Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO-cGMP signaling in lung adenocarcinoma cells in vitro and in vivo

Hiroki Nagai, Hiroyasu Yasuda, Yukimasa Hatachi, Deng Xue, Takahiko Sasaki, Mutsuo Yamaya, Yuichi Sakamori, Yousuke Togashi, Katsuhiro Masago, Isao Ito, Young Hak Kim, Tadashi Mio, Michiaki Mishima

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Pemetrexed (PEM) is a novel, multitargeted, antifolate, antineoplastic agent for the treatment of non-small cell lung cancer and malignant pleural mesothelioma. Additional effects of nitric oxide (NO) donors on the chemosensitivity of cancers have been reported. However, the effects of an NO donor on PEM-induced cytotoxicity remain unknown. In this study, we investigated the effects of the NO donors, NOC-18 on the cytotoxicity in A549 cells in vitro and of nitroglycerin (GTN), on the tumor growth of Lewis lung carcinoma cells in a murine syngraft model treated with PEM. The effects of NO donors on the expression of proteins associated with PEM metabolism, including thymidylate synthase (TS), reduced folate carrier 1 (RFC1), folylpolyglutamate synthase (FPGS), γ-glutamyl hydrolase (GGH) and multidrug resistance-related protein (MRP)5, and the effects of cyclic guanosine monophosphate (cGMP) signaling on these proteins were examined in A549 cells. Treatment with 100 nM NOC-18 for 3 days significantly enhanced PEM-induced cytotoxicity and increased the expression of RFC1 and FPGS in A549 cells. Treatment with 10 nM 8-bromo-cGMP (8-Br-cGMP) for 3 days also increased the expression of RFC1 and FPGS in A549 cells. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 μm) significantly reversed the increase in RFC1 and FPGS expression induced by 100 nM NOC-18 in A549 cells. Combination therapy with GTN and PEM significantly reduced tumor growth compared with PEM alone in the syngraft model. The enhanced antitumor effect of GTN plus PEM was significantly reversed by the concomitant addition of ODQ. These findings suggest that NO donors, such as NOC-18 and GTN, enhance the anticancer effects of PEM by increasing the RFC1 and FPGS expression and stimulating cGMP signaling pathways in cancer cells.

Original languageEnglish
Pages (from-to)24-30
Number of pages7
JournalInternational journal of oncology
Volume41
Issue number1
DOIs
Publication statusPublished - 2012 Jul

Keywords

  • Cyclic guanosine monophosphate
  • Hypoxia
  • Nitric oxide
  • Nitroglycerin
  • Pemetrexed

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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