Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Investigating the Activity of Indole-2-on Derivative Src Kinase Inhibitors Against Chronic Myeloid Leukemia Cells

Author(s): Aysegul Cort-Donmez, Sureyya Olgen*, Ersin Guner, Gulsum Akgun-Cagliyan, Ferhat Hanikoglu, Melek Tunc-Ata and Emine Kilic-Toprak

Volume 23, Issue 1, 2023

Published on: 11 August, 2022

Page: [113 - 122] Pages: 10

DOI: 10.2174/1871520622666220513114205

Price: $65

Abstract

Background: Src family tyrosine kinases play a potential role in Bcr-Abl-induced leukemogenesis. Src kinase inhibitors are reported as selective inhibitors of chronic myeloid leukemia.

Objective: Since Src kinase inhibitors have an inhibitive effect on chronic myeloid leukemia, indole derivatives (C-1, C-2, C-3) previously found as potent inhibitors of Src kinase were tested against chronic myeloid leukemia in this study.

Methods: Cell viability of K562 and R/K562 cells, antiproliferative and antioxidant effects, and inhibition profiles of Bcr-Abl kinase of indole derivatives were determined compared to dasatinib and imatinib.

Results: The results showed that compounds affected cell proliferation and decreased the levels of Bcr/Abl. These results confirmed that the antileukemic activity of compounds was related to Bcr/Abl expression. Docking studies also presented that compounds are inhibitors of both Src and Abl kinases. Calculation of drug-like properties showed that compounds could be potential drug candidates.

Conclusion: Among indole-2-on derivatives, previously identified as Src kinase inhibitors, C-2 has been discovered to be a strong anticancer drug that is active against susceptible and resistant K562 cell lines and induces apoptosis.

Keywords: Indole-2-on derivatives, anti-proliferative, cell viability, Src, ABl, docking.

« Previous Next »
Graphical Abstract

[1]
Massimino, M.; Stella, S.; Tirrò, E.; Pennisi, M.S.; Vitale, S.R.; Puma, A.; Romano, C.; D.I., Gregorio S.; Tomarchio, C.; DI Raimondo, F.; Manzella, L. ABL1-directed inhibitors for CML: Efficacy, resistance and future perspectives. Anticancer Res., 2020, 40(5), 2457-2465.
[http://dx.doi.org/10.21873/anticanres.14215] [PMID: 32366389]
[2]
Roy, M.; Sarkar, R.; Mukherjee, A.; Mukherjee, S. Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells. Chem. Biol. Interact., 2015, 242, 195-201.
[http://dx.doi.org/10.1016/j.cbi.2015.10.004] [PMID: 26456889]
[3]
O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera, V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.; Metcalf, C.A., III; Tyner, J.W.; Loriaux, M.M.; Corbin, A.S.; Wardwell, S.; Ning, Y.; Keats, J.A.; Wang, Y.; Sundaramoorthi, R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.; Sawyer, T.K.; Dalgarno, D.C.; Deininger, M.W.; Druker, B.J.; Clackson, T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell, 2009, 16(5), 401-412.
[http://dx.doi.org/10.1016/j.ccr.2009.09.028] [PMID: 19878872]
[4]
Dorey, K.; Engen, J.R.; Kretzschmar, J.; Wilm, M.; Neubauer, G.; Schindler, T.; Superti-Furga, G. Phosphorylation and structure-based functional studies reveal a positive and a negative role for the activation loop of the c-Abl tyrosine kinase. Oncogene, 2001, 20(56), 8075-8084.
[http://dx.doi.org/10.1038/sj.onc.1205017] [PMID: 11781820]
[5]
Huang, Y.H.; Henriques, S.T.; Wang, C.K.; Thorstholm, L.; Daly, N.L.; Kaas, Q.; Craik, D.J. Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold. Sci. Rep., 2015, 5(1), 12974.
[http://dx.doi.org/10.1038/srep12974] [PMID: 26264857]
[6]
Trela, E.; Glowacki, S. Błasiak, J. Therapy of chronic myeloid leukemia: Twilight of the imatinib era? ISRN Oncol., 2014, 2014596483
[http://dx.doi.org/10.1155/2014/596483] [PMID: 24634785]
[7]
Gagic, Z.; Ruzic, D.; Djokovic, N.; Djikic, T.; Nikolic, K. In silico Methods for design of kinase inhibitors as anticancer drugs. Front Chem., 2020, 7, 873.
[http://dx.doi.org/10.3389/fchem.2019.00873] [PMID: 31970149]
[8]
Kilic-Kurt, Z.; Bakar, F.; Ölgen, S. Synthesis, biological, and computational evaluation of novel 1,3,5-substituted indolin-2-one derivatives as inhibitors of src tyrosine kinase. Arch. Pharm. (Weinheim), 2015, 348(10), 715-729.
[http://dx.doi.org/10.1002/ardp.201500109] [PMID: 26260414]
[9]
Nam, S.; Kim, D.; Cheng, J.Q.; Zhang, S.; Lee, J.H.; Buettner, R.; Mirosevich, J.; Lee, F.Y.; Jove, R. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res., 2005, 65(20), 9185-9189.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1731] [PMID: 16230377]
[10]
Finotti, A.; Gasparello, J.; Breveglieri, G.; Cosenza, L.C.; Montagner, G.; Bresciani, A.; Altamura, S.; Bianchi, N.; Martini, E.; Gallerani, E.; Borgatti, M.; Gambari, R. Development and characterization of K562 cell clones expressing BCL11A-XL: Decreased hemoglobin production with fetal hemoglobin inducers and its rescue with mithramycin. Exp. Hematol., 2015, 43(12), 1062-1071.e3.
[http://dx.doi.org/10.1016/j.exphem.2015.08.011] [PMID: 26342260]
[11]
Deininger, M.W.; Druker, B.J. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol. Rev., 2003, 55(3), 401-423.
[http://dx.doi.org/10.1124/pr.55.3.4] [PMID: 12869662]
[12]
Shah, N.P.; Kasap, C.; Weier, C.; Balbas, M.; Nicoll, J.M.; Bleickardt, E.; Nicaise, C.; Sawyers, C.L. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell, 2008, 14(6), 485-493.
[http://dx.doi.org/10.1016/j.ccr.2008.11.001] [PMID: 19061839]
[13]
Tsukatani, T.; Suenaga, H.; Shiga, M.; Ikegami, T.; Ishiyama, M.; Ezoe, T. Rapid susceptibility testing for slowly growing nontuberculous mycobacteria using a colorimetric microbial viability assay based on the reduction of water-soluble tetrazolium WST-1. Eur. J. Clin. Microbiol. Infect. Dis., 2015, 34(10), 1965-1973.
[14]
Gordon, J.L.; Brown, M.A.; Reynolds, M.M. Cell-Based methods for determination of efficacy for candidate therapeutics in the clinical management of cancer. Diseases, 2018, 6(4)E85
[http://dx.doi.org/10.3390/diseases6040085] [PMID: 30249005]
[15]
Kosova, B.; Tezcanli, B.; Ekiz, H.A.; Cakir, Z.; Selvi, N.; Dalmizrak, A.; Kartal, M.; Gunduz, U.; Baran, Y. Suppression of STAT5A increases chemotherapeutic sensitivity in imatinib-resistant and imatinib-sensitive K562 cells. Leuk. Lymphoma, 2010, 51(10), 1895-1901.
[http://dx.doi.org/10.3109/10428194.2010.507830] [PMID: 20849385]
[16]
Olive, P.L.; Banáth, J.P. The comet assay: A method to measure DNA damage in individual cells. Nat. Protoc., 2006, 1(1), 23-29.
[http://dx.doi.org/10.1038/nprot.2006.5] [PMID: 17406208]
[17]
Erel, O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin. Biochem., 2004, 37(2), 112-119.
[http://dx.doi.org/10.1016/j.clinbiochem.2003.10.014] [PMID: 14725941]
[18]
Protein Data Bank (PDB) 2021. Available from: http://www.rcsb.org
[19]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[20]
Swiss ADMET prediction, swiss institute of bioinformatics. 2021. Available from: http://swissadme.ch/
[21]
Molinspiration Chem informatics 2021. Available from: http://www.molinspiration.com/services/properties.html
[22]
Yu, C.; Krystal, G.; Varticovksi, L.; McKinstry, R.; Rahmani, M.; Dent, P.; Grant, S. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res., 2002, 62(1), 188-199.
[PMID: 11782377]
[23]
Park, J.I.; Jeong, J.S.; Han, J.Y.; Kim, D.I.; Gao, Y.H.; Park, S.C.; Rodgers, G.P.; Kim, I.H. Hydroxyurea induces a senescence-like change of K562 human erythroleukemia cell. J. Cancer Res. Clin. Oncol., 2000, 126(8), 455-460.
[http://dx.doi.org/10.1007/s004320050013] [PMID: 10961388]
[24]
de Lavallade, H.; Apperley, J.F.; Khorashad, J.S.; Milojkovic, D.; Reid, A.G.; Bua, M.; Szydlo, R.; Olavarria, E.; Kaeda, J.; Goldman, J.M.; Marin, D. Imatinib for newly diagnosed patients with chronic myeloid leukemia: Incidence of sustained responses in an intention-to-treat analysis. J. Clin. Oncol., 2008, 26(20), 3358-3363.
[http://dx.doi.org/10.1200/JCO.2007.15.8154] [PMID: 18519952]
[25]
Aceves-Luquero, C.I.; Agarwal, A.; Callejas-Valera, J.L.; Arias-González, L.; Esparís-Ogando, A.; del Peso Ovalle, L.; Bellón-Echeverria, I.; de la Cruz-Morcillo, M.A.; Galán Moya, E.M.; Moreno Gimeno, I.; Gómez, J.C.; Deininger, M.W.; Pandiella, A.; Sánchez Prieto, R. ERK2, but not ERK1, mediates acquired and “de novo” resistance to imatinib mesylate: Implication for CML therapy. PLoS One, 2009, 4(7)e6124
[http://dx.doi.org/10.1371/journal.pone.0006124] [PMID: 19568437]
[26]
Morelli, M.B.; Amantini, C.; Santoni, M.; Soriani, A.; Nabissi, M.; Cardinali, C.; Santoni, A.; Santoni, G. Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells. Oncotarget, 2015, 6(34), 36245-36259.
[http://dx.doi.org/10.18632/oncotarget.5768] [PMID: 26474283]
[27]
Teppo, H.R.; Soini, Y.; Karihtala, P. Reactive oxygen species-mediated mechanisms of action of targeted cancer therapy. Oxid. Med. Cell. Longev., 2017, 20171485283
[http://dx.doi.org/10.1155/2017/1485283] [PMID: 28698765]
[28]
Rossari, F.; Minutolo, F.; Orciuolo, E. Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy. J. Hematol. Oncol., 2018, 11(1), 84.
[http://dx.doi.org/10.1186/s13045-018-0624-2] [PMID: 29925402]
[29]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]

Rights & Permissions Print Cite
Article Metrics
22
2
© 2024 Bentham Science Publishers | Privacy Policy