IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition

Authors

  • Rajagopalan Prasanna Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha
  • Martin Raju Department of Microbiology and Parasitology, College of Medicine, King Khalid University, Abha
  • Hateem Aseeri Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha
  • Ismail M. Helal 1. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia; 2. Plant Researches Department, Nuclear Research Center, Atomic Energy Authority, P. N. 13759, Egypt
  • Ashraf A Elbessoumy 1. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia; 2. Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt

Keywords:

Akt, acute myeloid leukemia (AML), apoptosis, cell cycle, IOX-101

Abstract

Cancer of the blood continues to be a major mortality factor globally. Arylidene compounds are well known for their anticancer effects. Here we describe the biological efficacy of IOX-101, a potential lead-compound of arylidene in acute myeloid leukemia (AML). Initially, molecular docking analysis was performed to check the binding efficacy of the compound with protein kinase B (Akt). The ability of the molecule to inhibit AML proliferation was assessed in THP-1 and Kasumi-6 cells by a standard MTT assay. Hoechst 333258/propidium iodide (PI) staining was carried out to analyze the nuclear damage. Flow cytometry was performed to check the apoptotic and cell cycle changes in THP-1 cells. The effect of IOX-101 on Akt phosphorylation was assessed by Western blot analysis. Molecular docking revealed interaction and binding of IOX-101 with the active site of Akt enzyme. The compound reduced proliferation of both AML cell lines in a dose-responsive way. Nuclear staining and cell cycle results revealed DNA damage by IOX-101 in THP-1 cells, and a significant increase in early and late phase apoptotic cells. A dose-dependent dephosphorylation of Akt (Ser 473) by IOX-101 was observed, which indicated allosteric inhibition of Akt by the compound. Our results showed that the DNA damage-mediated antiproliferative effect of IOX-101 in AML cells was mediated by Akt enzyme inhibition, and that this molecule possesses an effective chemotherapeutic potential against AML.

https://doi.org/10.2298/ABS170922049R

Received: September 22, 2017; Revised: November 1, 2017; Accepted: November 7, 2017; Published online: November 28, 2017

How to cite this article: Rajagopalan Prasanna, Raju M, Aseeri H, Helal IM, Elbessoumy AA. IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition. Arch Biol Sci. 2018;70(2):321-7.

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References

Ramos NR, Mo CC, Karp JE, Hourigan CS. Current Approaches in the Treatment of Relapsed and Refractory Acute Myeloid Leukemia. J Clin Med. 2015;4(4):665-95.

Herrmann H, Blatt K, Shi J, Gleixner KV, Cerny-Reiterer S, Müllauer L, Vakoc CR, Sperr WR, Horny HP, Bradner JE, Zuber J, Valent P. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem-and progenitor cells in acute myeloid leukemia (AML). Oncotarget. 2012;3:1588-99.

Mateen S, Tyagi A, Agarwal C, Singh RP, Agarwal R. Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators. Mol Carcinog. 2010;49(3):247-58

Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988-04.

Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signaling controls tumour cell growth. Nature. 2006;441:424-30.

Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol. 2006;7:285-94.

Fong Y, Lin YC, Wu CY, Wang HM, Lin LL, Chou HL, Teng YN, Yuan SS, Chiu CC. The Antiproliferative and Apoptotic Effects of Sirtinol, a Sirtuin Inhibitor on Human Lung Cancer Cells by Modulating Akt/β-Catenin-Foxo3A Axis. ScientificWorldJournal. 2014;2014:937051.

Prasanna R, Harish CC. Anticancer Effect of a Novel 2-Arylidene-4,7-dimethyl indan-1-one Against Human Breast Adenocarcinoma Cell Line by G2/M Cell Cycle Arrest. Oncol Res. 2010;18(10):461-8.

Rajagopalan Prasanna, Alahmari KA, Elbessoumy AA, Balasubramaniam M, Suresh R, Shariff ME, Chandramoorthy HC. Biological evaluation of 2-arylidene-4, 7-dimethyl indan-1-one (FXY-1): a novel Akt inhibitor with potent activity in lung cancer. Cancer Chemother Pharmacol. 2016;77(2):393-04.

Eswar N, Marti-Renom MA, Webb B, Madhusudhan MS, Eramian D, Shen M, Pieper U, Sali A. Comparative Protein Structure Modeling With MODELLER. Curr Protoc Protein Sci. 2006;05:5:5-6.

Lovell SC, Davis IW, Arendall III WB, de Bakker PIW, Word JM, Prisant MG, Richardson JC, Richardson DC . Structure validation by Calpha geometry: phi,psi and Cbeta deviation. Proteins. 2002;50:437-50.

Luthy R, Bowie JU, Eisenberg D. Assessment of protein models with three-dimensional profiles. Nature. 1992;356(6364):83-5.

Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun. 1995. 91:43–56.

Nathan Schmid , Andreas P, Eichenberger, Alexandra Choutko, SereinaRiniker, Moritz Winger, Alan E. Mark, Wilfred F, van Gunsteren . Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur Biophys J. 2011;40:843-56.

Chemskech [Internet]. Version 14.01. Toronto ON,Canada: Advanced Chemistry Department. 2014- [Updated November 2017, cited 2014 May 01]. Available from :http//www.acdlabs.com

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Computational Chemistry. 2009;16:2785-91.

Laskowski R A, Swindells M B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf. 2011;51: 2778-86.

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55-63.

Belloc F, Dumain P, Boisseau MR, Jalloustre C, Reiffers J, Bernard P. A flow cytometric method using Hoechst 33342 and propidium iodide for simultaneous cell cycle analysis and apoptosis determination in unfixed cells. Cytometry. 1994;17:59-65.

Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997;16:6151-61.

Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V, Venuta S, Romano MF. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood. 2005;106:1400-06.

Mahavir C, Anil Kumar S, Vijay T. Synthesis of 5-arylidine amino-1,3,4-thiadiazol-2-[(N-substituted benzyol)]sulphonamides endowed with potent antioxidants and anticancer activity induces growth inhibition in HEK293, BT474 and NCI-H226 cells.Med Chem Res. 2014;23(6):3049-64.

Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991;26:407-14.

Zeng P, Liu B, Wang Q, Fan Q, Diao JX, Tang J, Fu XQ, Sun XG. Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2. Oxid Med Cell Longev. 2015;2015:379538.

Zhang BG, Du T, Zang MD, Chang Q, Fan ZY3, Li JF, Yu BQ, Su LP, Li C, Yan C, Gu QL, Zhu ZG, Yan M, Liu B. Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9. Oncotarget. 2014;5(21):10584-95.

Searle J, Lawson TA, Abott PJ, Harmon B, Kerr JFR. An electron-microscope study of the mode of cell death induced by cancer chemotherapeutic agents in populations of proliferating normal and neoplastic cells. J Pathol 1994;116:129-38.

Hsu SL, Yin SC, Liu MC, Reichert U, Ho WL. Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. Exp Cell Res. 1999;252(2):332-41

Yoshihiro Higuchi. Glutathione depletion – induced chromosomal DNA fragmentation associated with apoptosis and necrosis. J Cell Mol Med. 2004;18(4):445-64.

Tanel A, Averill-Bates DA. P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. Cell Signal. 2007;19(5):968-77.

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Published

2018-05-30

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Prasanna R, Raju M, Aseeri H, Helal IM, Elbessoumy AA. IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition. Arch Biol Sci [Internet]. 2018May30 [cited 2024Mar.29];70(2):321-7. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/2201

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