(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal

Abstract

Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.

Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling

“…Some PTK inhibitors such as gefitinib and crizotinib can cause DNA damage [30,31] and result in increased expression of RAD51, a DNA repair protein in the homologous recombination repair pathway [32,33]. We evaluated the expression level of RAD51 in response to ponatinib treatment (Figure 3C).…”

“…Another broad PTKI, dasatinib, has also been shown to activate Akt [46]. Crizotinib, a Met kinase inhibitor, was shown to activate Akt signaling in gastric cancer cells [31], even though it had an overall antiproliferative effect on these cells. Furthermore, co-inhibition of Akt signaling enhanced the anti-proliferative effect of crizotinib on gastric cancer cells, indicating that the activation of the Akt pathway was counterproductive in crizotinib’s antiproliferative effect on gastric cancer cells.…”

Gastroprotective effects of Kangfuxin against water-immersion and restraint stress-induced gastric ulcer in rats: roles of antioxidation, anti-inflammation, and pro-survival

“…2019) and pro-survival (Ji et al. 2018). Recently, Akt inhibition could suppress gastric cancer cell metastasis has been confirmed (Wang et al.…”

Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

“…As a key player of cell survival and DNA repair 39 , protective function of AKT activation has been confirmed in various cell-types and tissues, including vascular endothelial cells 40 , cortical neurons 24 , chondrocytes 41 and so on. SC79 is a unique specific AKT activator that may be used to enhance AKT activity in various physiological and pathological conditions 24 .…”