- |||||||||| Kadcyla (ado-trastuzumab emtansine) / Roche
Journal: The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells. (Pubmed Central) - Jun 6, 2020
Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1.
- |||||||||| quercetin (LY294002) / Eli Lilly, buparlisib (BKM120) / Novartis, Adlai Nortye
Journal: Phosphoinositide 3-kinase/protein kinase B inhibition restores regulatory T cell's function in pulmonary sarcoidosis. (Pubmed Central) - Jun 5, 2020
These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add-on drugs to treat pulmonary sarcoidosis.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway. (Pubmed Central) - Jun 5, 2020
SHMT2 can contribute to liver regeneration after PH, and this is likely related with the activation of Akt/mTOR signaling pathway by its metabolic product, glycine, in hepatocytes. These results might have therapeutic implications for the prognosis of patients undergoing hepatic resection or transplantation.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Nimotuzuma restrains proliferation and induces apoptosis in human osteosarcoma cells by regulation of EGFR/PI3K/AKT signal pathway. (Pubmed Central) - Jun 5, 2020
Eventually, Nimotuzuma together EGRF or PI3K inhibitor (LY294002) were utilized to dispose MG-63 to further uncover the latent mechanism...Besides, we discovered the repressive functions of Nimotuzuma in OS cells proliferation and apoptosis via hindering the EGFR/PI3K/AKT pathway. These investigations testified that Nimotuzuma repressed cell growth by restraining the EGFR/PI3K/AKT pathway in OS cells, hinting the antitumor activity of Nimotuzuma in OS.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity. (Pubmed Central) - Jun 5, 2020
Rat organotypic hippocampal slices were exposed to vehicle (Veh) or to 5 μM kA for 24 h in the absence or presence of 0.1, 1 and 10 μM T1AM or to 0.1, 1 and 10 μM T1AM and 1 μM N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB), the only available TAAR1 antagonist, or to 1 μM T1AM in the absence or in the presence of 10 μM LY294002, an inhibitor of phosphoinositide 3-kinases (PI3Ks)...Of note, in the presence of EPPTB T1AM degradation by MAO was reduced. Our results indicate that the neuroprotection offered by T1AM depends, as for TA1, on AKT activation but do not allow to conclusively indicate TAAR1 as the target implicated.
- |||||||||| quercetin (LY294002) / Eli Lilly
Clinical, Journal, IO Biomarker: Hypoxic postconditioning activates the Wnt/β-catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK-3β inactivation. (Pubmed Central) - Jun 5, 2020
Finally, the administration of LY294002, an inhibitor of PI3K, increased GSK-3β activity and blocked nuclear β-catenin accumulation, thereby decreasing survivin expression and elevating the Bax-to-Bcl-2 ratio after HPC. These results suggest that activation of the Wnt/β-catenin pathway through Dkk1 inhibition and PI3K/protein kinase B pathway-mediated GSK-3β inactivation contributes to the neuroprotection of HPC against tGCI.-Zhan, L., Liu, D., Wen, H., Hu, J., Pang, T., Sun, W., Xu, E. Hypoxic postconditioning activates the Wnt/β-catenin pathway and protects against transient global cerebral ischemia through Dkk1 inhibition and GSK-3β inactivation.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: EVA1 promotes hepatocellular carcinoma Growth and metastasis via ERBB-PI3K-AKT pathway. (Pubmed Central) - Jun 4, 2020
LY294002, a PI3K inhibitor, inhibited AKT phosphorylation and rescued the tumor-promoting effect of EVA1 overexpression. Altogether, the present study has revealed the oncogenic role of EVA1 during HCC progression and metastasis through ERBB-PI3K-AKT signaling pathway, reiterating the potential use of EVA1 as a therapeutic target and/or prognostic marker for HCC.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Ursodeoxycholic acid stimulates alveolar fluid clearance in LPS-induced pulmonary edema via ALX/cAMP/PI3K pathway. (Pubmed Central) - May 31, 2020
Besides, the detailed mechanisms were explored in primary rat alveolar type (AT) II epithelial cells by determining the effects of BOC-2 (ALX [lipoxin A4 receptor] inhibitor), Rp-cAMP (cAMP inhibitor), LY294002 (PI3K inhibitor), and H89 (PKA inhibitor) on the therapeutic effects of UDCA against lipopolysaccharide (LPS)-induced changes...The therapeutic efficacy of UDCA against LPS was mainly achieved through the ALX/cAMP/PI3K pathway. Our results suggested that UDCA might be a potential drug for the treatment of pulmonary edema induced by LPS.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Role of the mTOR signaling pathway in salivary gland development. (Pubmed Central) - May 31, 2020
Moreover, rapamycin-treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle-treated neonatal mice. The present data indicate that the mTOR signaling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo submandibular salivary gland organ culture and ICR neonatal mice in vivo.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Timosaponin AIII inhibits metastasis of renal carcinoma cells through suppressing cathepsin C expression by AKT/miR-129-5p axis. (Pubmed Central) - May 23, 2020
Combining TSAIII and PI3K inhibitors, LY294002 synergically reduced the migration and invasion of 786-O and A-498 cells, as well as decreased the CTSC expression in both the cell types...In conclusion, our findings reveal that TSAIII inhibits the metastatic properties of RCC cells, contributing to the inhibition of PI3K/AKT and the increase of miR-129-5p and the subsequent downregulation of CTSC. This suggests that TSAIII has significant antimetastatic activity against RCC cells and may be beneficial to RCC treatments.
- |||||||||| quercetin (LY294002) / Eli Lilly, AG1478 / IDT Australia, PD98059 / Wayne State University
Journal, IO Biomarker: HS restores the cardioprotective effects of ischemic post-conditioning by upregulating HB-EGF/EGFR signaling. (Pubmed Central) - May 23, 2020
The beneficial effects of NaHS during PC were inhibited by EGFR knockdown, AG1478 (EGFR inhibitor), PD98059 (ERK1/2 inhibitor) or LY294002 (PI3K inhibitor). These results suggest that exogenous HS restores PC-mediated cardioprotection by up-regulating HB-EGF/EGFR signaling, which activates the ERK1/2-c-myc (and fos and c-jun) and PI3K-Akt- GSK-3β pathways in the aged cardiomyocytes.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: The protective underlying mechanisms of Schisandrin on SH-SY5Y cell model of Alzheimer's disease. (Pubmed Central) - May 23, 2020
Treatment with 10 μmol/L Schisandrin of SH-SY5Y cells with the p-Akt inhibitor LY294002 demonstrated that the herbal-induced rise in p-Akt protein expression was diminished by this inhibitor indicating that signal transduction occurred in the observed cellular effects...Consequently, restoration of neuronal cell viability was noted. Our findings suggest that the use of Schisandrin may be considered beneficial as a therapeutic agent in AD.
- |||||||||| cisplatin / Generic mfg.
Journal: The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. (Pubmed Central) - May 21, 2020
Moreover, p-PI3K and p-AKT were significantly enhanced by PAX6, which was reversed by the addition of the PI3K-AKT inhibitor, LY294002. These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2, thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Knockdown of TRIM27 expression suppresses the dysfunction of mesangial cells in lupus nephritis by FoxO1 pathway. (Pubmed Central) - May 19, 2020
In addition, the protein kinase B (Akt) signal pathway inhibitor LY294002 significantly reduced the expression of TRIM27 and inhibited the dysfunction of mesangial cells. These above data suggested that TRIM27 mediated abnormal mesangial cell proliferation in kidney of lupus and might be the potential target for treating mesangial cell proliferation of lupus nephritis.
- |||||||||| quercetin (LY294002) / Eli Lilly, PD98059 / Wayne State University
Journal, IO Biomarker: Naringenin Inhibit the Hydrogen Peroxide-Induced SH-SY5Y Cells Injury Through Nrf2/HO-1 Pathway. (Pubmed Central) - May 19, 2020
The HO-1 inhibitor ZnPP abolished the neuroprotective effect of NGN against HO-induced neurotoxicity. Taken together, the present study demonstrates that regulation of Nrf2/HO-1 pathway through activation of ERK and PI3 K/Akt, and the inhibition of mitochondria-dependent apoptosis together may render NGN protect SH-SY5Y cells from HO-induced neurotoxicity.
- |||||||||| quercetin (LY294002) / Eli Lilly, Alverix (amiloride hydrochloride) / Remedica
Journal: Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis. (Pubmed Central) - May 19, 2020
The proliferative effects of PLTMax are suggested to function via multiple signaling pathways, similar to FBS. Interleukin-10 induces the uptake of HDL and LDL by fluid-phase endocytosis by increasing actin-filament rearrangement in macrophages, thus providing a plausible mechanism contributing to "Disappearing HDL Syndrome".
- |||||||||| quercetin (LY294002) / Eli Lilly, SP600125 / BMS
Journal, IO Biomarker: Lipopolysaccharide-Induced Matrix Metalloproteinase-9 Expression Associated with Cell Migration in Rat Brain Astrocytes. (Pubmed Central) - May 19, 2020
In addition, LPS-stimulated binding of c-Jun to the MMP-9 promoter was confirmed by chromatin immunoprecipitation (ChIP) assay, which was blocked by pretreatment with c-Src inhibitor II, PF431396, AG1296, LY294002, Akt inhibitor VIII, p38 MAP kinase inhibitor VIII, SP600125, and tanshinone IIA. These results suggest that in RBA-1 cells, LPS activates a TLR4/c-Src/Pyk2/PDGFR/PI3K/Akt/p38 MAPK and JNK1/2 pathway, which in turn triggers activator protein 1 (AP-1) activation and ultimately induces MMP-9 expression and cell migration.
- |||||||||| quercetin (LY294002) / Eli Lilly
Novel approach for automated sequential immunoassay for quantitation and characterization of PI3K-Akt pathway proteins (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_766;
Akt is a target for specific inhibition and recently, a number of small molecules have been developed to improve the pharmacologic properties of known inhibitors like wortmannin and LY294002...This approach enables normalization of phosphorylation levels and/or target abundance in cell line or tissue samples, correcting for change in protein content due to treatment, loading, and/or other systematic errors. These results present the utility of the Multiple Detection Approach to quickly characterize and quantify proteins involved in signaling pathways targeted during development of cancer therapies.
- |||||||||| quercetin (LY294002) / Eli Lilly
Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1401;
In summary, PTEN deficiency leads to the upregulation of RCC2, which may promote tumorigenesis of glioblastoma by dysregulating cell cycle progression.To further explore the RCC2 roles, we will find the potential downstream target of RCC2 in dysregulating cell cycle and its potential therapeutic effect in vivo. Funding: General Research Fund Grant #14113519 from The Research Grants Council of Hong Kong
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt. (Pubmed Central) - May 15, 2020
Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well...Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.-Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.
- |||||||||| quercetin (LY294002) / Eli Lilly, Kuvan (sapropterin) / Merck (MSD), BioMarin, Daiichi Sankyo
Preclinical, Journal: Activation of ATM/Akt/CREB/eNOS Signaling Axis by Aphidicolin Increases NO Production and Vessel Relaxation in Endothelial Cells and Rat Aortas. (Pubmed Central) - May 14, 2020
Prolonged (over 24 h) treatment with aphidicolin increased NO production and endothelial NO synthase (eNOS) protein expression, which was accompanied by increased eNOS dimer/monomer ratio, tetrahydrobiopterin levels, and eNOS mRNA expression...Co-treatment with LY294002 decreased the aphidicolin-stimulated increase in p-CREB-Ser level, eNOS expression, and NO production...Lastly, aphidicolin increased acetylcholine-induced vessel relaxation in rat aortas, which was accompanied by increased p-ATM-Ser, p-Akt-Ser, p-CREB-Ser, and eNOS expression. In conclusion, our results demonstrate that in response to aphidicolin, activation of ATM/Akt/CREB/eNOS signaling cascade mediates increase of NO production and vessel relaxation in endothelial cells and rat aortas.
- |||||||||| quercetin (LY294002) / Eli Lilly, ABT-737 / AbbVie
Combination therapies targeting apoptosis pathways in paediatric AML () - May 14, 2020 - Abstract #BSH2020BSH_94;
(ABT‐737‐ 100 nmol/l + Purvalanol A‐ 1 µmol/l) (ABT‐737‐ 100 nmol/l + LY294002‐ 2 µmol/l)...Our combinations showed interesting therapeutic potential, which to our knowledge has not been reported by other groups investigating these drug pairings. We believe that our combination screening approach has potential for future use with a larger cohort of drugs including FDA approved compounds and patient material.
- |||||||||| quercetin (LY294002) / Eli Lilly, U0126 / Promega
[VIRTUAL] The Effect of IL-6-Primed Platelets on ADAMTS13-Mediated Clearance of Platelet-Bearing ULVWF and its Mechanism (Virtual Meeting Room 6) - May 14, 2020 - Abstract #ISTH2020ISTH_1550;
Treatment of IL-6-treated platelets with either the phosphoinositol-3 kinase inhibitor LY294002 or the mitogen-activated protein kinase kinase inhibitor U0126 reduced the formation of platelet strings and restored the ability of ADAMTS-13 to cleave IL-6-treated platelet strings compared to the group treated with IL-6 alone. These results indicate that IL-6 increased the formation of ULVWF-platelet strings and reduced their cleavage by ADAMTS13.
- |||||||||| quercetin (LY294002) / Eli Lilly, U0126 / Promega
Journal: Steered migration and changed morphology of human astrocytes by an applied electric field. (Pubmed Central) - May 13, 2020
In conclusion, applied EFs steered the patient-derived HAs directional migration and changed morphology, in which PI3K and ERK pathways at least partially participate. The characteristics of HAs to EF stimulation may be involved in wound healing and neural regeneration, which could be utilized as a novel treatment strategy in brain injury.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption. (Pubmed Central) - May 13, 2020
Inhibitors of bone resorption, such as alendronate, bafilomycin A1, and the PI3K inhibitor LY294002, suppressed the expression of Pmepa1 in osteoclasts...In addition, in sites of bone destruction observed in rats with adjuvant-induced arthritis, a marked high level of Pmepa1 expression was associated with the osteoclasts' resorbing bone. Our results suggest that Pmepa1 is a critical regulator of bone resorption and is a promising marker for activated osteoclasts and a potential therapeutic target in pathologic bone destruction.-Xu, X., Hirata, H., Shiraki, M., Kamohara, A., Nishioka, K., Miyamoto, H., Kukita, T., Kukita, A. Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption.
- |||||||||| NVP-AEW541 / Novartis, quercetin (LY294002) / Eli Lilly
Clinical, Journal: IGF-1 alleviates serum IgG-induced neuronal cytolysis through PI3K signaling in children with opsoclonus-myoclonus syndrome and neuroblastoma. (Pubmed Central) - May 13, 2020
Our results suggest that Pmepa1 is a critical regulator of bone resorption and is a promising marker for activated osteoclasts and a potential therapeutic target in pathologic bone destruction.-Xu, X., Hirata, H., Shiraki, M., Kamohara, A., Nishioka, K., Miyamoto, H., Kukita, T., Kukita, A. Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption. IGF-1/PI3K signaling alleviates the cytolysis of cultured neurons induced by serum IgG from children with OMS and NB, which may be innovation therapy targets.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Connexin43 enhances Wnt and PGE2-dependent activation of β-catenin in osteoblasts. (Pubmed Central) - May 13, 2020
Finally, we show that the activation of β-catenin by PGE2 required signaling through the phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase 3 beta (GSK3β) pathway, as the PI3K inhibitor, LY-294002, disrupted the synergy between connexin43 and PGE2. These data show that connexin43 regulates Akt and β-catenin activity and synergistically enhances both Wnt-dependent and Wnt-independent β-catenin signaling in osteoblasts.
- |||||||||| Radicava (edaravone) / Mitsubishi Tanabe, edaravone (MT-1186) / Mitsubishi Tanabe
Preclinical, Journal, IO Biomarker: Edaravone protects rat astrocytes from oxidative or neurotoxic inflammatory insults by restoring Akt/Bcl-2/Caspase-3 signaling axis. (Pubmed Central) - May 10, 2020
In addition, edaravone mitigated LPS-induced morphological changes in astrocytes and alleviated the inflammatory activation and expression of TNF-α, IL-1β, IL-6 and NOS2. In summary, our data suggested that edavarone effectively protects astrocytes from oxidative stress or infectious insults, which may pave a new avenue for its application in preclinical research and human disease therapeutics.
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