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

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.

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

“…On the other hand, the PI3K/Akt signaling pathway is also activated when chemotherapy is administered, which leads to drug resistance (5). In vitro and in vivo studies have indicated that the inhibition of the PI3K/Akt signaling pathway leads to increases in sensitivity to drugs; for example, this increases the sensitivity of ovarian cancer cells to cisplatin and gastric cancer to vincristine (6,7).…”

LY294002 suppresses the malignant phenotype and sensitizes osteosarcoma cells to pirarubicin chemotherapy

“…LY294002 is a commonly used pharmacological PI3K inhibitor, which acts on the ATP-binding site of the PI3K enzyme and thus selectively inhibits the PI3K-AKT nexus. Numerous studies have demonstrated that LY294002 enhances the chemosensitivity of various cancer types to a wide variety of drugs (16)(17)(18)(19). However, whether LY294002 enhances the effects of pirarubicin on OS remains unclear.…”

“…Due to its versatile effects, LY294002 is a leading compound in the development of more effective and tolerable reagents in cancer treatment. For example, Xie et al (16) revealed that LY294002 enhanced the chemosensitivity of human gastric cancer to vincristine. In the present study, LY294002 was found to induce OS cell apoptosis and inhibit growth in a dose-dependent manner.…”

Phase III biotransformation enzyme involvement in the ovarian response to ovotoxic environmental exposures

“…We therefore interrogated whether ABCB1 and ABCC1 were also regulated via PI3K. Xie et al (2013) revealed that expression of ABCB1 was down regulated with PI3K inhibition in gastric cancer cells and there was upregulated expression of pro-apoptotic Caspase-3 and Bax [84]. A clinical study by Imai et al, demonstrated that LY294002 promoted inhibition of ABCC1 in human stem cells via competitive inhibition and alteration of protein expression [85].…”

“…As a detrimental side effect of CPA/PM treatments in females, PM induces primordial, small primary, and growing follicle loss [79,83]. PM can further spontaneously transform into a volatile, cytotoxic compound, chloroethylaziridine (CEZ) [84], which negatively affects ovarian function [79]. Previous research from our group demonstrated that depleted primordial and growing follicles [79].…”