Humans ; Leukemia ; drug therapy ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; TOR Serine-Threonine Kinases ; antagonists & inhibitors

The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.
Antineoplastic Agents, Hormonal ; therapeutic use ; Apoptosis ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Cellular Senescence ; Class I Phosphatidylinositol 3-Kinases ; Disease-Free Survival ; Early Detection of Cancer ; Female ; Humans ; Mutation ; Neoplasm Metastasis ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; genetics ; metabolism ; Survival Rate

Currently, about 300 million people worldwide are affected by asthma. Most of these sufferers inhale immunosuppressants (ie corticosteroids) and beta-adrenergic receptor agonists for their asthma treatment. However, about 5%-10% of patients of asthma have poor response to such treatment. Investigation of kinase signaling pathway and nuclear transcription factor as a target molecule in the treatment of allergic asthma has been the concern of scholars home and abroad. This paper reviewed inhibitors of kinase signaling pathway and nuclear transcription factors for the treatment of asthma.
Animals ; Asthma ; drug therapy ; enzymology ; Humans ; Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; Phosphatidylinositol 3-Kinase ; antagonists & inhibitors ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; metabolism ; Signal Transduction ; Transcription Factors ; antagonists & inhibitors

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Drug Resistance, Neoplasm ; Female ; Humans ; Ovarian Neoplasms ; drug therapy ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; physiology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; physiology ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; physiology

OBJECTIVETo investigate the effects of LY294002, a phosphatidylinositol 3-kinase inhibition, on sperm motility in asthenozoospermia patients in vitro, and further analyze the possible molecular mechanism.

METHODSSperm aseptically obtained by masturbation and prepared by swim-up technique from 10 patients with asthenozoospermia and 10 healthy fertile men were incubated with different concentrations of LY294002. Measurements of motility were carried out at 10, 30 and 60 min in all specimens by CASA.

RESULTSThe sperm in asthenozoospermia patients treated with LY294002 showed a significant increase in sperm progressive motility, the percentage of motile cells, VSL and VAP.

CONCLUSIONLY294002 can enhance the motility of sperm in asthenozoospermia patients in vitro.

Asthenozoospermia ; drug therapy ; Cells, Cultured ; Chromones ; pharmacology ; Dose-Response Relationship, Drug ; Humans ; Male ; Morpholines ; pharmacology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Sperm Motility ; drug effects ; Spermatozoa ; drug effects

OBJECTIVETo investigate the effects on chemotherapeutic sensitization of the PI3K inhibitor LY294002 in diffuse large B cell Lymphoma (DLBCL) cell lines ly1, ly8, ly10.

METHODSThe three cell lines were treated with LY294002, or doxorubicin alone or combined or sequentially respectively. Western blotting was used to detect the level of phospho-AKT after the treatment. Flow cytometry combined with annexin V-FITC assay and Brdu incorporation assay were used to analyze the alterations of cell cycle, proliferation, and apoptosis, respectively.

RESULTSLY294002 decreased the level of phospha-AKT efficiently in the three DLBCL cell lines. The ratio of S phase cells was significantly decreased (P < 0.05). Sequential use of LY294002 and doxorubicin increased the ratio of apoptosis and there was significant difference between the sequential group and the other four groups (P < 0.05) at 24, 48, 72(ly1), 48, 72 (ly8) or 24 h (ly10).

CONCLUSIONLY294002 can sensitize doxorubicin-induced apoptosis and may be a potential molecular therapeutic agent targeted at AKT signaling pathway in DLBCL.

Apoptosis ; drug effects ; Cell Line, Tumor ; Humans ; Lymphoma, Large B-Cell, Diffuse ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; metabolism

OBJECTIVETo explore the mechanisms involved in Staphylococcus aureus (S. aureus) invading human monocytic U937 cells.

METHODSS. aureus were added to U937 cells at multiplicity of infections (MOI) of 20:1 for 0, 15, 30, 60, and 90 minutes, respectively. Cell apoptosis was analyzed with Hoechst 33258 staining and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) flow cytometry analysis. Akt and nuclear factor-kappaB (NF-kappaB) activities were detected by Western blotting.

RESULTSInfection of U937 cells with S. aureus induced rapid cell death in a time-dependent manner, and the cells displayed characteristic features of apoptosis. S. aureus-induced apoptosis was associated with a prominent downregulation of activated (phosphorylated) Akt and NF-kappaB. The inhibition of phosphorylated Akt by LY294002 led to the inhibition of NF-kappaB in a dose-dependent manner. Inhibition of Akt with LY294002 caused further increase in apoptosis of U937 cells.

CONCLUSIONSS. aureus can stimulate the apoptosis of U937 cells. S. aureus induces apoptosis of U937 cells by inhibiting Akt-regulated NF-kappaB.

Apoptosis ; Chromones ; pharmacology ; Humans ; Morpholines ; pharmacology ; NF-kappa B ; physiology ; Phosphatidylinositol 3-Kinases ; physiology ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; physiology ; Staphylococcus aureus ; pathogenicity ; U937 Cells

OBJECTIVESTo explore the effects of insulin on the expression and the regulatory pathway of AQP9 in normal human liver cells.

METHODSNormal human liver cells L02 were cultured and treated with PI3K inhibitor LY294002, AKT inhibitor A-443654, MAPK inhibitors SB2030580 and insulin at different concentrations respectively. The AQP9 mRNA and protein expressions were detected with semi-quantitative RT-PCR and Western blot respectively.

RESULTSThe insulin (100 nmol/L approximately 500 nmol/L) treatment decreased the expression of AQP9 in normal human liver cells (P less than 0.05) concentration dependently, and the expression of AQP9 began to reduce from 3 hours of insulin stimulation (P less than 0.05), especially at insulin treatment for 12 hours (P less than 0.05); Incubated with the selective inhibitor of PI3K (LY294002) and AKT (A-443654), the inhibitory effects of insulin on AQP9 expression decreased (P less than 0.05); but it did not change significantly by blocking the MAPK signaling pathway.

CONCLUSIONThe insulin treatment inhibited the expression of AQP9 and the PI3K/akt signal transduction pathway was involved in the mechanism.

Aquaporins ; metabolism ; Cells, Cultured ; Chromones ; pharmacology ; Hepatocytes ; drug effects ; metabolism ; Humans ; Insulin ; pharmacology ; Morpholines ; pharmacology ; Phosphatidylinositol 3-Kinase ; antagonists & inhibitors ; metabolism ; Protein-Serine-Threonine Kinases ; metabolism ; Signal Transduction

Rapamycin and its derivatives (rapalogs), a group of allosteric inhibitors of mammalian target of rapamycin (mTOR), have been actively tested in a variety of cancer clinical trials, and some have been approved by the Food and Drug Administration for the treatment of certain types of cancers. However, the single agent activity of these compounds in many tumor types remains modest. The mTOR axis is regulated by multiple upstream signaling pathways. Because the genes (e.g., PIK3CA, KRAS, PTEN, and LKB1) that encode key components in these signaling pathways are frequently mutated in human cancers, a subset of cancer types may be addicted to a given mutation, leading to hyperactivation of the mTOR axis. Thus, efforts have been made to demonstrate the potential impact of genetic alterations on rapalog-based or mTOR-targeted cancer therapy. This review will primarily summarize research advances in this direction.
Antibiotics, Antineoplastic ; therapeutic use ; Cell Line, Tumor ; Class I Phosphatidylinositol 3-Kinases ; Humans ; Mutation ; Neoplasms ; drug therapy ; metabolism ; PTEN Phosphohydrolase ; genetics ; metabolism ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Proto-Oncogene Proteins ; genetics ; metabolism ; Proto-Oncogene Proteins p21(ras) ; Signal Transduction ; Sirolimus ; analogs & derivatives ; therapeutic use ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; metabolism ; ras Proteins ; genetics ; metabolism

OBJECTIVETo study the effects of combinative therapy of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and PI3-K-Akt inhibitor on the growth and apoptosis of nasopharyngeal carcinoma (NPC) cells and underlying mechanisms.

METHODSWith cell growth assay, flow cytometric analysis and Western blotting, the effects of TRAIL and PI3-K-Akt special inhibitor (LY294002) on cell growth, apoptosis and related proteins expressions in CNE-2 cell lines were studied.

RESULTSWhen concentrate of TRAIL>1 ng/ml, viability rate of cells in combinative treatment group with TRAIL and LY294002 was higher than that in the single treatment group with TRAIL (all P<0.05). When concentrate of TRAIL were 10 ng/ml and 100 ng/ml, the combinative treatment induced CNE-2 apoptosis more obviously than single treatments (t were 7.167 and 7.206, all P<0.05). The combination group showed more cleavage of Caspase-8, Caspase-3, Caspase-9 than single treatment groups.

CONCLUSIONSCombinative application of TRAIL and PI3-K-Akt pathway inhibitor inhibits the growth of CNE-2 and induces apoptosis. The mitochondrial dependent pathway is implicated for the underlying mechanism.

Apoptosis ; Carcinoma ; Caspases ; metabolism ; Cell Line, Tumor ; drug effects ; Chromones ; pharmacology ; Humans ; Morpholines ; pharmacology ; Nasopharyngeal Neoplasms ; pathology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; TNF-Related Apoptosis-Inducing Ligand ; pharmacology