Effects of LY294002 on the invasiveness of human gastric cancer in vivo in nude mice

Abstract

AIM:To investigate the effects of class Ⅰ phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 on the invasiveness and related mechanisms of implanted tumors of SGC7901 human gastric carcinoma cells in nude mice. METHODS:Nude mice were randomly divided into model control groups and LY294002 treatment groups. On days 5, 10 and 15 after treatment, the inhibitory rate of tumor growth, pathological changes in tumor specimens, expression levels of matrix metalloproteinase (MMP)-2, MMP-9, CD34 [representing microvessel density (MVD)] and vascular endothelial growth factor (VEGF), as well as apoptosis indexes in tumor samples were observed. RESULTS:In this study, we showed that treating the tumors with LY294002 could significantly inhibit carcinoma growth by 11.3%, 29.4% and 36.7%, after 5, 10 and 15 d, respectively, compared to the control group. Hematoxylin & eosin staining indicated that the rate of inhibition increased progressively (23.51% ± 3.11%, 43.20% ± 3.27% and 63.28% ± 2.10% at 5, 10 and 15 d, respectively) along with apoptosis. The expression of MMP-2 was also downregulated (from 71.4% ± 1.6% to 47.9% ± 0.7%, 31.9% ± 0.9% and 7.9% ± 0.7%). The same effects were observed in MMP-9 protein expression (from 49.4% ± 1.5% to 36.9% ± 0.4%, 23.5% ± 0.9% and 7.7% ± 0.6%), the mean MVD (from 51.2% ± 3.1% to 41.9% ± 1.5%, 30.9% ± 1.7% and 14.9% ± 0.8%), and the expression of VEGF (from 47.2% ± 3.1% to 25.9% ± 0.5%, 18.6% ± 1.2% and 5.1% ± 0.9%) by immunohistochemical staining. CONCLUSION:The class Ⅰ PI3K inhibitor LY294002 could inhibit the invasiveness of gastric cancer cells by downregulating the expression of MMP-2, MMP-9, and VEGF, and reducing MVD.

The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma

“…A recent investigation demonstrated that PI3K inhibition induces mitochondrial function and upregulates p53 and PUMA levels [ 40 ]. A synthetic small-molecule pan-PI3K inhibitor, LY294002, significantly inhibits the growth of gastric carcinoma while promoting apoptosis, resulting in the downregulation of MMP-2, MMP-9, and VEGF [ 41 ]. Impairment of PI3K/Akt activity attenuates the activity of κ-light-chain enhancer of activated B cells (NF-κB) and increases apoptosis in gastric carcinoma cells.…”

2381 The expression of the PI3K/AKT/mTOR pathway in gastric cancer and its role in gastric cancer prognosis

“…[4][5][6][7] Several drugs targeting PI3K/AKT/mTOR pathways are currently in clinical trials for gastric cancer, including PI3K inhibitor (LY294002, MK2206), AKT inhibitor (MLN1117), and mTOR inhibitor (everolimus). [8][9][10][11] PI3K inhibitor and AKT inhibitor monotherapy showed promising effects in Phases I-II, while mTOR inhibitor failed to improve survival in the GRANITE-1 Stage III trial for advanced gastric cancer. It remains unclear and requires further investigation whether the negative results of GRANITE-1 were because of the limited function of the PI3K/AKT/mTOR pathway in gastric cancer progression, the lack of molecular markers for patient screening, or the limited efficacy of mTOR monotherapy.…”

Phosphatidylinositol 3-Kinase Inhibitor LY294002 Suppresses Proliferation and Sensitizes Doxorubicin Chemotherapy in Bladder Cancer Cells

“…PI3K enzymes exist in cytoplasm and consist of both regulatory and catalytic subunits, which regulate a vast array of fundamental cellular processes. Increased signaling through this pathway has been shown to lead to downstream phosphorylation of AKT in vitro and in vivo [13] . It has been suggested to be a key step leading to the resistance of cancer cells to chemotherapy, especially when using DNA-damaging agents such as doxorubicin and cisplatin [14,15] .…”

“…Therefore, inhibition of PI3K signaling is under investigation as a potentially useful approach for cancer treatment. However, the detailed mechanisms are poorly understood [13] .…”