Nanoparticle technology has been used to boost the top penetration of hydrophobic materials such as glucocorticoids to posterior ocular structures. Furthermore, nanoparticles injected in to the vitreous have demonstrated intraretinal localization for reversible HSP90 inhibitor several months after initial dosing, thereby, serving as a local drug release site. A microparticle system containing a villain to a leukocyte antigen applied topically for the ocular surface has demonstrated sufficient ocular penetration to influence leukocyte dynamics and vascular leakage in the retina, both symptoms of diabetic retinopathy. Utilization of electrical currents applied to the ocular surface in the technique of iontophoresis or macroesis are being used experimentally to effectively get retinal concentrations of ranibizumab and triamcinalone when applied to the sclera. Additional methods and methods have now been enhanced using the specific aim of treating disorders of the posterior pole. These methods allow a sustained and steady multi-fold upsurge in drug concentration to reach the retina without inducing systemic side effects while improving therapeutic outcome. Sustained drug release intraocular implants for distribution of Metastatic carcinoma polylacticglycolic and triamcinalone acid microspheres to provide dexamethasone to treat diabetic retinal difficulties and inflammation have now been used successfully. Fat nanoparticles have been used to deliver bevacizumab directly into the vitreous of rabbits with the results of constantly raising the concentration and bioavailability of the drug in the vitreous a few folds. These biodegradable or non-biodegradable intraocular implants can be put into the vitreous or via cannulation in the suprachoroidal space to lessen the volume of intraocular injections, improve drug bio-availability in the retina, and bypass the possibility of systemic natural product library unwanted effects. Of specific interest, in light of the style of this review, is the use of microemulsion to improve the permeation of the mTOR inhibitor everolimus with sustained balance of the drug and the use of thermoresponsive hydrogels which were used to supply ranibizumab and bevacizumab. Combination or sequential healing agents aremore likely to yield beneficial., although it is unlikely that a single drug will soon be efficacious for managing most of the different levels of diabetic retinopathy. Combinatorial usage of a combined mTOR inhibitor with anti VEGF antibodies or VEGF capture could neutralize cross talk inducers of VEGF expression and be considered a effective combination way of ocular anti angiogenic therapy. Compelling evidence for enhanced efficacy of combined drug treatment to combat ocular angiogenesis has been previously offered, and the evidence underscores the considerable overlap of regulatory signaling involved in the angiogenic cascade.

We have shown that ACL restriction make a difference both E ras mutant and EGFR mutant lung cancer cell lines. Certainly such dual blockade is beneficial in several cancer models, including breast cancer, cancer, leukemia, ovarian carcinoma, Evacetrapib mesothelioma, Ewing sarcoma, and in lung cancer, where an engineered mouse lung tumor was driven by mutant E ras. Interestingly, statin therapy also decreased ACL phosphorylation, showing that statin on ACL function itself may exert inhibitory effects. Whether this is determined by inhibition of the PI3K/AKT pathway or independent of it remains to be discovered. Our findings have clinical significance. Cancer trials with statins have been unimpressive, as noted and it’s impossible that using ACL inhibitors alone could make more than the usual response. Additional benefit might be produced by a combination of the type described here, potentially in conjunction with traditional chemotherapies or ideally with targeted therapies used for NSCLC. Also, as noted above, the concentration of statin employed in our in vitro studies has been realized in clinical trials. Anti tumor effects of ACL bad state is somewhat Retroperitoneal lymph node dissection decreased by acetate and enhanced by citrate treatment Since acetyl CoA cannot move freely from mitochondria to cytosol, mitochondrially made citrate is transported into the cytosol where it is cleaved by ACL and cytosolic acetyl CoA is generated. Cytosolic acetyl-coa is the prerequisite building block for endogenous synthesis of cholesterol, essential fatty acids and isoprenoids together with for acetylation reactions that modify proteins. Consequently, ACL is located upstream of another lipogenic enzymes and connects glucose metabolism and lipogenesis. ACL inhibition should result in the reduced production of acetate, and accumulation of citrate. Acetate therapy partially reduced the anti tumor effects of ACL deficient state, suggesting the level of cytosolic acetyl-coa could be important for the anti tumor effects of the ACL deficient condition. The way the diminished acetyl supplier OSI-420 CoA or the potentially increased citrate contributes to inhibition of PI3K/AKT signaling isn’t comprehended but it is conceivable that these molecules alter kinase activity of one or more of its members and interact with a part of the PI3K/AKT signaling pathway. In conclusion, we have found that mixture of both ACL knock-down and statin therapy diminishes tumor growth in vivo and in vitro, through inhibiting both PI3K and MAPK signals, two significant success trails for cancer cells. The effects in vivo are far more impressive than in vitro, suggesting that this combination could have additional effects on the tumor microenvironment. These findings are corroborated by our studies in a tet inducible ACL knockdown system.

both the translocation and the occasions were inhibited by pre-treatment with PIK90. As a Enzalutamide manufacturer further test of the design and to rule out any non catalytic action mediated indicators from Akt we carried out a double Akt transfection experiment. The experiment depends on the co transfection of HA asAkt1 and flag wtAkt1. In the event the occupancy of the ATP website was the only determinant of hyperphosphorylation, then only the Akt able to drug binding must be hyperphosphorylated. In cells denver transfected with flagwtAkt1 and HA asAkt1, treatment with PrIDZ revealed Thr308 and Ser473 phosphorylation is induced only on HA asAkt1 and not on drug insensitive flag wtAkt1 after immunoprecipitation. The finding demonstrates that feedback mediated by signaling of Akt isn’t involved in hyperphosphorylation of Akt. The ability of hole described Akt1 to become hyperphosphorylated by Akt inhibitors was proved individually. An additional labeled construct of asAkt1 containing mCherry, which Lymphatic system indicates a sizable MW solution move from endogenous Akt was also examined, with similar.. Akt inhibitor triggers Akt membrane localization The finding that drug binding to Akt in Akt hyperphosphorylation mediated with a kinase built-in mechanism was particularly astonishing in light of our early finding that both membrane localization of drug and Akt binding were necessary for the hyperphosphorylation. One prediction of the kinase intrinsic model of inhibitor induced Akt hyperphosphorylation is that drug binding must cause relocalization of Akt from the cytoplasm to the membrane. No known kinase inhibitors that we know about stimulate cellular translocation of the goal kinase upon binding. We completed immunofluorescence studies of Akt, to determine whether such a drug induced cellular buy Avagacestat relocalization was in fact developing. We made a decision to employ A 443654 and untransfected HEK293 cells, in place of PrIDZ and asAkt transfected cells, to avoid overexpression of the kinase. In particular, the untransfected cells maintain the stoichiometry between Akt and PIP3 whereas excess asAkt molecules may be mislocalized in asAkt overexpressed cells due to insufficient PIP3. Fixed cells were stained with anti pThr308 and anti Akt to determine the place of Akt and pAkt, after HEK293 cells were treated with A 443654. In the lack of any growth factor stimulation, treatment with A 443654 resulted in translocation of Akt to the plasma membrane. More over, the membrane localized Akt was phosphorylated at Thr308. Hyperphosphorylation is restricted by Akti 1,2 Merck has reported an allosteric Akt inhibitor, Akti 1,2, which inhibits in vitro kinase activity and binds outside the active site.

Out of this siRNA knockdown experiment were verified in three independent experiments. Immunoblotting. Cells grown at 0. 5 106/ml were prepared after treatment, washed in PBS, and gathered in RIPA lysis buffer containing Protease Inhibitor. Protein concentrations pan HDAC inhibitor were determined by the BCA method and similar amounts were loaded onto precast 4?12% NuPAGE ties in. Western blotting was performed with appropriate dilutions of primary and secondary antibody. Antibodies were directed against JAK2, HA, HSP70, CRLF2, STAT5, phospho STAT5, tubulin, phospho JAK2, AKT, phospho AKT, ERK1/2, phospho ERK1/2, STAT1, and phospho STAT1. In vitro chemical analysis. Viable cells were plated in white opaque 384 well plates applying EL406 Combination Washer Dispenser at a density of 0. 01?0. 05 0 and 106 cells/ml. 25 106 cells/ml. Inhibitors or vehicle were included using a JANUS Automated Workstation. After 48 h or 96 h, CellTiter Glo Luminescent Cell Viability Assay was read and added by the 2104 EnVision Multilabel Reader. Each data point was quantified in quadruplicate and Infectious causes of cancer tests were repeated at least twice. Analysis of pairwise dose?response knowledge and isobologram plots was done based on the average effect principle of Chou and Talalay. Plots and dose response curves were generated with GraphPad Prism software. Dimension of inhibition of JAK in vitro kinase activity and assessment of anti-proliferative activity, together with biochemical profiling in SET 2, MB 02, UKE K, CMK and 1, MV4,11 562 cell lines was done as previously explained Competitive growth assay. Ba/F3 EpoRpuro cells were stably transduced with Jak2 V617F or Jak2 V617F plus-one of the three kinase domain mutations. Cells were cultured in media lacking IL 3 and mixed at a 1:1 rate. Additionally, cells were treated with either 1 uM BVB808 or Imatinib structure 10 nM AUY922. Cells were stained with PE anti Thy1. 1 and flow cytometry was performed daily for 3 d and then as indicated. The sensible population was estimated according to forward scatter and side scatter. In vivo murine experiments. Mouse bone marrow transplants were done essentially as previously described. In temporary, female BALB/c mice 8?9 wk of age were lethally irradiated, and then adopted with 3 106 donor bone marrow cells that have been transduced with pMSCV Jak2 V617F IRES GFP retrovirus. Complete blood counts were generally determined 4?6 wk after implant utilizing a blood analyzer, and rats were randomized into treatment groups depending on hematocrit. Dosing with car or 50 mg/kg BVB808 by oral gavage twice daily was initiated these day. After 3 wk of dosing, animals were given a final dose and sacrificed 2 or 12 h later for studies.

Phosphoinositide phosphatase activity is vital for Akt activation by either effector, but, the system by which this intersects with the canonical PI3K/Akt pathway to cause Akt activation remains unclear. Inhibition of SopB/IpgD dependent Akt phosphorylation by the PI3K inhibitor LY294002 supports Erlotinib 183319-69-9 a role for PI3K, but, an alternative study found that this inhibitor didn’t hinder Salmonella dependent accumulation of both PtdIns P3 or PtdIns P2 in membrane ruffles. IpgD has been demonstrated to activate the PI 3 kinase/Akt process service using a process that involves conversion of PI P2 into PtdIns P. And more recently it had been shown that PtdIns P may act indirectly to improve Akt phosphorylation by inhibiting the PP2A phosphatase. In vitro phosphatase assays have demonstrated that IpgD and SopB have relatively low specific activity compared to mammalian homologues Retroperitoneal lymph node dissection and that they’ve somewhat different substrate specificities. Sop Bhas a preference for PtdIns P2 and PtdIns P3, whereas IpgD features a preference for PtdIns P2 followed closely by PtdIns P3. Ergo the participation of PI3K in Salmonella dependent Akt service has not been definitively established. Where the intestinal epithelium is targeted sopb dependent Akt activation in epithelial cells has important implications for Salmonella pathogenesis, especially through the phase of infection. We have examined the role of PI3K, and other known components of the PI3K/Akt route, in SopB dependent Akt phosphorylation and membrane localization in Salmonella induced membrane ruffles, to achieve a better understanding of how Salmonella initiates this essential cellular kinase in epithelial cells. SopB is enough for Akt phosphorylation A few features Linifanib ic50 of Salmonella pathogenesis require the concerted activities of multiple T3SS1 effectors. In particular, SopB co-operates with SopE2 and SopE to cause the actin rearrangements leading to invasion. HeLa cells were infected with mutant S, to research whether these, or other effectors, bring about SopB dependent Salmonella mediated Akt phosphorylation. Typhimurium strains that lacked both certain effectors or even the ability to translocate them. Akt phosphorylation was then evaluated by immunoblotting using phospho certain antibodies that recognize Akt if it is phosphorylated at Ser473 or Thr308. As shown previously, wild-type Salmonella causes Akt phosphorylation although a sopB deletion mutant, DsopB, doesn’t. A strain lacking SopE and SopE2 induced Akt phosphorylation levels comparable to WT, whereas the triple mutant DsopE/ sopE2/sopB was indistinguishable from your DsopB strain. A DSPI1 mutant, which lacks the T3SS1 structural and regulatory components and is unable to translocate any T3SS1 effectors into host cells, also did not encourage Akt activation.

the progression from C4 HI to C4 HIR tumors could be inhibited with such combinatorial treatment. Future studies will undoubtedly be aimed to try this hypothesis in animals. To conclude, based on the biomarkers of cyst progression order Linifanib resulting from the studies in 3D countries of the MPA breast cancer model, it will be possible in the future to design and test multitargeted treatments involving a combination of selective inhibitors of hormonal reaction, protein kinases and extra-cellular matrix signals. Our research contributes to your appropriate preclinical model system that is ideal for testing the success of novel therapies in targeting the whole tumor and not merely the epithelial component. Furthermore, the animal model that we used here has got the added advantage that it is made up of several cyst types that were independently derived. As time goes by, we could decide if the processes that result in opposition and hormone independency are general and not really a unique event that occurs in this specific form of tumor. Practices Animals and materials pyrazine Two month old virgin female BALB/c mice were used. All animal procedures were approved by the Ethical Committee in the Institute of Experimental Biology and Medicine : Dr. Enrique Segura, Dr. Ricardo Calandra, Dr. Claudia Marro, Dr. Alberto Baldi and Dr Carlos Libertum. Adjustment and animal care were in agreement with institutional instructions and the Guide for the Care and Use of Laboratory Animals. Tumors Hormone dependent C4 HD is just a transplantable ductal mammary cyst that’s maintained by serial subcutaneous transplantations into medroxyprogesterone acetate addressed syngeneic BALB/c female rats. Tumor growth is induced with a s. H. Resource of MPA in the pifithrin alpha contralateral flank of the mice. A hormoneindependent tumefaction variant named C4 HI was derived from a C4 HDtumor that grew in amouse that had not been treated withMPA. Both C4 HI tumor versions and C4 HD express ER and PR and regress once silastic pellets of antiprogestin RU486 were s. c. Inserted in the rear of the animals. A group of females carrying C4 HD or C4 HI tumors was inoculated i. G. every other day for 12 times with saline solution, PD98059 or LY294002. Amounts were used from the literature and, respectively. The tumor size was assessed every 2 days using a Vernier caliper to determine tumor area in mm2. Solutions with the inhibitors began once the tumors reached a size of approximately 30 mm2. The era of tumors with acquired resistance to antiprogestin, C4 HIR, was conducted by s. H. administration of RU486 to mice carrying C4 HI tumors as described previously and preserved by syngeneic transplantation. All studies concerning animals were repeated two or three times using at least three mice per group each time, as indicated in each figure.

we considered the possibility of CLL cells cultured on hyaluronic acid coated plates. In these experiments, CLL cells were incubated in wells coated with hyaluronic BIX01294 dissolve solubility acid at increasing concentrations. After 96 hours of culture, CLL cell stability increased in a dose dependent fashion. At the highest HA focus cell stability increased by two decades compared with cells cultured in the lack of HA. CD44 triggers the MAPK/ERK and PI3K/AKT pathways and raises MCL 1 protein expxression We next investigated the consequence of CD44 activation to the PI3K/AKT and MAPK/ERK pathways, that have been reported to be activated by CD44 in solid tumor cell lines. CD44 engagement on CLL cells was followed closely by a prompt and strong increase of AKT phosphorylation and activation of ERK1/2. We confirmed AKT service within an lengthy cohort of U Retroperitoneal lymph node dissection CLL samples and M CLL. In both subtypes, a lot of samples showed improved AKT phosphorylation which typically reached 2. 3 fold compared to control There was no significant difference between your CLL subtypes. In order to ascertain whether expression of BCL 2 family members could possibly be directly managed by CD44, we considered alterations in the protein expression of MCL 1, BCL XL and BCL 2, which have now been proven to play a part in defending CLL cells from apoptosis. We detected higher MCL 1 protein levels in CLL cells stimulated by CD44 than in cells subjected to isotype control antibody for 24 hours. The escalation in MCL 1 was established within an prolonged cohort of U CLL samples and M CLL. Irrespective of the CLL sub-type, MCL 1 protein levels increased on average by 1. 45 collapse after CD44 service when compared with control. In keeping with an even more powerful professional survival effect in U CLL, MCL 1 expression showed a tendency for increased amounts in U CLL than in M CLL after CD44 activation. Also among M CLL samples LY2484595 just one of ten showed a 2 fold increase, while 5 of 12 U CLL samples showed at least a 2 fold increase in MCL 1 protein expression after CD44 proposal. MCL 1 mRNA levels were unaffected by CD44 stimulation. The bigger MCL 1 protein expression in the absence of increased transcription is consistent with recognized translational and post translation aftereffects of PI3K/AKT and MAPK/ERK signaling. On the other hand, BCL 2 protein expression wasn’t afflicted, and BCL XL was increased in just among 5 samples after CD44 stimulation. PI3K and MEK inhibitors block the protective effect of CD44 on leukemic cell survival Having shown that CD44 activation induced activation of the PI3K/AKT and MEK signal transduction pathways and guarded CLL cells from apoptosis, we wanted to consider whether specific inhibitors directed against these signal transduction pathways might inhibit the professional survival effect of CD44.

Currently over 20 different Hsp90 inhibitors have handed pre clinical toxicity studies and higher level into phase I clinical trials. Our reports went beyond the first era 17 DMAG Hedgehog inhibitor Vismodegib geldanamycin structural class of hsp90 inhibitors and evaluated four new, absolutely synthetic, chemically distinct ATPcompetitive inhibitors: PU H71, AUY922, BIIB021, BEP800. All inhibited KS and PEL tumefaction development at low nanomolar concentrations and all lowered the levels of other, known Hsp90 customer proteins for example cdc2 and Akt. While all PEL were susceptible to Hsp90 inhibitors, we did discover cell line alternative. This is expected since these PEL cell lines have accumulated both common and cell line specific genomic alterations. Others and we observed similar variations to other targeted drugs previously, some of the variation could be explained by p53 status, other drug unique variation has yet to be determined. This is a common effect seen in almost all studies that use systems of cell lines rather than a single cell line as read out. AUY922 had the best Infectious causes of cancer IC50 against a battery of KS cell lines. It’s a product of design guided optimization of 4, 5 diarylisoxazole compounds, which block the ATP binding pocket of Hsp90. AUY922 inhibited a tumor growth in a xenograft KSHV tumor model with similar efficacy as reported previously for other anti KS compounds. Recent studies have demonstrated that, being a small molecule inhibitor, AUY922 indicates promising therapeutic potential in a number of cancers as a result as lung cancer, glioblastoma, myeloma, etc.. PEL and KS are now able to be put into the list and ought to be contained in early phase clinical explorations of the compound. It is likely that the pronounced anti tumor effect of Hsp90 inhibitors arrives to the downregulation of numerous targets: LANA, which is important for viral maintenance, cdc2, Akt, which transduces paracrine and autocrine growth indicators in PEL, KS and other cancers, NFkB activators, ephrin B2, and EphA2, which help KSHV re-infection of endothelial cells and therefore tumor maintenance and even targets of surface bound Hsp90. Ephrins and Ephrin receptors are fundamental molecules in tumorigenesis, endothelial cell proliferation, and essential co-factors for KSHV illness. Ephrin receptor tyrosine kinases and their ephrin ligands transduce signals in cell cell contact dependent manner. Their expression in endothelial cells promotes angiogenesis. We found two different elements in this network to become client meats of Hsp90 in KS: EphA2 GW9508 GPR Agonists and ephrin B2 The EphA2 receptor kinase was once recognized as an Hsp90 client. Our studies showed that EphA2 was expressed abundantly in L1T2, SLK KSHV, and KS IMM cells and that Hsp90 inhibitors reduced EphA2 expression.

The reduction in mitochondrial membrane potential and the release of cytochrome C to the cytoplasm might arise upon apoptotic stimulation. Caspase 9 is activated due to the mix of released cytochrome C and apoptotic protease activating factor 1, thus processing other caspase people, including caspase 3 and caspase 7, to begin a caspase cascade, which deubiquitination assay results in apoptosis. Despite we did not immediately examined the release of cytochrome H, our results unveiled a dose dependent decrease in the mitochondrial membrane potential and increase in the activation of caspase 3 in A20 cells following therapy with fluvastatin, suggesting that the mitochondrial pathway is also involved in fluvastatininduced cell apoptosis. Because PARP is one of the key cleavage goals of caspase 3, we next examined the cleavage of PARP. As expected, the cleavage of PARP was observed in lymphoma cells, suggesting that cells were undergoing apoptosis. 31 On another hand, the disorders are mainly determined by a balance among pro and anti-apoptotic members of the Bcl 2 nucleophilic substitution family, often related to resistance of CLL B cells to chemotherapy. In this study, the expression of Bax was increased but that of Bcl2 was diminished in fluvastatin addressed lymphoma cells, indicating that the resistance of lymphoma cells to apoptosis may be blocked by the addition of fluvastatin. Many signaling pathways, including p38, Erk and Akt were demonstrated to be essential for cell cycle progression and proliferation. In our study, treatment with fluvastatin significantly suppressed the activation of Akt and Erk. But, the phosphorylation of p38 route was considerably improved by fluvastatin in A20 cells, suggesting the involvement of the three pathways in Cabozantinib 849217-68-1 fluvasatin induced apoptotic demise in lymphoma cells. The theory was further supported by previous studies. For instance, statin could reduce the activation of Akt, an important prosurvival pathway, in cancer cells. Moreover, p38 route mediated apoptosis was also seen in different cell types. Additionally, Erk service is essential for carcinogenesis, and constitutively activated Erk can be found in various human cancers. Recent studies show that increased intracellular ROS generation might be involved with statin induced cytotoxicity in MCF 7 breast cancer cells. Furthermore, atorvastatin therapy is related to increased levels of lipid peroxidation and myocardial protein oxidation in a mouse model. These previous studies are in least partly in keeping with our data showing the potential involvement of intracellular ROS generation in fluvastatin induced cytotoxicity towards lymphoma cells. Inhibition of HMG-COA reductase by statins is decreasing for your biosynthesis of not just cholesterol, but also other important isoprenoid intermediary metabolites including dolichols, and the electron transport chain meats heme ubiquinone and A.

Treatment of adult NRP 152 cells with SB431542 or another TbRI chemical, HTS 466284, each induced Survivin expression to the same level as that Erlotinib solubility induced by 2 nM LR3 IGF I alone, and combined treatments with these agents didn’t further enhance Survivin levels. Together these data strongly suggest that most ramifications of LR3 IGF I on inducing quantities of Survivin in NRP 152 cells does occur through reversing TGF b autocrine activity. The aforementioned TbRI kinase and another more particular TbRI Kinase Domain Inhibitor 1H pyrazol 4 yl naphthyridine also induced Survivin levels in VCaP cells and RWPE 1, but didn’t further enhance the induction of Survivin by IGF I alone. IGF I stimulates cell growth through avoiding growth suppression by endogenous TGF b We next examined whether the ability of IGF I to encourage growth of NRP 152 cells was through suppressing autocrine activity of TGF b. For this, NRP 152 cells were plated overnight in medium, treated with different TbRI mRNA kinase inhibitors and changes in cell growth was assessed after 5 to 6 times by crystal violet staining of fixed cells and by counting total cell numbers. All these TbRI kinase inhibitors improved cell growth between 4 to 10 fold. The most active and unique of these inhibitors, TKDI, optimally induced growth of NRP 152 cells to the same level as that by LR3 IGF I, suggesting that both activation of IGF IR and selective elimination of the TbRI kinase are equally effective in promoting the growth of NRP 152 cells under the same condition. TKDI maximally checks TGF b receptor signaling at 0. 1 to 0. 2 mM, whereas 16 mM TKDI had minimal effects on 9 closely related kinases, including p38 MAPK. as mediators of the growth reaction to look at the role of Smads 2 and 3, we compared 5-day growth rates of sh Smad2 3 NRP 152 versus sh LacZ NRP 152 in choice. Relative to control, silencing Smads 2 and 3 ignited robust cell proliferation. In still another experiment, daily changes in development of sh LacZ and sh Smad2 3 cells was assessed each in the absence and presence of 2 nM LR3 IGF I for 6 days. LR3 IGF I induced growth of sh LacZ cells similar to that of the sh Smad2 3 cells without LR3 IGF I, and addition of LR3 IGF I didn’t further encourage the growth of the shSmad2 3 cells. These results indicate that the mitogenic activity of LR3 IGF I and of silencing Smad2 3 are essentially the same, and suggest that the effects of IGF I on growth of NRP 152 cells are entirely through repressing the growth inhibitory activity of autocrine Evacetrapib, which will be dependent on the activation of Smad2 3, similar to the regulation of Survivin expression by TGF w. Role of TGF w signaling as a mediator of growth reduction and inhibition of Survivin expression by inhibitors of PI3K, Akt, mTOR and MEK The above results support our hypothesis that IGF I promotes the growth of NRP 152 cells and their expression of Survivin through inactivating autocrine TGF b/Smad activity.