Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

2021 ◽  
Vol 22 (9) ◽  
pp. 4370
Author(s):  
Cássia de Fáveri ◽  
Paula M. Poeta Fermino ◽  
Anna P. Piovezan ◽  
Lia K. Volpato
Keyword(s):  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Integrative Review ◽  
Inflammatory Factors ◽  
Resolvin D1 ◽  
Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

scholarly journals The Role of HCN Channels on Membrane Excitability in the Nervous System

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Daisuke Kase ◽  
Keiji Imoto
Keyword(s):  
Intracellular Signaling ◽  
Hcn Channels ◽  
Heart Cells ◽  
Hcn Channel ◽  
Membrane Excitability ◽  
Wide Range ◽  
Inward Currents ◽  
Range Of Functions ◽  
Channel Currents

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP2, and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons.

Prognostic and predictive value of vessels encapsulating tumor clusters (VETC) in renal cell carcinoma (RCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16554-e16554
Author(s):  
Salvatore Lorenzo Renne ◽  
Marina Valeri ◽  
Matteo Perrino ◽  
Luca Di Tommaso ◽  
Luigi Terracciano ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Cox Regression ◽  
Hierarchical Modeling ◽  
Progression Free Survival ◽  
Type I ◽  
Prognostic Role ◽  
Endothelial Lining ◽  
Mesenchymal Transition ◽  
Tumor Dissemination

e16554 Background: VETC has been described as an epithelial-to-mesenchymal-transition independent process of metastasis in hepatocellular carcinoma (HCC): endothelium covers small clusters of neoplastic cells allowing tumor dissemination. It has also been noted that VETC-positive HCCs benefit more from tyrosine kinase inhibitors (TKI) therapy. Interestingly, this type of angiogenesis was also found in RCC - and other cancers - and associated with poor prognosis. The objectives of the present study are: 1) to investigate the prognostic role of VETC in a cohort of primary consecutive RCC. 2) to model the predictive role VETC to TKI response in a cohort of metastatic RCC patients treated with sunitinib or pazopanib. Methods: The study was observational and retrospective. To evaluate the VETC effect on overall survival (OS) for Cox regression, with power .8, Hazard Ratio 2.35, proportion of subject VETC+ .4, proportion of events .6, correlation among covariates .4 and a type I error rate .5, the estimated sample size was n=89. We included consecutive patients undergoing surgery at our institution for primary RCC from 2005 to 2007, (Surgical Series; n=92 cases). Moreover, to investigate the possible role of VETC in predicting TKIs benefit, we considered all RCC patients treated with first line TKIs at our center (TKI Series; sunitinib, n = 39; pazopanib n = 17), and recorded the progression free survival (PFS). VETC was assessed with CD34 immunohistochemistry and defined as a continuous endothelial lining around tumor clusters. We used Bayesian probabilistic modeling to detect small effects and multilevel hierarchical modeling to reduce overfitting. Models were fit using Stan and R. The study was approved by institutional review board (n. 865/20) and registered on ClinicalTrials.gov. Results: VETC+ RCC had a worse prognosis in the Surgical Series, with a posterior probability density (PPD) of median OS of 88 months (mo) (standard deviation, SD: 16 mo) for VETC positive Vs 136 mo (SD: 26 mo) for VETC-; the expected loss of median OS was 48 mo (SD: 31 mo) for patients having a VETC + RCC. Conversely in the TKI Series, VETC+ RCC showed longer PFS compared to VETC- ones: with sunitinib a PPD of median PFS of 35 mo (SD:11 mo) for VETC+ Vs 19 mo (SD: 5 mo) for VETC-. Under Pazopanib a PPD of median PFS of 20 mo (SD: 8 mo) for VETC+ Vs 11 mo (SD: 7 mo) for VETC-. The expected gain of median PFS for of VETC+ cases, was 17 and 9 mo (SD: 12 and 11 mo), respectively in sunitinib and pazopanib treated cases. Conclusions: Our results confirmed the general adverse prognostic role of VETC in RCC, however this phenotype gave a substantial PFS gain for patients treated with TKI, similarly to what have been observed in HCC. VETC could be a new predictive bio-marker that allows the delivery of a personalized treatment: patients affected by RCC might directly benefit from a better selection of already approved drugs.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals Cancer Biology and Prevention in Diabetes

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1380 ◽  
Author(s):  
Swayam Prakash Srivastava ◽  
Julie E. Goodwin
Keyword(s):  
Type Ii Diabetes ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Type I Diabetes ◽  
Type I ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Risk Of Cancer

The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

Signal transduction and TGF-β superfamily receptors

1996 ◽  
Vol 74 (3) ◽  
pp. 299-314 ◽  
Author(s):  
Steven M. Kolodziejczyk ◽  
Brian K. Hall
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Intracellular Signaling ◽  
Specific Cell ◽  
Type I ◽  
Type Ii ◽  
Type Iii ◽  
Wide Range ◽  
Transduction Mechanisms ◽  
Kinase Cascade

The TGF-β superfamily includes a large number of related growth and differentiation factors expressed in virtually all phyla. Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their effects. Candidate receptors fall into two primary groups, termed type I and type II receptors. Both types are serine/threonine kinases. Upon activation by the appropriate ligand, type I and type II receptors physically interact to form hetero-oligomers and subsequently activate intracellular signaling cascades, ultimately regulating gene transcription and expression. In addition, TGF-β binds to a third receptor class, type III, a membrane-anchored proteoglycan lacking the kinase activity typical of signal transducing molecules. Type III receptors appear to regulate ligand availability to type I and type II receptors. Although a number of transduction mechanisms may be available to TGF-β superfamily members, evidence gathered through the use of specific kinase and G-protein inhibitors and through assays measuring activation and levels of signaling intermediates suggests that at least one signaling pathway interacts with Ras and Raf proteins via a G-protein intermediate. Raf begins the cytoplasmic kinase cascade that leads to gene regulation. The myriad responses regulated by TGF-β superfamily members makes the understanding of signal transduction mechanisms utilized by these proteins of great interest to a wide range of biological disciplines.Key words: TGF-β superfamily, serine/threonine kinase receptors, G-proteins, Ras, cytoplasmic kinase cascade.

scholarly journals Role of MxB in Alpha Interferon-Mediated Inhibition of HIV-1 Infection

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Bin Xu ◽  
Qinghua Pan ◽  
Chen Liang
Keyword(s):  
G Protein ◽  
Transmembrane Protein ◽  
Alpha Interferon ◽  
Wild Type Virus ◽  
Target Cells ◽  
Type I ◽  
Wide Range ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTType I interferon inhibits viruses through inducing the expression of antiviral proteins, including the myxovirus resistance (Mx) proteins. Compared to the human MxA protein, which inhibits a wide range of viruses, the MxB protein has been reported to specifically inhibit primate lentiviruses, including HIV-1, and herpesviruses. Further, the role of endogenous MxB in alpha interferon-mediated inhibition of HIV-1 infection was questioned by a recent study showing that MxB knockout did not increase the level of infection by HIV-1 which carried the G protein of vesicular stomatitis virus (VSV), allowing infection of CD4-negative HT1080 cells. In order to further examine the anti-HIV-1 activity of endogenous MxB, we have used CRISPR/Cas9 to deplete MxB in different cell lines and observed a substantial restoration of HIV-1 infection in the presence of alpha interferon treatment. However, this rescue effect of MxB knockout became much less pronounced when infection was performed with HIV-1 carrying the VSV G protein. Interestingly, a CRISPR/Cas9 knockout screen of alpha interferon-stimulated genes in U87-MG cells revealed that the genes for interferon-induced transmembrane protein 2 (IFITM2) and IFITM3 inhibited VSV G-pseudotyped HIV-1 much more strongly than the rest of the genes tested, including the gene for MxB. Therefore, our results demonstrate the importance of MxB in alpha interferon-mediated inhibition of HIV-1 infection, which, however, can be underestimated if infection is performed with VSV G protein-pseudotyped HIV-1, due to the high sensitivity of VSV G-mediated infection to inhibition by IFITM proteins.IMPORTANCEThe results of this study reconcile the controversial reports regarding the anti-HIV-1 function of alpha interferon-induced MxB protein. In addition to the different cell types that may have contributed to the different observations, our data also suggest that VSV G protein-pseudotyped HIV-1 is much less inhibited by alpha interferon-induced MxB than HIV-1 itself is. Our results clearly demonstrate an important contribution of MxB to alpha interferon-mediated inhibition of HIV-1 in CD4+T cells, which calls for using HIV-1 target cells and wild-type virus to test the relevance of the anti-HIV-1 activity of endogenous MxB and other restriction factors.

scholarly journals Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

2020 ◽  
Author(s):  
Richa Mishra ◽  
Sanjana Bhattacharya ◽  
Bhupendra S Rawat ◽  
Ashish Kumar ◽  
Akhilesh Kumar ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mouse Model ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Innate Immune ◽  
Locked Nucleic Acid ◽  
Type I ◽  
Innate Immune Responses ◽  
Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

Molecular network of the comprehensive multiple sclerosis brain-lesion proteome

2009 ◽  
Vol 15 (5) ◽  
pp. 531-541 ◽  
Author(s):  
JI Satoh ◽  
H Tabunoki ◽  
T Yamamura
Keyword(s):  
Multiple Sclerosis ◽  
Pathway Analysis ◽  
Brain Lesion ◽  
Molecular Networks ◽  
Coagulation Cascade ◽  
Integrin Signaling ◽  
Type I ◽  
Lesion Development ◽  
Wide Range

Background A recent proteomics study of multiple sclerosis (MS) lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination. However, among thousands of proteins examined, nearly all of remaining proteins are yet to be characterized in terms of their implications in MS brain-lesion development. Methods By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaques, chronic active plaques (CAP), and chronic plaques (CP). Results The database search on Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER) indicated the relevance of extracellular matrix (ECM)–mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain-lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Ingenuity pathway analysis (IPA) identified the network constructed with a wide range of ECM components, such as collagen, type I α1, type I α2, type VI α2, type VI α3, fibronectin 1, fibulin 2, laminin α1, vitronectin, and heparan sulfate proteoglycan, as one of the networks highly relevant to CAP proteome. Conclusions Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These in silico observations indicate that the selective blockade of the interaction between ECM and integrins in brain lesions in situ would be a target for therapeutic intervention in MS.

scholarly journals Tricetin Protects Rat Chondrocytes against IL-1β-Induced Inflammation and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Fang-Fang Sun ◽  
Peng-Fei Hu ◽  
Yan Xiong ◽  
Jia-Peng Bao ◽  
Jing Qian ◽  
...  
Keyword(s):  
Western Blotting ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Griess Reaction ◽  
Wide Range ◽  
Cancer And Inflammation

Tricetin is a well-studied flavonoid with a wide range of pharmacological activities in cancer and inflammation. However, the ability of tricetin to ameliorate the inflammation that occurs in osteoarthritis (OA) has not been determined. This study explored the effects of tricetin on interleukin- (IL-) 1β-induced rat chondrocytes. Chondrocytes harvested from rat cartilage were incubated in vitro with tricetin in the presence of IL-1β. The expression of matrix metalloproteinase- (MMP-) 1, MMP-3, MMP-13, nitric oxide (NO), prostaglandin E2 (PGE2), Bax, and Bcl-2 was evaluated by real-time-PCR, ELISA, Griess reaction, and western blotting. Caspase-3 activity in chondrocytes was determined using a caspase-3 activity assay and MAPK pathway activity by western blotting. Tricetin decreased the expression of MMP-1, MMP-3, and MMP-13 at both the gene and protein level in IL-1β-induced rat chondrocytes. It also inhibited IL-1β-induced NO and PGE2 production, by modulating inducible NO synthase and cyclooxygenase 2 gene expression. An antiapoptotic role of tricetin involving the Bax/Bcl-2/caspase-3 pathway was also determined. The chondroprotective effect of tricetin was shown to be partly related to the suppression of the MAPK signaling pathway. The results of this study demonstrate the chondroprotective role of tricetin, based on its anticatabolic, anti-inflammatory, and antiapoptotic effects in chondrocytes. The therapeutic potential of tricetin in OA patients should be explored in future studies.

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