Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

Frequent activation of phosphatidylinositol-3 kinases(PI3K)/Akt/m TOR signaling pathway in gastric cancer(GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3 CA gene or loss of function of PTEN,a tumor suppressor protein,to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis,hence,there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development,further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein,we review the common dysregulation of PI3K/Akt/m TOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/m TOR pathway inhibition.

Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

OBJECTIVE Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma(HNSCC).In the present study,we investigated whether garcinol,apolyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin.METHODS The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse model.RESULTS We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines,enhanced the apoptotic effect of cisplatin,suppressed constitutive as well as cisplatin-induced NF-κB activation,and downregulated the expression of various oncogenic gene products(cyclin D1,Bcl-2,survivin and VEGF).In vivo study showed that administration of garcinol alone(0.5 mg·kg-1,ip five times/week)significantly suppressed the growth of the tumor,and this effect was further increased by cisplatin.Both the markers of proliferation index(Ki-67)and microvessel density(CD31)were downregulated in tumor tissues by the combination of cisplatin and garcinol.The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,respectively.CONCLUSION Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.

Garcinol suppresses the growth of human hepatocellular carcinoma by inducing abrogation of STAT3 phosphorylation,acetylation and dimerization

OBJECTIVE Hepatocellular carcinoma(HCC)is the fifth most common malignancy worldwide and the third cause of global cancer mortality.Activation of signal transducer and activator of transcription 3(STAT3)is commonly observed in tumor cells and is a critical mediator of on cogenic signaling in HCC and controls the expression of several genes involved in proliferation,survival,metastasis and angiogenesis.Current drug-targeted therapies,besides being expensive,are associated with serious side effects and morbidity.Thus,novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC.In the present report,we investigated whether the potent HAT/KAT inhibitor,garcinol,(apolyisoprenylatedbenzophenone),could suppress STAT3 activation in HCC cells and in nude mice model.METHODS The effect of garcinol on HCC cell lines wasdetermined by MTT assay,immunoblotting,DNA binding assays,immuno-fluorescenceand immune-histochemical analysis.The effect of garcinolon the inhibition of tumor growth in vivo was also investigated using HCCxenograft tumor modelin athymic nu/nu mice.RESULTS We found that garcinol could inhibit constitutive STAT3 activation in a dose-and time-dependent manner both by inhibiting STAT3 phosphorylation and acetylation in HCC cells.When investigated for molecular mechanism(s),we found that garcinol interferes with the dimer formation of STAT3 thereby inhibits its nuclear localization.Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppresses its dimerization in vitro.To understand the cellular mechanism(s)of inhibition of STAT3 function by garcinol,we observed that upon inhibition of STAT3 dimerization bygarcinol,STAT3 DNA binding ability gets repressed.The inhibition of STAT3 activation by garcinol led to the suppression of various gene products involved in proliferation,survival,and angiogenesis.Finally,when administered i.p.,garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice.CONCLUSION Results frominvitroand in vivo studies suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling cascade in HCC by inhibiting its phosphorylation,acetylation and ultimately dimerization.

Potential role of nimbolide in chemoprevention and therapy of prostate cancer

OBJECTIVE Prostate cancer is one of the most commonly diagnosed cancers worldwide.Current therapies for metastatic prostate cancer are only marginally effective,and hence novel treatment modalities are urgently needed.Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of prostate cancer.Thus agents that can suppress these inflammatory mediators could form the basis of novel therapy for prostate cancer patients.In our study,we focused on analyzing the potential anticancer effects of nimbolide,a terpenoid lactone derived from Azadirachta indica(Neem tree)against prostate cancer.METHODS Molecular biology techniques such as western blot analysis,DNA binding,luciferase assays,and immunohistochemistry were used for both in vitro and in vivo experiments.RESULTS Data from the in vitrostudies indicated that nimbolide could inhibit cell proliferation,induce apoptosis and suppress cellular invasion and migration.Interestingly,nimbolide also abrogated the activation of pro-inflammatory STAT 3 transcription factor,and this effect was found to be mediated via an increased production of reactive oxygen species(ROS),whereas depletion of ROS attenuated pSTAT 3 inhibitory effects of the drug.The in vivo efficacy of nimbolide was also noted in transgenic adenocarcinoma of mouse prostate(TRAMP)model,in which this triterpenoid significantly suppressed the tumor progression and growth without exhibiting any substantial adverse effects.CONCLUSION Overall our findings indicate that nimbolide exhibits significant anticancer effects in prostate cancer,and these effects may be mediated at least in part through the modulation of STAT 3 signaling pathway.