Inhibition Of PI3K Signaling Pathway Research Articles

Resveratrol inhibits glioblastoma cells and chemoresistance progression through blockade P-glycoprotein and targeting AKT/PTEN signaling pathway

Malignant gliomas have been categorized as a debilitating class of brain tumors that are resistant to radiation and chemotherapeutic drugs, and have a poor prognosis. Hyper-activation of PI3K/AKT pathway and overexpression of p-glycoprotein transporter contributes to enhanced glioblastoma survival and chemoresistance. Resveratrol which possibly inhibits PI3K pathway, has been thus investigated for a potential therapeutic role in glioma. In the present study, the effect of resveratrol on human U87MG and doxorubicin-resistant glioblastoma cells (U87MG/DOX) survival evaluated by MTT. The ability of resveratrol to overcome doxorubicin resistance in glioblastoma cells was also explored with Rhodamines 123 uptake and ELISA assays. Resveratrol reduced cell survival in a PTEN and P53-dependent manner which was an effect associated with the inhibition of PI3K signaling pathway and via the activation of P-glycoprotein. Our finding showed that resveratrol, as a glioblastoma cell growth inhibitor and chemosensitizer, could be promising if used in the treatment of brain cancer. Resveratrol inhibits the progression of glioblastoma cells and reverses chemoresistance by upregulating PTEN, and suppressing AKT and P-glycoprotein. Targeting PTEN with resveratrol may offer a novel therapeutic approach for the chemo-sensitization of glioblastoma cells.

PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis

PI3K pathway exerts its function through its downstream molecule AKT in regulating various cell functions including cell proliferation, cell transformation, cell apoptosis, tumor growth and angiogenesis. PTEN is an inhibitor of PI3K, and its loss or mutation is common in human prostate cancer. But the direct role and mechanism of PI3K/PTEN signaling in regulating angiogenesis and tumor growth in vivo remain to be elucidated. In this study, by using chicken chorioallantoic membrane (CAM) and in nude mice models, we demonstrated that inhibition of PI3K activity by LY294002 decreased PC-3 cells-induced angiogenesis. Reconstitution of PTEN, the molecular inhibitor of PI3K in PC-3 cells inhibited angiogenesis and tumor growth. Immunohistochemical staining indicated that PTEN expression suppressed HIF-1α, VEGF and PCNA expression in the tumor xenographs. Similarly, expression of AKT dominant negative mutant also inhibited angiogenesis and tumor growth, and decreased the expression of HIF-1α and VEGF in the tumor xenographs. These results suggest that inhibition of PI3K signaling pathway by PTEN inhibits tumor angiogenesis and tumor growth. In addition, we found that AKT is the downstream target of PI3K in controlling angiogenesis and tumor growth, and PTEN could inhibit angiogenesis by regulating the expression of HIF-1 and VEGF expression through AKT activation in PC-3 cells.

Constitutive Phosphoinositide-3kinase Activation Represents a Good Prognostic Factor in De Novo AML Patients under 60 Years.

Abnormal activation of kinases may promote leukemogenesis by conferring cell proliferation and survival advantage in acute myelogenous leukemia (AML). New targeted therapies are currently developed to disrupt such kinases activation to improve the long term prognosis of AML patients. However, the prognosis impact on AML patients has only been evaluated for a few kinases, including FLT3 and ERK/MAPK. Recent reports suggest that PI3K activation may confer poor survival to AML patients. Pre-treatment primary bone marrow blast cells samples from 92 patients registered for the LAM2001 trial of the French GOELAMS group were analyzed and PI3 kinase constitutive activation was correlated with outcome. As previously reported (V Bardet, Haematologica , 2006, 91, 757–764), the status of AKT phosphorylation on Ser 473 was determined using either Western Blot analysis (in samples >90% blasts) or flow cytometry in the CD45Low positive population of blast cells. Phosphorylation of AKT on Ser473 was determined after a 4 hour period of deprivation in cytokine and serum-free medium. In such conditions, we can clearly define to groups of patients, one with constitutive activation of PI3K (PI3K+) and the other without detectable phosphorylation of AKT (PI3K−). At inclusion, 42 patients were males and 50 were females. Median age at diagnosis was 46 (17,3–64,5) years. Leukocytosis was 12000/μL (range 400–251800). Patients were classified in low-risk, standard-risk and high-risk cytogenetic subgroups in respectively 16%, 61% and 23%. 16/61 (25%) had FLT3-ITD mutation, 9/60 (15%) had Ras (N-Ras or K-Ras) mutations and 15/59 (25%) had NPM mutations. 46 of 92 (50%) patients had constitutive PI3K activation (PI3K+ group). No difference was observed between the PI3K+ and PI3K− groups for all previously descripted parameters, except concerning FLT3 mutational status: 5/32 (16%) PI3K+ patients had FLT3-ITD versus 11/29 (38%) in the PI3K− (p = 0,048). All patients received one course of induction chemotherapy (3+7 regimen), and 31 (34%) a second induction course at day 15. Complete remission was obtained in 74 patients (80%) with no difference between the two groups (p = 0,60). Among responders, 30 (41%) had autologous stem cell transplantation, 24 (32%) had allogenic bone marrow transplantation and 16 (22%) had consolidation chemotherapy. With a median follow-up of 26 months (range 3 days–37 months), 48 patients died. Overall survival was 56% in the PI3K+ group and 33% in the PI3K− group (p=0.007). Among responders, 30 patients had relapse. Relapse free survival was 72% in the PI3K+ group and 41% in the PI3K− group (p=0.001). Thus constitutive PI3K activity detected in leukemic cells at diagnosis confer a better prognosis in AML. We observed significantly more relapses in PI3K− patients. These results suggest that PI3K activity in AML may confer a particular sensitivity to chemotherapy, the demonstration of which remain to be made. Furthermore, inhibition of PI3K signaling pathway may not be as beneficial as expected, and a better understanding of downstream effectors is clearly needed before targeting PI3K in AML.