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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Combination of Salinomycin and AZD3463 Reveals Synergistic Effect on Reducing the Viability of T98G Glioblastoma Cells

Author(s): Aycan Asik, Neslihan P.O. Ay, Bakiye G. Bagca, Hasan O. Caglar, Cumhur Gunduz and Cigir B. Avci*

Volume 20, Issue 18, 2020

Page: [2267 - 2273] Pages: 7

DOI: 10.2174/1871520620666200721121517

Price: $65

Abstract

Background: Salinomycin, an ionophore antibiotic, is known to be an effective agent in reducing the viability of Glioblastoma (GBM) cells. The combination of salinomycin with other chemotherapeutic drugs would help to overcome the drug resistance of GBM cells.

Objective: This study aims to test the combinatorial effect of salinomycin and AZD3463 in T98G GBM cells.

Methods: The cytotoxic effects of drugs on T98G GBM cells were determined by using WST-8 assay. Flow cytometry was used to identify apoptosis and cell cycle profiles after treatments. Real-time PCR was used to portray mRNA expression profiles of genes in the Wnt-signaling pathway after treatments.

Results: IC50 concentrations of AZD3463 and salinomycin were 529nM and 7.3μM for 48h, respectively. The combination concentrations of AZD3463 and salinomycin were 3.3μM and 333nM, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. AZD3463, salinomycin, and their combination induced apoptosis in 1.2, 1.4, and 3.2 folds, respectively. AZD3463 and the combination treatment induced the cell cycle arrest at the G1 phase. Salinomycin and AZD3463 treatments, either alone or in combination, resulted in the downregulation or upregulation of mRNA expression levels of genes in the Wntsignaling pathway.

Conclusion: Salinomycin, AZD3463, and their combination may inhibit proliferation and induce apoptosis in GBM cells due to a decrease in expression levels of genes acting in both the canonical and non-canonical Wnt signaling pathways. The Wnt signaling pathway may be involved in salinomycin-AZD3463 drug interaction.

Keywords: Anaplastic lymphoma kinase, anticancer drug combination, AZD3463, glioblastoma, salinomycin, Wnt signaling pathway.

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[1]
Thakkar, J.P.; Dolecek, T.A.; Horbinski, C.; Ostrom, Q.T.; Lightner, D.D.; Barnholtz-Sloan, J.S.; Villano, J.L. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol. Biomarkers Prev., 2014, 23(10), 1985-1996.
[http://dx.doi.org/10.1158/1055-9965.EPI-14-0275] [PMID: 25053711]
[2]
Choucair, A.K.; Levin, V.A.; Gutin, P.H.; Davis, R.L.; Silver, P.; Edwards, M.S.; Wilson, C.B. Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J. Neurosurg., 1986, 65(5), 654-658.
[http://dx.doi.org/10.3171/jns.1986.65.5.0654] [PMID: 3021931]
[3]
Osuka, S.; Van Meir, E.G. Overcoming therapeutic resistance in glioblastoma: the way forward. J. Clin. Invest., 2017, 127(2), 415-426.
[http://dx.doi.org/10.1172/JCI89587] [PMID: 28145904]
[4]
Parker, N.R.; Khong, P.; Parkinson, J.F.; Howell, V.M.; Wheeler, H.R. Molecular heterogeneity in glioblastoma: potential clinical implications. Front. Oncol., 2015, 5, 55.
[http://dx.doi.org/10.3389/fonc.2015.00055] [PMID: 25785247]
[5]
Skaga, E.; Kulesskiy, E.; Fayzullin, A.; Sandberg, C.J.; Potdar, S.; Kyttälä, A.; Langmoen, I.A.; Laakso, A.; Gaál-Paavola, E.; Perola, M.; Wennerberg, K.; Vik-Mo, E.O. Intertumoral heterogeneity in patient-specific drug sensitivities in treatment-naïve glioblastoma. BMC Cancer, 2019, 19(1), 628.
[http://dx.doi.org/10.1186/s12885-019-5861-4] [PMID: 31238897]
[6]
Frei, E., III Combination chemotherapy. Proc. R. Soc. Med., 1974, 67(6 Pt 1), 425-436.
[http://dx.doi.org/10.1177/00359157740676P101] [PMID: 4851085]
[7]
Zhou, S.; Wang, F.; Wong, E.T.; Fonkem, E.; Hsieh, T.C.; Wu, J.M.; Wu, E. Salinomycin: A novel anti-cancer agent with known anti-coccidial activities. Curr. Med. Chem., 2013, 20(33), 4095-4101.
[http://dx.doi.org/10.2174/15672050113109990199] [PMID: 23931281]
[8]
Gupta, P.B.; Onder, T.T.; Jiang, G.; Tao, K.; Kuperwasser, C.; Weinberg, R.A.; Lander, E.S. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 2009, 138(4), 645-659.
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730]
[9]
Kaplan, F.; Teksen, F. Apoptotic effects of salinomycin on human ovarian cancer cell line (OVCAR-3). Tumour Biol., 2016, 37(3), 3897-3903.
[http://dx.doi.org/10.1007/s13277-015-4212-6] [PMID: 26476539]
[10]
Kim, K.Y.; Yu, S.N.; Lee, S.Y.; Chun, S.S.; Choi, Y.L.; Park, Y.M.; Song, C.S.; Chatterjee, B.; Ahn, S.C. Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem. Biophys. Res. Commun., 2011, 413(1), 80-86.
[http://dx.doi.org/10.1016/j.bbrc.2011.08.054] [PMID: 21871443]
[11]
Kim, J.H.; Chae, M.; Kim, W.K.; Kim, Y.J.; Kang, H.S.; Kim, H.S.; Yoon, S. Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein. Br. J. Pharmacol., 2011, 162(3), 773-784.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01089.x] [PMID: 20973777]
[12]
Fuchs, D.; Heinold, A.; Opelz, G.; Daniel, V.; Naujokat, C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem. Biophys. Res. Commun., 2009, 390(3), 743-749.
[http://dx.doi.org/10.1016/j.bbrc.2009.10.042] [PMID: 19835841]
[13]
Chen, T.; Yi, L.; Li, F.; Hu, R.; Hu, S.; Yin, Y.; Lan, C.; Li, Z.; Fu, C.; Cao, L.; Chen, Z.; Xian, J.; Feng, H. Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells. Mol. Med. Rep., 2015, 11(4), 2407-2412.
[http://dx.doi.org/10.3892/mmr.2014.3027] [PMID: 25435259]
[14]
Calzolari, A.; Saulle, E.; De Angelis, M.L.; Pasquini, L.; Boe, A.; Pelacchi, F.; Ricci-Vitiani, L.; Baiocchi, M.; Testa, U. Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines. PLoS One, 2014, 9(4)e94438
[http://dx.doi.org/10.1371/journal.pone.0094438] [PMID: 24740347]
[15]
Rothenstein, J.M.; Chooback, N. ALK inhibitors, resistance development, clinical trials. Curr. Oncol., 2018, 25(Suppl. 1), S59-S67.
[http://dx.doi.org/10.3747/co.25.3760] [PMID: 29910648]
[16]
Karagkounis, G.; Stranjalis, G.; Argyrakos, T.; Pantelaion, V.; Mastoris, K.; Rontogianni, D.; Komaitis, S.; Kalamatianos, T.; Sakas, D.; Tiniakos, D. Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: Correlations with clinical outcome. J. Clin. Pathol., 2017, 70(7), 593-599.
[http://dx.doi.org/10.1136/jclinpath-2016-204102] [PMID: 27993946]
[17]
Ferguson, S.D.; Xiu, J.; Weathers, S.P.; Zhou, S.; Kesari, S.; Weiss, S.E.; Verhaak, R.G.; Hohl, R.J.; Barger, G.R.; Reddy, S.K.; Heimberger, A.B. GBM-associated mutations and altered protein expression are more common in young patients. Oncotarget, 2016, 7(43), 69466-69478.
[http://dx.doi.org/10.18632/oncotarget.11617] [PMID: 27579614]
[18]
Junca, A.; Villalva, C.; Tachon, G.; Rivet, P.; Cortes, U.; Guilloteau, K.; Balbous, A.; Godet, J.; Wager, M.; Karayan-Tapon, L. Crizotinib targets in glioblastoma stem cells. Cancer Med., 2017, 6(11), 2625-2634.
[http://dx.doi.org/10.1002/cam4.1167] [PMID: 28960893]
[19]
Das, A.; Cheng, R.R.; Hilbert, M.L.; Dixon-Moh, Y.N.; Decandio, M.; Vandergrift, W.A., III; Banik, N.L.; Lindhorst, S.M.; Cachia, D.; Varma, A.K.; Patel, S.J.; Giglio, P. Synergistic effects of crizotinib and temozolomide in experimental FIG-ROS1 fusion-positive glioblastoma. Cancer Growth Metastasis, 2015, 8, 51-60.
[http://dx.doi.org/10.4137/CGM.S32801] [PMID: 26648752]
[20]
Lu, D.; Choi, M.Y.; Yu, J.; Castro, J.E.; Kipps, T.J.; Carson, D.A. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc. Natl. Acad. Sci. USA, 2011, 108(32), 13253-13257.
[http://dx.doi.org/10.1073/pnas.1110431108] [PMID: 21788521]
[21]
Wang, F.; He, L.; Dai, W.Q.; Xu, Y.P.; Wu, D.; Lin, C.L.; Wu, S.M.; Cheng, P.; Zhang, Y.; Shen, M.; Wang, C.F.; Lu, J.; Zhou, Y.Q.; Xu, X.F.; Xu, L.; Guo, C.Y. Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo. PLoS One, 2012, 7(12)e50638
[http://dx.doi.org/10.1371/journal.pone.0050638] [PMID: 23284640]
[22]
Olmez, I.; Shen, W.; McDonald, H.; Ozpolat, B. Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth. J. Cell. Mol. Med., 2015, 19(6), 1262-1272.
[http://dx.doi.org/10.1111/jcmm.12479] [PMID: 25787115]
[23]
Wu, C.; Zhang, H.F.; Gupta, N.; Alshareef, A.; Wang, Q.; Huang, Y.H.; Lewis, J.T.; Douglas, D.N.; Kneteman, N.M.; Lai, R. A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma. J. Hematol. Oncol., 2016, 9(1), 120.
[http://dx.doi.org/10.1186/s13045-016-0349-z] [PMID: 27821172]
[24]
Armanious, H.; Gelebart, P.; Anand, M.; Lai, R. Identification of a novel crosstalk between casein kinase 2α and NPM-ALK in ALK-positive anaplastic large cell lymphoma. Cell. Signal., 2013, 25(2), 381-388.
[http://dx.doi.org/10.1016/j.cellsig.2012.11.005] [PMID: 23153582]
[25]
Xipell, E.; Gonzalez-Huarriz, M.; Martinez de Irujo, J.J.; García-Garzón, A.; Lang, F.F.; Jiang, H.; Fueyo, J.; Gomez-Manzano, C.; Alonso, M.M. Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma. Oncotarget, 2016, 7(21), 30626-30641.
[http://dx.doi.org/10.18632/oncotarget.8905] [PMID: 27121320]
[26]
Magrath, J.W.; Kim, Y. Salinomycin’s potential to eliminate glioblastoma stem cells and treat glioblastoma multiforme. (Review) Int. J. Oncol., 2017, 51(3), 753-759.
[http://dx.doi.org/10.3892/ijo.2017.4082] [PMID: 28766685]
[27]
Wang, F.; Zheng, Z.; Guan, J.; Qi, D.; Zhou, S.; Shen, X.; Wang, F.; Wenkert, D.; Kirmani, B.; Solouki, T.; Fonkem, E.; Wong, E.T.; Huang, J.H.; Wu, E. Identification of a panel of genes as a prognostic biomarker for glioblastoma. EBioMedicine, 2018, 37, 68-77.
[http://dx.doi.org/10.1016/j.ebiom.2018.10.024] [PMID: 30341039]
[28]
Lorente, M.; Torres, S.; Salazar, M.; Carracedo, A.; Hernández-Tiedra, S.; Rodríguez-Fornés, F.; García-Taboada, E.; Meléndez, B.; Mollejo, M.; Campos-Martín, Y.; Lakatosh, S.A.; Barcia, J.; Guzmán, M.; Velasco, G. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ., 2011, 18(6), 959-973.
[http://dx.doi.org/10.1038/cdd.2010.170] [PMID: 21233844]
[29]
Zhang, Y.; Li, F.; Liu, L.; Jiang, H.; Hu, H.; Du, X.; Ge, X.; Cao, J.; Wang, Y. Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells. BMC Cancer, 2019, 19(1), 381.
[http://dx.doi.org/10.1186/s12885-019-5590-8] [PMID: 31023247]
[30]
Wang, Y.; Wang, L.; Guan, S.; Cao, W.; Wang, H.; Chen, Z.; Zhao, Y.; Yu, Y.; Zhang, H.; Pang, J.C.; Huang, S.L.; Akiyama, Y.; Yang, Y.; Sun, W.; Xu, X.; Shi, Y.; Zhang, H.; Kim, E.S.; Muscal, J.A.; Lu, F.; Yang, J. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci. Rep., 2016, 6, 19423.
[http://dx.doi.org/10.1038/srep19423] [PMID: 26786851]
[31]
Ma, T.; Tzavaras, N.; Tsokas, P.; Landau, E.M.; Blitzer, R.D. Synaptic stimulation of mTOR is mediated by Wnt signaling and regulation of glycogen synthetase kinase-3. J. Neurosci., 2011, 31(48), 17537-17546.
[http://dx.doi.org/10.1523/JNEUROSCI.4761-11.2011] [PMID: 22131415]
[32]
Komiya, Y.; Habas, R. Wnt signal transduction pathways. Organogenesis, 2008, 4(2), 68-75.
[http://dx.doi.org/10.4161/org.4.2.5851] [PMID: 19279717]
[33]
MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell, 2009, 17(1), 9-26.
[http://dx.doi.org/10.1016/j.devcel.2009.06.016] [PMID: 19619488]
[34]
Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene, 2017, 36(11), 1461-1473.
[http://dx.doi.org/10.1038/onc.2016.304] [PMID: 27617575]
[35]
Cadigan, K.M.; Waterman, M.L. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb. Perspect. Biol., 2012, 4(11)a007906
[http://dx.doi.org/10.1101/cshperspect.a007906] [PMID: 23024173]

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