In vitro growth inhibitory effects of arsenic trioxide in non-small cell lung cancer with different K-ras mutations

Abstract

K-Ras mutation is frequently related to resistance of tyrosine kinase inhibitor (TKI) therapy for non-small cell lung cancer (NSCLC). Arsenic trioxide (ATO), as a novel anticancer drug, is primarily used to cure acute promyolocytic leukemia. However, for other types of cancers the effects of ATO are still unveiled. Here we test in vitro growth inhibitory effects of ATO in two NSCLC cell lines: H23 (K-Ras mutant) and HCC827 (K-Ras wild type) in hope of shedding light on overcoming the de novo resistance resulted by TKI treatments. ATO induces more cell death compared to Erlotinib (one small-molecule TKI in clinical use) as well as cell apoptosis. ATO leads to down-regulations of both phosphor-Akt and Akt while Erlotinib just diminishes phosphor-Akt. Of the Ras/Raf/Erk pathway, ATO enhances the phosphorylation of Erk1/2 significantly in H23 but not in HCC827. In order to prove that downstream signalings following activation of Erk1/2 are driven to apoptosis instead of cell proliferation in H23, we examined the change of Bax which is believed to play an important role at intrinsic apoptosis. Surprisingly, Bax is down-regulated in a dose- and time-dependent manner. Before the further explorations of this phenomenon, current acceptable explanation would be either that ATO is working through extrinsic apoptotic pathways or that ATO effects diversified signaling which combined together lead to final apoptosis at K-Ras mutant cell lines of NSCLC.