I přes veškerý pokrok posledních let je stále hlavní léčebnou modalitou u většiny pacientek a pacientů s karcinomem prsu hormonální terapie. Nicméně i na tuto léčbu může vzniknout postupem času rezistence a dojít k progresi onemocnění, pak je třeba najít terapii pro druhou a vyšší linie léčby. Vhodným kandidátem pro tuto situaci se zdá být alpelisib - α-specifický inhibitor fosfatidylinositol-3-kinázy (phosphatidylinositol-3-kinase, PI3K), který v kombinaci s fulvestrantem prokazuje svoji účinnost u pacientů s pokročilým hormonálně dependentním karcinomem prsu s negativitou receptoru 2 pro lidský epidermální růstový faktor (human epidermal growth factor receptor 2, HER2) kde byla zjištěna mutace onkogenu pro izoformu PI3K alfa (PI3K catalytic subunit alpha, PIK3CA), po progresi onemocnění na hormonální léčbě, a to i v případě, že byly využity inhibitory cyklin-dependentní kinázy 4/6 (cyclin dependent kinase 4/6, CDK4/6). Tato účinnost byla dokumentována v rámci studie SOLAR-1 u pacientů po selhání hormonální léčby v porovnání s placebem a v rámci studie BYLieve, kam byli zařazováni pacienti po předchozí progresi na CDK4/6 inhibitorech.

Despite all the progress of recent years, hormone therapy is still the main treatment modality in most patients with breast cancer. However, even for this treatment, resistance and disease progression may develop over time then it is necessary to find therapy for the second and higher lines of treatment. A suitable candidate for this situation appears to be alpelisib - an α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor which, in combination with fulvestrant, has been shown to be effective in patients with advanced hormone-dependent, human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer where PI3K catalytic subunit alpha (PIK3CA) mutations have been identified, after disease progression to hormonal therapy, even if cyclin dependent kinase 4/6 (CDK4/6) inhibitors have been used. This efficacy was documented in the SOLAR-1 study in patients after hormonal treatment failure compared to placebo and in the BYLieve study, which enrolled patients after previous progression to CDK4/6 inhibitors.

• Klíčová slova
• alpesilib, PI3K, SOLAR-1, BYLieve,
• MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• fulvestrant aplikace a dávkování   MeSH
• inhibitory fosfoinositid-3-kinasy * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• klinická studie jako téma MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• mutace MeSH
• nádory prsu * farmakoterapie   MeSH
• proteinkinasy farmakologie   MeSH
• protinádorové látky aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

Karcinom prsu patří mezi nejčastější zhoubná onemocnění u žen. Signální dráha PI3K/Akt/mTOR hraje důležitou roli v řadě buněčných procesů podílejících se na proliferaci, metabolismu, buněčném růstu a přežití. Alterace této signální dráhy byly nalezeny u celé řady nádorů, včetně nádoru prsu. Konstitutivní aktivace PI3K/Akt/mTOR signální dráhy hraje klíčovou roli v patogenezi nádoru a rezistenci na konvenční terapii. V souvislosti s nově schválenou léčbou pomocí inhibitorů PI3K nabývá na významu i stanovení PIK3CA mutačního statusu jako prediktivního markeru léčebné odpovědi.

Breast cancer is one of the most common malignancies in women. The PI3K/Akt/mTOR signaling pathway plays an important role in several cellular processes involved in proliferation, metabolism, cell growth, and survival. Alterations in this signaling pathway have been found in a variety of tumors, including breast cancer. Constitutive activation of the PI3K/Akt/mTOR signaling pathway plays a key role in tumor pathogenesis and resistance to conventional therapy. In connection with the newly approved treatment with PI3K inhibitors, the determination of PIK3CA mutation status as a predictive marker is also gaining in importance.

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• cílená molekulární terapie * MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• racionální návrh léčiv MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Publikační typ
• abstrakt z konference MeSH

β -catenin signaling is required for hair follicle deve lopment and regeneration which are involved in the resuscitation of hair follicle stem cells (HFSCs). To further characterize the role of β -catenin in the regulation of proliferation of HFSCs, the β -catenin expression was measured in the defined stages of hair follicle cycle and the proliferative potency was determined by using an in vitro cell growth assay. Our results showed that activation of β -catenin correlated with HFSCs proliferation, which appeared to be mediated by the nuclear translocation of stabilized β -catenin and the activation of responsib le cell cycle genes (cyclin D1 and p21). In addition, PI3K/Akt pathway was also involved in the HFSCs proliferation, partly regulated by β -catenin signaling pathway. These results demonstrate that β -catenin is an essential factor in the regulation of HFSCs proliferation via PI3K/Akt pathway and might be a potential therapeutic target for the regulation of the yield of keratinocytes from HFSCs.

• Klíčová slova
• PI3K/Akt,
• MeSH
• beta-katenin * MeSH
• cyklin D1 MeSH
• fosfatidylinositol-3-kinasy MeSH
• imunohistochemie MeSH
• jaderné proteiny MeSH
• kmenové buňky * MeSH
• krysa rodu rattus MeSH
• onkogenní protein p21(ras) MeSH
• proliferace buněk MeSH
• transkripční faktory MeSH
• vlasový folikul * metabolismus   růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.

• MeSH
• fosfatidylinositol-3-kinasy * metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas farmakologie   chemie   terapeutické užití   MeSH
• lidé MeSH
• mTOR inhibitory farmakologie   terapeutické užití   MeSH
• protinádorové látky * farmakologie   chemie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt * metabolismus   antagonisté a inhibitory   MeSH
• sarkom * farmakoterapie   metabolismus   patologie   MeSH
• signální transdukce * účinky léků   MeSH
• TOR serin-threoninkinasy * antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

This study systematically evaluated the therapeutic effects of podophyllotoxin in a DSS-induced mouse model of ulcerative colitis. A total of 374 podophyllotoxin-related targets were identified through database screening, and by intersecting them with 1,741 UC-related targets, 120 potential therapeutic targets were obtained. Subsequent GO and KEGG enrichment analyses revealed that these targets are primarily involved in biological processes such as the positive regulation of protein kinase B signaling, cellular response to lipopolysaccharide, and inflammatory responses, with significant enrichment in key pathways like the PI3K-Akt signaling pathway. Molecular docking results indicated that podophyllotoxin has strong binding activity with several targets related to inflammation and signal transduction. Animal experiments further validated the significant therapeutic effects of podophyllotoxin in the DSS-induced ulcerative colitis mouse model. Particularly at high doses, podophyllotoxin effectively alleviated ulcerative colitis symptoms, reduced pathological damage to colonic tissues, and enhanced intestinal barrier function. Additionally, podophyllotoxin significantly lowered the levels of inflammatory cytokines (TNF-?, IL-1?, IL-6) in the serum and colonic tissues of ulcerative colitis model mice and improved oxidative stress status. More importantly, podophyllotoxin effectively restored the impaired intestinal mucosal barrier function by enhancing the expression of tight junction proteins such as ZO-1 and occludin. Finally, the study revealed that podophyllotoxin may alleviate ulcerative colitis symptoms and promote colonic tissue repair by activating the PI3K/AKT signaling pathway. These findings provide strong experimental evidence for the potential use of podophyllotoxin as a therapeutic agent for ulcerative colitis and offer valuable insights for the future development of ulcerative colitis treatment strategies targeting the PI3K/AKT pathway. Key words: Podophyllotoxin, Ulcerative Colitis, Inflammation, PI3K/AKT.

• MeSH
• fosfatidylinositol-3-kinasy * metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• podofylotoxin * farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• simulace molekulového dockingu MeSH
• síran dextranu toxicita   MeSH
• ulcerózní kolitida * farmakoterapie   chemicky indukované   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• Tumor specifická terapie, dráha PI3K/AKT/PTEN,
• MeSH
• aktivované STAT proteiny - proteinové inhibitory MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prsu * farmakoterapie   MeSH
• receptor erbB-2 genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• zprávy MeSH

Recent studies have suggested that the hypothalamus has an important role in aging by regulating nuclear factor-?B (NF-?B)-directed gonadotropin-releasing hormone (GnRH) decline. Moreover, our previous study has shown that ischemia-reperfusion (IR) injury activates NF-?B to reduce hypothalamic GnRH release, thus suggesting that IR injury may facilitate hypothalamic programming of system aging. In this study, we further examined the role of phosphoinositide 3-kinase (PI3K)/Protein kinase B (Akt) pathway, a critical intracellular signal pathway involved in the repair process after IR, in hypoxia-reoxygenation (HR)-associated GnRH decline in vitro. We used GT1-7 cells and primarily-cultured mouse GnRH neurons as cell models for investigation. Our data revealed that the activation of the PI3K/Akt/Forkhead box protein O3a (FOXO3a) pathway protects GnRH neurons from HR-induced GnRH decline by preventing HR-induced gnrh1 gene inhibition and NF-?B activation. Our results further the understanding of the regulatory mechanisms of HR-associated hypothalamic GnRH decline.

• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• hormon uvolňující gonadotropiny * genetika   metabolismus   farmakologie   MeSH
• hypothalamus metabolismus   MeSH
• hypoxie metabolismus   MeSH
• myši MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The potential pro-survival role of phosphatidylinositol 3-kinase (PI3K)/Akt during endoplasmic reticulum stress has been well-characterized. However, the detailed mechanisms remain largely unknown. Here, we showed that PI3K/Akt inhibition promoted endoplasmic reticulum stress-induced apoptosis in a glucose-regulated protein 78 (GRP78)-dependent manner. During endoplasmic reticulum stress, high levels of Akt phosphorylation were sustained for at least 18 h in HEK293 cells. Importantly, PI3K/Akt enhanced GRP78 accumulation through increasing its stability following endoplasmic reticulum stress. Furthermore, Akt1, but not Akt2 or Akt3, was involved in GRP78 stability regulation. These results suggest that PI3K/Akt inhibits endoplasmic reticulum stress-induced apoptosis in HEK293 cells, at least in part, by promoting GRP78 protein stability.

• MeSH
• apoptóza fyziologie   účinky léků   MeSH
• buněčné linie MeSH
• buňky NIH 3T3 MeSH
• dithiothreitol farmakologie   MeSH
• endoplazmatické retikulum metabolismus   účinky léků   MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• fyziologický stres MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• myši MeSH
• proteiny teplotního šoku genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• thapsigargin farmakologie   MeSH
• transkripční faktor CHOP metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH