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

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.

• 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
• Journal: Oncology reports (Oncol Rep) Vol. 45 Issue 4 (04 2021) ISSN: 1791-2431 [Electronic] Greece
• PMID: 33649854 (Publication Type: Journal Article)

Chemical References

• NVP-TAE684
• Pyrimidines
• ALK protein, human
• Anaplastic Lymphoma Kinase

Topics

• Adenocarcinoma (drug therapy, pathology)
• Anaplastic Lymphoma Kinase (antagonists & inhibitors, metabolism)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Pancreatic Neoplasms (drug therapy, pathology)
• Pyrimidines (pharmacology, therapeutic use)
• Signal Transduction (drug effects)