Lansoprazole Alone or in Combination With Gefitinib Shows Antitumor Activity Against Non-small Cell Lung Cancer A549 Cells in vitro and in vivo

Xiaoxia Zhao; Ning Zhang; Yingying Huang; Xiaojing Dou; Xiaolin Peng; Wei Wang; Zhe Zhang; Ran Wang; Yuling Qiu; Meihua Jin; Dexin Kong

doi:10.3389/fcell.2021.655559

Lansoprazole Alone or in Combination With Gefitinib Shows Antitumor Activity Against Non-small Cell Lung Cancer A549 Cells in vitro and in vivo

Front Cell Dev Biol. 2021 Apr 20:9:655559. doi: 10.3389/fcell.2021.655559. eCollection 2021.

Authors

Xiaoxia Zhao¹, Ning Zhang¹, Yingying Huang¹, Xiaojing Dou¹, Xiaolin Peng², Wei Wang², Zhe Zhang¹, Ran Wang¹, Yuling Qiu¹, Meihua Jin¹, Dexin Kong^{1

3}

Affiliations

¹ Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
² Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China.
³ School of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, China.

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.

Keywords: autophagy; combination; gefitinib; lansoprazole; lung cancer.