Anaplastic lymphoma kinase inhibitor NVP‑TAE684 suppresses the proliferation of human pancreatic adenocarcinoma cells

Duong,Hong-Quan; Than,Van Thai; Nguyen,Huyen-Trang; Nguyen,Phuong-Thoa; Thi,Huyen Trang Ha; Bui,Thi Ngoc Ha; Dang,Vu Phuong Linh; Dinh,Thi-Thanh; You,Kyu Sic; Dang,The-Hung; Seong,Yeon-Sun

doi:10.3892/or.2021.7979

Anaplastic lymphoma kinase inhibitor NVP‑TAE684 suppresses the proliferation of human pancreatic adenocarcinoma cells

Authors:
- Hong-Quan Duong
- Van Thai Than
- Huyen-Trang Nguyen
- Phuong-Thoa Nguyen
- Huyen Trang Ha Thi
- Thi Ngoc Ha Bui
- Vu Phuong Linh Dang
- Thi-Thanh Dinh
- Kyu Sic You
- The-Hung Dang
- Yeon-Sun Seong
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Affiliations: Laboratory Center, Hanoi University of Public Health, Hanoi 100000, Vietnam, Faculty of Biotechnology, Chemistry and Environmental Engineering, Phenikaa University, Hanoi 100000, Vietnam, Department of Biochemistry, College of Medicine, Dankook University, Cheonan‑si, Chungcheongnam‑do 31116, Republic of Korea
Published online on: February 18, 2021 https://doi.org/10.3892/or.2021.7979
Article Number: 28

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Abstract

Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVP‑TAE684, a well‑known inhibitor of ALK, was revealed to exert antitumor effects in several different malignancies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVP‑TAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase‑3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVP‑TAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC‑1, Panc‑1, MIA PaCa‑2, Capan‑1, CFPAC‑1, Colo‑357 and BxPC‑3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVP‑TAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased proliferation and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVP‑TAE684 or siRNA synergistically enhanced gemcitabine‑induced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVP‑TAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A, Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Ryan DP, Hong TS and Bardeesy N: Pancreatic adenocarcinoma. N Engl J Med. 371:1039–1049. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kamisawa T, Wood LD, Itoi T and Takaori K: Pancreatic cancer. Lancet. 388:73–85. 2016. View Article : Google Scholar : PubMed/NCBI
5	Oberstein PE and Olive KP: Pancreatic cancer: Why is it so hard to treat? Therap Adv Gastroenterol. 6:321–327. 2013. View Article : Google Scholar : PubMed/NCBI
6	Moore M: Activity of gemcitabine in patients with advanced pancreatic carcinoma. A review. Cancer. 78:633–638. 1996. View Article : Google Scholar : PubMed/NCBI
7	Carmichael J, Fink U, Russell RC, Spittle MF, Harris AL, Spiessi G and Blatter J: Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 73:101–105. 1996. View Article : Google Scholar : PubMed/NCBI
8	Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD, Trochanowski B and Tarassoff PG: Phase II trial of gemcitabine (2,2-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs. 12:29–34. 1994. View Article : Google Scholar : PubMed/NCBI
9	Roskoski R Jr: Anaplasmic lymphoma kinase (ALK): Structure, oncogenic activation and pharmacological inhibition. Pharmacol Res. 68:68–94. 2013. View Article : Google Scholar : PubMed/NCBI
10	Yan HH, Jung KH, Son MK, Fang Z, Kim SJ, Ryu YL, Kim J, Kim MH and Hong SS: Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer. Oncotarget. 5:9150–9168. 2014. View Article : Google Scholar : PubMed/NCBI
11	Jamshed MB, Munir F, Shahid N, Sadiq U, Muhammad SA, Ghanem NB, Zhong H, Li X and Zhang Q: Antitumor activity and combined inhibitory effect of ceritinib with gemcitabine in pancreatic cancer. Am J Physiol Gastrointest Liver Physiol. 318:G109–G119. 2019. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Wang L..Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC, et al: Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. Sci Rep. 6:194232016. View Article : Google Scholar : PubMed/NCBI
13	Chiarle R, Voena C, Ambrogio C, Piva R and Inghirami G: The anaplastic lymphoma kinase in the phathogenesis of cancer. Nat Rev Cancer. 8:11–23. 2008. View Article : Google Scholar : PubMed/NCBI
14	Mossé YP, Wood A and Maris JM: Inhibition of ALK signaling for cancer therapy. Clin Cancer Res. 15:5609–5614. 2009. View Article : Google Scholar : PubMed/NCBI
15	Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, et al: Identification of NVP-TAE684, a potent, selective and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci USA. 104:270–275. 2007. View Article : Google Scholar : PubMed/NCBI
16	McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, et al: Genomic alternations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 68:3389–3395. 2008. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Ye X, Liu J, Zha J and Pei L: Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 13:1–11. 2011. View Article : Google Scholar : PubMed/NCBI
18	Van Roosbroeck K, Cools J, Dierickx D, Thomas J, Vandenberghe P, Stul M, Delabie J, De Wolf-Peeters C, Marynen P and Wlodarska I: ALK-Positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica. 95:509–513. 2010. View Article : Google Scholar : PubMed/NCBI
19	Cerchietti L, Damm-Welk C, Vater I, Klapper W, Harder L, Pott C, Yang SN, Reiter A, Siebert R, Melnick A and Woessmann W: Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas. PLoS One. 6:e184362011. View Article : Google Scholar : PubMed/NCBI
20	Duijkers FA, Gaal J, Meijerink JP, Admiraal P, Pieters R, de Krijger RR and van Noesel MM: Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels. Cell Oncol (Dordr). 34:409–417. 2011. View Article : Google Scholar : PubMed/NCBI
21	Ye S, Zhang J, Shen J, Gao Y, Li Y, Choy E, Cote G, Harmon D, Mankin H, Gray NS, et al: NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function. Br J Pharmacol. 173:613–626. 2016. View Article : Google Scholar : PubMed/NCBI
22	Dai Y, Wei Q, Schwager C, Hanne J, Zhou C, Herfarth K, Rieken S, Lipson KE and Debus J: Oncogene addition and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC. Radiat Oncol. 13:12018. View Article : Google Scholar : PubMed/NCBI
23	Huang XX, Xie FF, Hou LJ, Chen XX, Ou RY, Yu JT, Qiu JG, Zhang WJ, Jiang QW, Yang Y, et al: Crizotinib synergizes with cisplatin in preclinical models of ovarian cancer. Am J Transl Res. 9:1667–1679. 2017.PubMed/NCBI
24	Liu Z, Jiang L, Li Y, Xie B, Xie J, Wang Z, Zhou X, Jiang H, Fang Y, Pan H and Han W: Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca²⁺/calcineurin/erk pathway. EBioMedicine. 42:326–339. 2019. View Article : Google Scholar : PubMed/NCBI
25	Alam MW, Borenäs M, Lind DE, Cervantes-Madris D, Umapathy G, Palmer RH and Hallberg B: Alectinib, an anaplastic lymphoma kinase inhibitor, abolishes ALK activity and growth in ALK-positive neuroblastoma cells. Front Oncol. 9:5792019. View Article : Google Scholar : PubMed/NCBI
26	Osawa T, Davies D and Hartley JA: Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells. Cell Dealth Dis. 2:e1872011. View Article : Google Scholar
27	Stark GR and Taylor WR: Analyzing the G2/M checkpoint. Methods Mol Biol. 280:51–82. 2004.PubMed/NCBI
28	Duong HQ, Hwang JS, Kim HJ, Kang HJ, Seong YS and Bae I: Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells. Int J Oncol. 41:855–861. 2012. View Article : Google Scholar : PubMed/NCBI
29	Duong HQ, Hwang JS, Kim HJ, Seong YS and Bae I: BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells. Int J Oncol. 41:2227–2236. 2012. View Article : Google Scholar : PubMed/NCBI
30	Furukawa T, Duquid WP, Rosenberg L, Viallet J, Galloway DA and Tsao MS: Long-term culture and immortalization of epithelial cells from normal adult human pancreatic ducts transfected vy the E6E7 gene of human papilloma virus 16. Am J Pathol. 148:1763–1770. 1996.PubMed/NCBI
31	Duong HQ, Kim HJ, Kang HJ, Seong YS and Bae I: ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine. Oncol Rep. 27:182–188. 2012.PubMed/NCBI
32	Duong HQ, Hong YB, Kim JS, Lee HS, Yi YW, Kim YJ, Wang A, Zhao W, Cho CH, Seong YS and Bae I: Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. J Cell Mol Med. 17:1261–1270. 2013. View Article : Google Scholar : PubMed/NCBI
33	You KS, Yi YW, Kwak SJ and Seong YS: Inhibition of RPTOR overcomes resistance to EGFR inhibition in triple-negative breast cancer cells. Int J Oncol. 52:828–840. 2018.PubMed/NCBI
34	Laiho M and Latonen L: Cell cycle control, DNA damage checkpoints and cancer. Ann Med. 35:391–397. 2003. View Article : Google Scholar : PubMed/NCBI
35	Lobrich M and Jeggo PA: The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer. 7:861–869. 2007. View Article : Google Scholar : PubMed/NCBI
36	Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Roncalli M, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res. 18:4570–4579. 2012. View Article : Google Scholar : PubMed/NCBI
37	Lovly CM, Heuckmann JM, de Stanchina E, Chen H, Thomas RK, Liang C and Pao W: Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 71:4920–4931. 2011. View Article : Google Scholar : PubMed/NCBI