Nitroglycerin Enhances Cisplatin-Induced Cytotoxicity via AKT Inactivation and Thymidylate Synthase Downregulation in Human Lung Cancer Cells
Journal
Pharmacology
Journal Volume
105
Journal Issue
44259
Pages
209-224
Date Issued
2020
Author(s)
Abstract
Nitroglycerin (NTG), a nitric oxide-donating drug, may increase tumor blood flow and consequently increase cancer drug delivery to tumor cells. Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of deoxythymidine monophosphate; we had found that knocking down the expression of TS sensitizes lung cancer cells to cisplatin-induced cytotoxicity. However, whether NTG and cisplatin could induce synergistic cytotoxicity in nonsmall cell lung cancer (NSCLC) cells through modulating TS expression is unknown. In this study, NTG decreased TS expression in an AKT, also known as Protein kinase B (PKB) inactivation dependent manner in human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells. Enhancement of AKT activity by transfection with constitutive active AKT vectors increased the TS expression level as well as the cell survival pretreated by NTG. Moreover, NTG synergistically enhanced cytotoxicity and cell growth inhibition by cisplatin treatment in NSCLC cells, which were associated with downregulation of TS expression and inactivation of AKT in A549 and H1703 cells. Together, these results may provide a rationale to combine NTG with cisplatin-based chemotherapy to enhance the therapeutic effect for lung cancer in the future. ? 2019 S. Karger AG, Basel. All rights reserved.
SDGs
Other Subjects
cisplatin; glyceryl trinitrate; protein kinase B; thymidylate synthase; antineoplastic agent; cisplatin; glyceryl trinitrate; protein kinase B; thymidylate synthase; A-549 cell line; Article; cancer inhibition; cell viability; controlled study; dose time effect relation; down regulation; drug cytotoxicity; drug potentiation; human; human cell; lung cancer cell line; mRNA expression level; NCI-H1703 cell line; priority journal; protein expression; protein stability; cell survival; drug effect; genetics; lung adenocarcinoma; lung tumor; metabolism; non small cell lung cancer; pathology; squamous cell carcinoma; tumor cell line; A549 Cells; Adenocarcinoma of Lung; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Cisplatin; Down-Regulation; Drug Synergism; Humans; Lung Neoplasms; Nitroglycerin; Proto-Oncogene Proteins c-akt; Thymidylate Synthase
Publisher
S. Karger AG
Type
journal article