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. 2019 May 16;16(5):1140-1149.
doi: 10.5114/aoms.2019.85146. eCollection 2020.

Ketamine exhibits anti-gastric cancer activity via induction of apoptosis and attenuation of PI3K/Akt/mTOR

Shiling Zhao  1 , Lin Shao  1 , Yingwei Wang  1 , Qingtao Meng  2 , Jinning Yu  3
Affiliations

Ketamine exhibits anti-gastric cancer activity via induction of apoptosis and attenuation of PI3K/Akt/mTOR

Shiling Zhao et al. Arch Med Sci. .

Abstract

Introduction: Gastric cancer (GC) is the most widespread type of cancer after lung and liver cancer in men and after breast cancer in women. Thus, the present study was intended to evaluate the effect of ketamine (KET) on gastric cancer cells.

Material and methods: The effect of KET was analyzed in vitro by the MTT assay against human gastric cancer cell lines BGC-823, MKN-45 and MKN-28. The effect KET on apoptosis, cell migration and cell cycle arrest was also quantified. Western blot analysis was performed to estimate the effect of KET on apoptosis mediators and PI3K/AKT/mTOR pathway mediators. A mouse xenograft assay was also conducted to further confirm the anticancer activity.

Results: KET causes reduction of cellular viability of BGC-823, MKN-45 and MKN-28, with a more significant effect against BGC-823 cells. The KET treatment showed a dose-dependent increase in apoptotic cells among BGC-823 cells. KET causes a significant dose-dependent decline in migration of treated cells. It causes induction of apoptosis mediated via the mitochondrial pathway, where it causes a decline in Bcl2 and mitochondrial cytochrome c level together with increase in expression of Bax, cytosolic cytochrome c and cytosolic apoptotic protease activating factor-1 (Apaf-1). The level of p-PI3K, p-mTOR, p-GSK3β and p-AKT was found to be downregulated in a dose-dependent manner in KET-treated cells. In a mouse xenograft model, KET causes a reduction in relative tumour volume and tumour weight.

Conclusions: Our results suggest that ketamine has the ability to inhibit progression of gastric cancer via induction of apoptosis and attenuation of PI3K/Akt/mTOR.

Keywords: Akt; PI3K; apoptosis; gastric cancer; ketamine; mTOR; viability.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of KET on cell viability assay, were: BGC-823 (A), MKN-45 and MKN-28 (B) and BGC-823 (C) Results represent means ± SD of three independent experiments. **P < 0.01; ***p < 0.001 vs. control group.
Figure 2
Figure 2
Effect of KET on apoptosis of BGC-823 cells. A – PI-annexin V-FITC binding assay using 2, 5, and 10 μg/ml of KET on BGC-823 cells, B – column representing the percentage of apoptotic cells, C – effect of KET on apoptosis as determined by fluorescence micrographs of BGC-823 cells Results represent means ± SD of three independent experiments. **P < 0.01 vs. control group.
Figure 3
Figure 3
Effect of KET in Transwell migration of BGC-823 cells. A – KET-treated BGC-823 cells were loaded into the upper migration chamber, B – representative bar graph of migratory BGC-823 cells Results represent means ± SD of three independent experiments. **P < 0.01 vs. control group.
Figure 4
Figure 4
Expression level of apoptosis-related proteins in BGC-823 cells after exposed to KET. A – Western blot analysis of Bax, Bcl-2, caspase-3, cytosolic cytochrome c, mitochondrial cytochrome c, cytosolic Apaf-1 expressions in BGC-823 cells. Quantitative analysis of Bcl-2 (B), Bax (C), caspase-3 (D), cytosolic cytochrome c (E), mitochondrial cytochrome c (F), cytosolic Apaf-1 (G) Results represent means ± SD of three independent experiments. **P < 0.01 vs. control group.
Figure 5
Figure 5
Effect of KET on expression of PI3K/AKT/TOR pathway proteins. A – Western blot analysis of PI3K, GS3Kβ, Akt, mTOR, p-PI3K, p-GS3Kβ, p-Akt, and p-mTOR. Quantitative analysis of p-PI3K (B),p-GSK3b (C), p-AKT (D), p-mTOR (E) Results represent means ± SD of three independent experiments. **P < 0.01 vs. control group.
Figure 6
Figure 6
Effect of KET on mouse BGC-823 xenograft model. A – Effect of KET on tumour volume on the indicated day. B – Weight of the tumour at the end of the study. C – Tumour image Results represent means ± SD of three independent experiments. **P < 0.01 vs. control group.
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