG. The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemia. PLoS One. 2015; 10: e0116919.

Cheon MG, Kim W, Choi M, Kim JE. AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. Cancer Lett. 2015; 356: 637-45.

Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, Edgerly C, Cipicchio PM, Lauver MA, Choi SH, Silverman RB, Ferrante RJ, Hersch S, Kazantsev AG. The sirtuin 2 inhibitor AK7 is neuroprotective in Huntington's disease mouse models. Cell Rep. 2012; 2: 1492-97.

Çınar Ayan İ, Çetinkaya S, Dursun HG, Süntar İ. Bioactive Compounds of Rheum ribes L. and its Anticancerogenic Effect via Induction of Apoptosis and miR-200 Family Expression in Human Colorectal Cancer Cells. Nutr Cancer. 2021a; 73: 1228-43.

Çınar Aİ, Güçlü E, Dursun H.G, Vural H. Tomentosin shows anticancer effect on U87 human glioblastoma multiforme cells. Bull Biotechnol. 2021b; 2: 23-26.

Du Y, Wu J, Zhang H, Li S, Sun H. Reduced expression of SIRT2 in serous ovarian carcinoma promotes cell proliferation through disinhibition of CDK4 expression. Mol Med Rep. 2017; 15: 1638-46.

Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007; 35: 495-516.

Funato K, Hayashi T, Echizen K, Negishi L, Shimizu N, Koyama-Nasu R, Nasu-Nishimura Y, Morishita Y, Tabar V, Todo T, Ino Y, Mukasa A, Saito N, Akiyama T. SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity. EMBO Rep. 2018; 19: e45587.

George J, Ahmad N. Mitochondrial sirtuins in cancer: Emerging roles and therapeutic potential. Cancer Res. 2016; 76: 2500-06.

Ghani ARI, Yahya EB, Allaq AA, Khalil ASA. Novel insights into genetic approaches in glioblastoma multiforme therapy. Biomed Res Ther. 2022; 9: 4851-64.

Güçlü E, Eroğlu Güneş C, Kurar E, Vural H. Knockdown of lncRNA HIF1A-AS2 increases drug sensitivity of SCLC cells in association with autophagy. Med Oncol. 2021; 38: 113.

Hu F, Sun X, Li G, Wu Q, Chen Y, Yang X, Luo X, Hu J, Wang G. Inhibition of SIRT2 limits tumour angiogenesis via inactivation of the STAT3/VEGFA signalling pathway. Cell Death Dis. 2018; 10: 9.

Huang S, Zhao Z, Tang D, Zhou Q, Li Y, Zhou L, Yin Y, Wang Y, Pan Y, Dorfman RG, Ling T, Zhang M. Down-regulation of SIRT2 inhibits invasion of hepatocellular carcinoma by inhibiting energy metabolism. Transl Oncol. 2017; 10: 917-27.

Inoue S, Browne G, Melino G, Cohen GM. Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway. Cell Death Differ. 2009; 16: 1053-61.

Jing H, Hu J, He B, Negrón Abril YL, Stupinski J, Weiser K, Carbonaro M, Chiang YL, Southard T, Giannakakou P, Weiss RS, Lin H. A SIRT2-Selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anti-cancer activity. Cancer Cell. 2016; 29: 297-310.

Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, Li C, Veenstra TD, Li B, Yu H, Ji J, Wang XW, Park SH, Cha YI, Gius D, Deng CX. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activi-ty. Cancer Cell. 2011; 20: 487-99.

Kozako T, Mellini P, Ohsugi T, Aikawa A, Uchida YI, Honda SI, Suzuki T. Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines. BMC Cancer. 2018; 18: 791.

Li C, Zhou Y, Kim JT, Sengoku T, Alstott MC, Weiss HL, Wang Q, Evers BM. Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells. Biochim Biophys Acta Mol Cell Res. 2021; 1868: 118966.

Ma W, Zhao X, Wang K, Liu J, Huang G. Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer. Cancer Biol Ther. 2018; 19: 835-46.

Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013; 56: 133-71.

Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, Fuchter MJ, Hsiao CD, Lam EW. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther. 2010; 9: 844-55.

Roshdy E, Mustafa M, Shaltout AE, Radwan MO, Ibrahim MAA, Soliman ME, Fujita M, Otsuka M, Ali TFS. Selective SIRT2 inhibitors as promising anti-cancer therapeutics: An update from 2016 to 2020. Eur J Med Chem. 2021; 224: 113709.

Salami R, Salami M, Mafi A, Vakili O, Asemi Z. Circular RNAs and glioblastoma multiforme: Focus on molecular mechanisms. Cell Commun Signal. 2022; 20: 13.

Shoba B, Lwin ZM, Ling LS, Bay BH, Yip GW, Kumar SD. Function of sirtuins in biological tissues. Anat Rec (Hoboken). 2009; 292: 536-43.

Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ, Ahmad N. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 2018; 28: 643-61.

Singh S, Kumar PU, Thakur S, Kiran S, Sen B, Sharma S, Rao VV, Poongothai AR, Ramakrishna G. Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells. Tumour Biol. 2015; 36: 6159-71.

Taylor OG, Brzozowski JS, Skelding KA. Glioblastoma multiforme: An overview of emerging therapeutic targets. Front Oncol. 2019; 9: 963.

Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors 2012; 38: 349-59.

Wang W, Im J, Kim S, Jang S, Han Y, Yang KM, Kim SJ, Dhanasekaran DN, Song YS. ROS-induced SIRT2 Up-regulation contributes to cisplatin sensitivity in ovarian cancer. Antioxidants (Basel) 2020; 9: 1137.

Wang Y, Yang J, Hong T, Chen X, Cui L. SIRT2: Controversy and multiple roles in disease and physiology. Ageing Res Rev. 2019; 55: 100961.

Westphal CH, Dipp MA, Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci. 2007; 32: 555-60.

Wong RS. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 2011; 30: 87.

Xu H, Li Y, Chen L, Wang C, Wang Q, Zhang H, Lin Y, Li Q, Pang T. SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway. Int J Oncol. 2016; 48: 613-23.

Xu W, Jiang K, Shen M, Qian Y, Peng Y. SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A. Biol Chem. 2015; 396: 929-36.

Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. Mol Endocrinol. 2007; 21: 1745-55.

Zhang GZ, Deng YJ, Xie QQ, Ren EH, Ma ZJ, He XG, Gao YC, Kang XW. Sirtuins and intervertebral disc degeneration: Roles in inflammation, oxidative stress, and mitochondrial function. Clin Chim Acta. 2020; 508: 33-42.

Zhang JH, Xu M. DNA fragmentation in apoptosis. Cell Res. 2000; 10: 205-11.

Zhu S, Dong Z, Ke X, Hou J, Zhao E, Zhang K, Wang F, Yang L, Xiang Z, Cui H. The roles of sirtuins family in cell metabolism during tumor development. Semin Cancer Biol. 2019; 57: 59-71.

Downloads

Published

2022-06-06

How to Cite

Güçlü, E., İlknur . Çınar Ayan, and H. Vural. “Inhibitory Effect of AK-7 Mediates by Apoptosis, Increases DNA Fragmentation and Caspase-3 Activity in Human Glioblastoma Multiforme Cells”. Bangladesh Journal of Pharmacology, vol. 17, no. 2, June 2022, pp. 42-50, doi:10.3329/bjp.v17i2.59809.

Issue

Section

Research Articles