title: 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.
authors.affiliation: Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xie
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.forename: Pengbing
authors.initials: P
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014750:Vincristine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3