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

The Synergistic Anti-colon Cancer Effect of Aurora A Inhibitors and AKT Inhibitors Through PI3K/AKT Pathway

Author(s): Cheng Sun, Zhen Qu, Weilin Liu, Zhigang Qiu, Yanfeng Lü* and Zhenqing Sun*

Volume 23, Issue 1, 2023

Published on: 11 August, 2022

Page: [87 - 93] Pages: 7

DOI: 10.2174/1871520622666220422133537

Price: $65

Abstract

Background: Both AKT and Aurora inhibitors are a potential therapeutic agent for the treatment of malignant tumors. However, the role of combined inhibition of AKT and Aurora in colon cancer and its underlying mechanism have yet to be fully investigated.

Objective: To investigate the role of combined AKT and Aurora inhibitors in colon cancer and its underlying mechanisms.

Methods: CCK8 assay, colony formation assay, and flow cytometry were performed to analyze the proliferation and apoptosis of colon cancer cell line SW480 treated with combined AKT inhibitor MK2206 and Aurora inhibitor Alisertib, respectively. And tumor formation and growth were measured in tumor allograft model mice administered with the combined inhibitors. Western blot analysis was used to examine the expression levels of apoptosis-related proteins and signal transduction pathway components. The PI3K agonist 740Y-P and Overexpression of AKT are used to verify whether the PI3K/AKT pathway plays an anti-tumor effect when combined with inhibitory administration.

Results: Aurora A inhibitor Alisertib and AKT inhibitor MK2206 displayed consistent and synergistic antiproliferation and proapoptotic effects. Combined inhibition of Aurora A and AKT down-regulated the expression of Bcl-2/Bax and up-regulated the expression of cleaved-caspase-3 and cleaved-PARP. While single-drug treatment can significantly inhibit the expression of P-PI3K and P-AKT as well as increase the expression of P53 and H2A.X, the combined drugs had a more significant inhibitory effect than the single drug. Moreover, administration of PI3K agonist 740Y-P and AKT1 overexpression in experiments proved that the combined drugs exert an anticancer effect by inhibiting the PI3K/AKT pathway. Meanwhile, we showed that the combined administration had an anti-colon cancer effect on tumor allograft mice, and the underlying mechanism involved inhibition of the PI3K/AKT pathway.

Conclusion: Combined administration of Aurora A inhibitor Alisertib and AKT inhibitor MK2206 can inhibit the proliferation of colon cancer cells and induce apoptosis, while inhibiting tumor growth in vivo. The underlying mechanism may involve the PI3K/AKT pathway and DNA damage pathway.

Keywords: Aurora kinase A, colon cancer, PI3K/Akt, P53, proliferation, apoptosis.

« Previous
Graphical Abstract

[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Pawlik, T.M. Colon Cancer. Surg. Oncol. Clin. N. Am., 2018, 27(2), xiii-xiv.
[http://dx.doi.org/10.1016/j.soc.2017.11.013] [PMID: 29496098]
[3]
Chang, G.J.; Kopetz, S. Coordination of care in colon cancer. Cancer, 2015, 121(18), 3201-3202.
[http://dx.doi.org/10.1002/cncr.29473] [PMID: 26043269]
[4]
Marchiori, C.; Scarpa, M.; Kotsafti, A.; Morgan, S.; Fassan, M.; Guzzardo, V.; Porzionato, A.; Angriman, I.; Ruffolo, C.; Sut, S.; Dall’Acqua, S.; Bardini, R.; De Caro, R.; Castoro, C.; Scarpa, M.; Castagliuolo, I. Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells. J. Exp. Clin. Cancer Res., 2019, 38(1), 190.
[http://dx.doi.org/10.1186/s13046-019-1205-0] [PMID: 31072360]
[5]
László, L. Predictive and prognostic factors in the complex treatment of patients with colorectal cancer. Magy. Onkol., 2010, 54(4), 383-394.
[http://dx.doi.org/10.1556/MOnkol.54.2010.4.13] [PMID: 21163770]
[6]
Borisa, A.C.; Bhatt, H.G. A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. Eur. J. Med. Chem., 2017, 140(11), 1-19.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.045] [PMID: 28918096]
[7]
Damodaran, A.P.; Vaufrey, L.; Gavard, O.; Prigent, C. Aurora A kinase is a priority pharmaceutical target for the treatment of cancers. Trends Pharmacol. Sci., 2017, 38(8), 687-700.
[http://dx.doi.org/10.1016/j.tips.2017.05.003] [PMID: 28601256]
[8]
Cammareri, P.; Scopelliti, A.; Todaro, M.; Eterno, V.; Francescangeli, F.; Moyer, M.P.; Agrusa, A.; Dieli, F.; Zeuner, A.; Stassi, G. Aurora-A is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. Cancer Res., 2010, 70(11), 4655-4665.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3953] [PMID: 20460511]
[9]
Korobeynikov, V.; Borakove, M.; Feng, Y.; Wuest, W.M.; Koval, A.B.; Nikonova, A.S.; Serebriiskii, I.; Chernoff, J.; Borges, V.F.; Golemis, E.A.; Shagisultanova, E. Combined inhibition of Aurora A and p21-activated kinase 1 as a new treatment strategy in breast cancer. Breast Cancer Res. Treat., 2019, 177(2), 369-382.
[http://dx.doi.org/10.1007/s10549-019-05329-2] [PMID: 31254157]
[10]
Wu, J.; Cheng, Z.; Xu, X.; Fu, J.; Wang, K.; Liu, T.; Wu, C.; Kong, X.; Yang, Q.; Yan, G.; Zhou, H. Aurora-A induces chemoresistance through activation of the AKT/mTOR pathway in endometrial cancer. Front. Oncol., 2019, 9, 422.
[http://dx.doi.org/10.3389/fonc.2019.00422] [PMID: 31192127]
[11]
Xie, Y.; Zhu, S.; Zhong, M.; Yang, M.; Sun, X.; Liu, J.; Kroemer, G.; Lotze, M.; Zeh, H.J., III; Kang, R.; Tang, D. Inhibition of aurora kinase a induces necroptosis in pancreatic carcinoma. Gastroenterology, 2017, 153(5), 1429-1443.e5.
[http://dx.doi.org/10.1053/j.gastro.2017.07.036] [PMID: 28764929]
[12]
Yan, M.; Wang, C.; He, B.; Yang, M.; Tong, M.; Long, Z.; Liu, B.; Peng, F.; Xu, L.; Zhang, Y.; Liang, D.; Lei, H.; Subrata, S.; Kelley, K.W.; Lam, E.W.; Jin, B.; Liu, Q. Aurora-A kinase: A potent oncogene and target for cancer therapy. Med. Res. Rev., 2016, 36(6), 1036-1079.
[http://dx.doi.org/10.1002/med.21399] [PMID: 27406026]
[13]
Lee, J.W.; Parameswaran, J.; Sandoval-Schaefer, T.; Eoh, K.J.; Yang, D.H.; Zhu, F.; Mehra, R.; Sharma, R.; Gaffney, S.G.; Perry, E.B.; Townsend, J.P.; Serebriiskii, I.G.; Golemis, E.A.; Issaeva, N.; Yarbrough, W.G.; Koo, J.S.; Burtness, B. Combined Aurora kinase A (AURKA) and WEE1 inhibition demonstrates synergistic antitumor effect in squamous cell carcinoma of the head and neck. Clin. Cancer Res., 2019, 25(11), 3430-3442.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0440] [PMID: 30755439]
[14]
Wang, F.; Li, H.; Yan, X.G.; Zhou, Z.W.; Yi, Z.G.; He, Z.X.; Pan, S.T.; Yang, Y.X.; Wang, Z.Z.; Zhang, X.; Yang, T.; Qiu, J.X.; Zhou, S.F. Alisertib induces cell cycle arrest and autophagy and suppresses epithelial-to-mesenchymal transition involving PI3K/Akt/mTOR and sirtuin 1-mediated signaling pathways in human pancreatic cancer cells. Drug Des. Devel. Ther., 2015, 9(9), 575-601.
[PMID: 25632225]
[15]
Zhang, L.; Liu, B. Sapylin inhibits lung cancer cell proliferation and promotes apoptosis by attenuating PI3K/AKT signaling. J. Cell. Biochem., 2019, 120(9), 14679-14687.
[http://dx.doi.org/10.1002/jcb.28729] [PMID: 31009136]
[16]
Uhlenbrock, N.; Smith, S.; Weisner, J.; Landel, I.; Lindemann, M.; Le, T.A.; Hardick, J.; Gontla, R.; Scheinpflug, R.; Czodrowski, P.; Janning, P.; Depta, L.; Quambusch, L.; Müller, M.P.; Engels, B.; Rauh, D. Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt. Chem. Sci. (Camb.), 2019, 10(12), 3573-3585.
[http://dx.doi.org/10.1039/C8SC05212C] [PMID: 30996949]
[17]
Winder, A.; Unno, K.; Yu, Y.; Lurain, J.; Kim, J.J. The allosteric AKT inhibitor, MK2206, decreases tumor growth and invasion in patient derived xenografts of endometrial cancer. Cancer Biol. Ther., 2017, 18(12), 958-964.
[http://dx.doi.org/10.1080/15384047.2017.1281496] [PMID: 28112582]
[18]
Chowdhury, P.; Perera, D.; Powell, R.T.; Talley, T.; Tripathi, D.N.; Park, Y.S.; Mancini, M.A.; Davies, P.; Stephan, C.; Coarfa, C.; Dere, R. Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells. Sci. Rep., 2021, 11(1), 10461.
[http://dx.doi.org/10.1038/s41598-021-89933-7] [PMID: 34002003]
[19]
Algaber, A.; Al-Haidari, A.; Madhi, R.; Rahman, M.; Syk, I.; Thorlacius, H. MicroRNA-340-5p inhibits colon cancer cell migration via targeting of RhoA. Sci. Rep., 2020, 10(1), 16934.
[http://dx.doi.org/10.1038/s41598-020-73792-9] [PMID: 33037251]
[20]
O’Connor, O.A.; Özcan, M.; Jacobsen, E.D.; Roncero, J.M.; Trotman, J.; Demeter, J.; Masszi, T.; Pereira, J.; Ramchandren, R.; Beaven, A.; Caballero, D.; Horwitz, S.M.; Lennard, A.; Turgut, M.; Hamerschlak, N.; d’Amore, F.A.; Foss, F.; Kim, W.S.; Leonard, J.P.; Zinzani, P.L.; Chiattone, C.S.; Hsi, E.D.; Trümper, L.; Liu, H.; Sheldon-Waniga, E.; Ullmann, C.D.; Venkatakrishnan, K.; Leonard, E.J.; Shustov, A.R. Randomized Phase III Study of Alisertib or Investigator’s Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma. J. Clin. Oncol., 2019, 37(8), 613-623.
[http://dx.doi.org/10.1200/JCO.18.00899] [PMID: 30707661]
[21]
Zhang, Y.; Guo, L.; Law, B.Y.; Liang, X.; Ma, N.; Xu, G.; Wang, X.; Yuan, X.; Tang, H.; Chen, Q.; Wong, V.K.; Wang, X. Resveratrol decreases cell apoptosis through inhibiting DNA damage in bronchial epithelial cells. Int. J. Mol. Med., 2020, 45(6), 1673-1684.
[http://dx.doi.org/10.3892/ijmm.2020.4539] [PMID: 32186748]
[22]
Collins, P.L.; Purman, C.; Porter, S.I.; Nganga, V.; Saini, A.; Hayer, K.E.; Gurewitz, G.L.; Sleckman, B.P.; Bednarski, J.J.; Bassing, C.H.; Oltz, E.M. DNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner. Nat. Commun., 2020, 11(1), 3158.
[http://dx.doi.org/10.1038/s41467-020-16926-x] [PMID: 32572033]
[23]
Bishnupuri, K.S.; Alvarado, D.M.; Khouri, A.N.; Shabsovich, M.; Chen, B.; Dieckgraefe, B.K.; Ciorba, M.A. IDO1 and kynurenine pathway metabolites Activate PI3K-Akt signaling in the neoplastic colon epithelium to promote cancer cell proliferation and inhibit apoptosis. Cancer Res., 2019, 79(6), 1138-1150.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0668] [PMID: 30679179]
[24]
Liu, Z.; Wang, F.; Zhou, Z.W.; Xia, H.C.; Wang, X.Y.; Yang, Y.X.; He, Z.X.; Sun, T.; Zhou, S.F. Alisertib induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and p38 MAPK-mediated pathways in human glioblastoma cells. Am. J. Transl. Res., 2017, 9(3), 845-873.
[PMID: 28386317]
[25]
Liu, X.; Shi, Y.; Woods, K.W.; Hessler, P.; Kroeger, P.; Wilsbacher, J.; Wang, J.; Wang, J.Y.; Li, C.; Li, Q.; Rosenberg, S.H.; Giranda, V.L.; Luo, Y. Akt inhibitor a-443654 interferes with mitotic progression by regulating aurora a kinase expression. Neoplasia, 2008, 10(8), 828-837.
[http://dx.doi.org/10.1593/neo.08408] [PMID: 18670641]

Rights & Permissions Print Cite
Article Metrics
36
4
World No Tabaco Day
© 2024 Bentham Science Publishers | Privacy Policy