Abstract
Lansoprazole (Lpz) is an FDA-approved proton pump inhibitor (PPI) drug for the therapy of acid-related diseases. Aiming to explore the new application of old drugs, we recently investigated the antitumor effect of Lpz. We demonstrated that the PPI Lpz played a tumor suppressive role in non-small cell lung cancer (NSCLC) A549 cells. Mechanistically, Lpz induced apoptosis and G0/G1 cell cycle arrest by inhibiting the activation of signal transducer and activator of transcription (Stat) 3 and the phosphoinositide 3-kinase (PI3K)/Akt and Raf/ERK pathways. In addition, Lpz inhibited autophagy by blocking the fusion of autophagosomes with lysosomes. Furthermore, Lpz in combination with gefitinib (Gef) showed a synergistic antitumor effect on A549 cells, with enhanced G0/G1 cell cycle arrest and apoptosis. The combination inhibited Stat3 phosphorylation, PI3K/Akt and Raf/ERK signaling, affecting cell cycle-related proteins such as p-Rb, cyclin D1 and p27, as well as apoptotic proteins such as Bax, Bcl-2, caspase-3, and poly (ADP-ribose) polymerase (PARP). In vivo, coadministration with Lpz and Gef significantly attenuated the growth of A549 nude mouse xenograft models. These findings suggest that Lpz might be applied in combination with Gef for NSCLC therapy, but further evidence is required.
Highlights
The tumor microenvironment plays a pivotal role in tumor malignancy
Proton pump inhibitors (PPIs) are prodrugs that are activated by acid and are currently used as anti-acid drugs for the treatment of acid-related diseases (Shi and Klotz, 2008; Shin and Kim, 2013); these disorders include peptic ulcer disease, gastroesophageal reflux disease, and idiopathic hypersecretion (Der, 2003)
Several studies have shown that PPIs have antitumor effects against different tumor types; for example, esomeprazole inhibits the proliferation of melanoma cells in vitro and reduces tumor growth in human melanoma engrafted mice (De Milito et al, 2010), and Lpz induces cell apoptosis in human breast cancer cells and attenuates tumorigenesis in MDA-MB-231 breast cancer cell xenografted mice (Zhang et al, 2014)
Summary
The tumor microenvironment plays a pivotal role in tumor malignancy. The acidic microenvironment strongly contributes to tumor progression by stimulating invasion and metastasis, inhibiting the immune surveillance of cancers, and conferring chemoresistance (Taylor et al, 2015; Ibrahim-Hashim and Estrella, 2019). Proton pump inhibitors (PPIs) are prodrugs that are activated by acid and are currently used as anti-acid drugs for the treatment of acid-related diseases (Shi and Klotz, 2008; Shin and Kim, 2013); these disorders include peptic ulcer disease, gastroesophageal reflux disease, and idiopathic hypersecretion (Der, 2003). PPIs include omeprazole, esomeprazole, lansoprazole (Lpz), pantoprazole, and rabeprazole (Shi and Klotz, 2008). They act as potent inhibitors of gastric acid pumps and have been used for short- or long-term treatments with very high doses without major side effects (Der, 2003; Martín de Argila, 2005). In the present study, we focused on the development of Lpz targeting acidic microenvironments in lung cancer
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