Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine

  • Authors:
    • Xia Xie
    • Bo Tang
    • Jianyun Zhou
    • Qing Gao
    • Pengbing Zhang
  • View Affiliations

  • Published online on: June 5, 2013     https://doi.org/10.3892/or.2013.2520
  • Pages: 773-782
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The phosphatidylinositol 3‑kinase (PI3K)/Akt signaling pathway plays a crucial role in tumorigenesis and tumor progression by promoting cell proliferation and inhibiting apoptosis, a process closely associated with multidrug resistance (MDR) of tumors. LY294002 is a commonly used pharmacological inhibitor that acts at the ATP‑binding site of the PI3K enzyme, selectively inhibiting the PI3K/Akt pathway. In the present study, we evaluated the effect of LY294002 on the chemosensitivity of gastric cancer cells to vincristine (VCR) in vitro and in vivo and investigated the possible underlying cellular mechanisms. The effect of LY294002 on cell viability, apoptosis induction and inhibition of tumor growth was analyzed using MTT and TUNEL assay in in vitro and in vivo models of gastric cancer. Intracellular accumulation of VCR was determined by high performance liquid chromatography. The activity of the PI3K/Akt pathway was evaluated by western blot analysis. Furthermore, reverse transcription PCR and immunohistochemistry were performed to determine the mRNA and protein expression levels of MDR1/ P-glycoprotein (P‑gp) and apoptosis‑related factors. We found that gastric cancer cells treated with LY294002 showed a significant inhibition of PI3K/Akt activity. The PI3K inhibitor LY294002 combined with VCR worked synergistically to promote growth inhibition, induce apoptosis and increase the intracellular drug accumulation in gastric cancer cell lines. Similarly, LY294002 could cooperate with VCR to reduce tumor growth in a gastric cancer model in vivo. Finally, LY294002 was able to decrease the expression of MDR1/P‑gp, Bcl‑2 and XIAP, and upregulate expression of Bax and caspase‑3, thereby enhancing chemosensitivity to VCR by inhibiting a drug pump and inducing apoptosis. These results suggested that the PI3K/Akt inhibitor LY294002 can enhance chemosensitivity of human gastric cancer to VCR. This preclinical evaluation of a rational combination of LY294002 and VCR may provide a new strategy to resolve the MDR of gastric cancer.
View Figures
View References

Related Articles

Journal Cover

August 2013
Volume 30 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Xie X, Tang B, Zhou J, Gao Q and Zhang P: Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine. Oncol Rep 30: 773-782, 2013
APA
Xie, X., Tang, B., Zhou, J., Gao, Q., & Zhang, P. (2013). Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine. Oncology Reports, 30, 773-782. https://doi.org/10.3892/or.2013.2520
MLA
Xie, X., Tang, B., Zhou, J., Gao, Q., Zhang, P."Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine". Oncology Reports 30.2 (2013): 773-782.
Chicago
Xie, X., Tang, B., Zhou, J., Gao, Q., Zhang, P."Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine". Oncology Reports 30, no. 2 (2013): 773-782. https://doi.org/10.3892/or.2013.2520