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2.
Clin Transl Med ; 14(5): e1655, 2024 May.
Article in English | MEDLINE | ID: mdl-38711203

ABSTRACT

BACKGROUND: Uterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some 'challenging-to-treat' cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB. METHODS: We performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient-derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single-agent and a combination of PI3K/mTOR inhibitors with PD-1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single-cell RNA/TCR sequencing of serially collected biopsies. RESULTS: PI3K/mTOR over-activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB-resistant humanized uLMS PDX model, fostering adaptive anti-tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti-tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD-1+ T cells displaying an exhausted phenotype. When combined with anti-PD-1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single-agent anti-PD-1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper-expansion of a cytotoxic CD8+ T-cell population supported by a CD4+ Th1 niche. CONCLUSIONS: Our findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.


Subject(s)
Leiomyosarcoma , Tumor Microenvironment , Uterine Neoplasms , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Leiomyosarcoma/drug therapy , Humans , Female , Uterine Neoplasms/drug therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/metabolism , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , MTOR Inhibitors/pharmacology , MTOR Inhibitors/therapeutic use , Animals , Mice , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use
3.
Int J Mol Sci ; 25(10)2024 May 09.
Article in English | MEDLINE | ID: mdl-38791198

ABSTRACT

MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, the specific mechanisms contributing to the acquired resistance to MTX-211 in human cancers remain elusive. Here, we discovered that the overexpression of the ATP-binding cassette (ABC) drug transporter ABCG2, a prevalent mechanism associated with multidrug resistance (MDR), could diminish the effectiveness of MTX-211 in human cancer cells. We showed that the drug efflux activity of ABCG2 substantially decreased the intracellular accumulation of MTX-211 in cancer cells. As a result, the cytotoxicity and effectiveness of MTX-211 in suppressing the activation of the EGFR and PI3K pathways were significantly attenuated in cancer cells overexpressing ABCG2. Moreover, the enhancement of the MTX-211-stimulated ATPase activity of ABCG2 and the computational molecular docking analysis illustrating the binding of MTX-211 to the substrate-binding sites of ABCG2 offered a further indication for the interaction between MTX-211 and ABCG2. In summary, our findings indicate that MTX-211 acts as a substrate for ABCG2, underscoring the involvement of ABCG2 in the emergence of resistance to MTX-211. This finding carries clinical implications and merits further exploration.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Drug Resistance, Neoplasm , ErbB Receptors , Neoplasm Proteins , Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Neoplasm Proteins/metabolism , Neoplasm Proteins/genetics , Neoplasm Proteins/antagonists & inhibitors , Cell Line, Tumor , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Molecular Docking Simulation , Signal Transduction/drug effects , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/genetics , Neoplasms/pathology
4.
Int J Mol Sci ; 25(10)2024 May 20.
Article in English | MEDLINE | ID: mdl-38791602

ABSTRACT

The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.


Subject(s)
Adenocarcinoma , Class I Phosphatidylinositol 3-Kinases , ErbB Receptors , Neoplastic Cells, Circulating , Signal Transduction , Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/metabolism , Stomach Neoplasms/genetics , ErbB Receptors/metabolism , Signal Transduction/drug effects , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/genetics , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/metabolism , Class I Phosphatidylinositol 3-Kinases/genetics , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/drug effects , Neoplastic Cells, Circulating/pathology , Phosphatidylinositol 3-Kinases/metabolism , Neoplasm Metastasis , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Thiazoles
5.
BMC Vet Res ; 20(1): 233, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38807154

ABSTRACT

Canine mammary gland tumors (MGT) have a poor prognosis in intact female canines, posing a clinical challenge. This study aimed to establish novel canine mammary cancer cell lines from primary tumors and characterize their cellular and molecular features to find potential therapeutic drugs. The MGT cell lines demonstrated rapid cell proliferation and colony formation in an anchorage-independent manner. Vimentin and α-SMA levels were significantly elevated in MGT cell lines compared to normal canine kidney (MDCK) cells, while CDH1 expression was either significantly lower or not detected at all, based on quantitative real-time PCR (qRT-PCR) analysis. Functional annotation and enrichment analysis revealed that epithelial-mesenchymal transition (EMT) phenotypes and tumor-associated pathways, particularly the PI3K/Akt signaling pathway, were upregulated in MGT cells. BYL719 (Alpelisib), a PI3K inhibitor, was also examined for cytotoxicity on the MGT cell lines. The results show that BYL719 can significantly inhibit the proliferation of MGT cell lines in vitro. Overall, our findings suggest that the MGT cell lines may be valuable for future studies on the development, progression, metastasis, and management of tumors.


Subject(s)
Dog Diseases , Mammary Neoplasms, Animal , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Animals , Dogs , Female , Cell Line, Tumor , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/genetics , Dog Diseases/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Signal Transduction , Phosphoinositide-3 Kinase Inhibitors/pharmacology
6.
Cancer Res Commun ; 4(6): 1430-1440, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38717161

ABSTRACT

The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC. SIGNIFICANCE: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Furans , Ketones , Pyrimidines , Triple Negative Breast Neoplasms , Xenograft Model Antitumor Assays , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Ketones/pharmacology , Ketones/administration & dosage , Ketones/therapeutic use , Animals , Furans/pharmacology , Furans/administration & dosage , Furans/therapeutic use , Humans , Female , Mice , Pyrimidines/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Apoptosis/drug effects , Quinazolines/pharmacology , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Signal Transduction/drug effects , Cell Proliferation/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Polyether Polyketides
7.
Mol Biol Rep ; 51(1): 698, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811424

ABSTRACT

BACKGROUND: Existing investigations suggest that the blockade of phosphoinositide 3-kinase (PI3K) activity contributes to inflammatory solution in allergic asthma, but whether this inhibition directly attenuates neutrophilic airway inflammation in vivo is still unclear. We explored the pharmacological effects of LY294002, a specific inhibitor of PI3K on the progression of neutrophilic airway inflammation and investigated the underlying mechanism. METHODS AND RESULTS: Female C57BL/6 mice were intranasally sensitized with ovalbumin (OVA) together with lipopolysaccharide (LPS) on days 0 and 6, and challenged with OVA on days 14-17 to establish a neutrophilic airway disease model. In the challenge phase, a subset of mice was treated intratracheally with LY294002. We found that treatment of LY294002 attenuates clinic symptoms of inflammatory mice. Histological studies showed that LY294002 significantly inhibited inflammatory cell infiltration and mucus production. The treatment also significantly inhibited OVA-LPS induced increases in inflammatory cell counts, especially neutrophil counts, and IL-17 levels in bronchoalveolar lavage fluid (BALF). LY294002 treated mice exhibited significantly increased IL-10 levels in BALF compared to the untreated mice. In addition, LY294002 reduced the plasma concentrations of IL-6 and IL-17. The anti-inflammatory effects of LY29402 were correlated with the downregulation of NLRP3 inflammasome. CONCLUSIONS: Our findings suggested that LY294002 as a potential pharmacological target for neutrophilic airway inflammation.


Subject(s)
Asthma , Bronchoalveolar Lavage Fluid , Chromones , Disease Models, Animal , Inflammasomes , Lipopolysaccharides , Mice, Inbred C57BL , Morpholines , NLR Family, Pyrin Domain-Containing 3 Protein , Neutrophils , Ovalbumin , Phosphatidylinositol 3-Kinases , Phosphoinositide-3 Kinase Inhibitors , Animals , Asthma/drug therapy , Asthma/chemically induced , Asthma/metabolism , Asthma/immunology , Lipopolysaccharides/pharmacology , Mice , Inflammasomes/metabolism , Inflammasomes/drug effects , Female , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Chromones/pharmacology , Morpholines/pharmacology , Neutrophils/drug effects , Neutrophils/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Lung/pathology , Lung/drug effects , Lung/metabolism , Interleukin-17/metabolism
8.
Cell Death Dis ; 15(5): 373, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811535

ABSTRACT

The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.


Subject(s)
Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p21 , Humans , Cellular Senescence/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , HCT116 Cells , Proteasome Endopeptidase Complex/metabolism , Apoptosis/drug effects , Phosphoinositide-3 Kinase Inhibitors/pharmacology , MCF-7 Cells , Proteolysis/drug effects , A549 Cells , Wortmannin/pharmacology , Senotherapeutics/pharmacology , Class I Phosphatidylinositol 3-Kinases/metabolism , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/genetics , DNA Damage/drug effects , Pyrimidines , Quinazolines
9.
BMC Cardiovasc Disord ; 24(1): 280, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811893

ABSTRACT

BACKGROUND: Myocardial ischemia-reperfusion injury (I/RI) is a major cause of perioperative cardiac-related adverse events and death. Studies have shown that sevoflurane postconditioning (SpostC), which attenuates I/R injury and exerts cardioprotective effects, regulates mitochondrial dynamic balance via HIF-1α, but the exact mechanism is unknown. This study investigates whether the PI3K/AKT pathway in SpostC regulates mitochondrial dynamic balance by mediating HIF-1α, thereby exerting myocardial protective effects. METHODS: The H9C2 cardiomyocytes were cultured to establish the hypoxia-reoxygenation (H/R) model and randomly divided into 4 groups: Control group, H/R group, sevoflurane postconditioning (H/R + SpostC) group and PI3K/AKT blocker (H/R + SpostC + LY) group. Cell survival rate was determined by CCK-8; Apoptosis rate was determined by flow cytometry; mitochondrial membrane potential was evaluated by Mito Tracker™ Red; mRNA expression levels of AKT, HIF-1α, Opa1and Drp1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR); Western Blot assay was used to detect the protein expression levels of AKT, phosphorylated AKT (p-AKT), HIF-1α, Opa1 and Drp1. RESULTS: Compared with the H/R group, the survival rate of cardiomyocytes in the H/R + SpostC group increased, the apoptosis rate decreased and the mitochondrial membrane potential increased. qRT-PCR showed that the mRNA expression of HIF-1α and Opa1 were higher in the H/R + SpostC group compared with the H/R group, whereas the transcription level of Drp1 was lower in the H/R + SpostC group. In the H/R + SpostC + LY group, the mRNA expression of HIF-1α was lower than the H/R + SpostC group. There was no difference in the expression of Opa1 mRNA between the H/R group and the H/R + SpostC + LY group. WB assay results showed that compared with the H/R group, the protein expression levels of HIF-1α, Opa1, P-AKT were increased and Drp1 protein expression levels were decreased in the H/R + SpostC group. HIF-1α, P-AKT protein expression levels were decreased in the H/R + SpostC + LY group compared to the H/R + SpostC group. CONCLUSION: SpostC mediates HIF-1α-regulated mitochondrial fission and fusion-related protein expression to maintain mitochondrial dynamic balance by activating the PI3K/AKT pathway and increasing AKT phosphorylation, thereby attenuating myocardial I/R injury.


Subject(s)
Apoptosis , Hypoxia-Inducible Factor 1, alpha Subunit , Membrane Potential, Mitochondrial , Mitochondria, Heart , Mitochondrial Dynamics , Myocardial Reperfusion Injury , Myocytes, Cardiac , Phosphatidylinositol 3-Kinase , Proto-Oncogene Proteins c-akt , Sevoflurane , Signal Transduction , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Proto-Oncogene Proteins c-akt/metabolism , Animals , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/enzymology , Sevoflurane/pharmacology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/enzymology , Mitochondrial Dynamics/drug effects , Cell Line , Rats , Apoptosis/drug effects , Phosphatidylinositol 3-Kinase/metabolism , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Mitochondria, Heart/enzymology , Membrane Potential, Mitochondrial/drug effects , Cell Hypoxia , Dynamins/metabolism , Dynamins/genetics , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/genetics , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Cytoprotection , Ischemic Postconditioning , Phosphorylation
10.
Cell Biochem Funct ; 42(3): e3998, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38561964

ABSTRACT

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy.


Subject(s)
Breast Neoplasms , Phosphatidylinositol 3-Kinase , Humans , Female , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinase/pharmacology , Phosphatidylinositol 3-Kinase/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use
11.
Signal Transduct Target Ther ; 9(1): 99, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38627366

ABSTRACT

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.


Subject(s)
Lymphoma, Follicular , Humans , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/genetics , Progression-Free Survival , Phosphoinositide-3 Kinase Inhibitors/therapeutic use
12.
J Med Chem ; 67(8): 6638-6657, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38577724

ABSTRACT

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases , Leukemia, Myeloid, Acute , Phosphoinositide-3 Kinase Inhibitors , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Animals , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacokinetics , Cell Proliferation/drug effects , Mice , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Structure-Activity Relationship , Apoptosis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Xenograft Model Antitumor Assays , Drug Discovery , Mice, Nude , Molecular Docking Simulation , Male
13.
Anticancer Res ; 44(5): 1863-1876, 2024 May.
Article in English | MEDLINE | ID: mdl-38677772

ABSTRACT

BACKGROUND/AIM: Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising in incidence. Compared to HPV-negative (HPV-) OPSCC, HPV+ cases have a better 5-year survival. With its severe side-effects, today's chemoradiotherapy has not improved outcome compared to radiotherapy alone, so new therapies are needed. Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 3 (FGFR3) and cell division cycle 27 (CDC27) are found in HPV+ OPSCC, and in vitro targeted therapy combining PI3K and FGFR inhibitors showed synergistic effects. Here the effects of targeting CDC27 with curcumin with/without various inhibitors or cisplatin on OPSCC cell lines were examined. MATERIALS AND METHODS: Curcumin was administered to HPV+ OPSCC cell lines CU-OP-2, CU-OP-3 and CU-OP-20, and HPV- CU-OP-17 with/without PI3K, cyclin-dependent kinase 4/6, FGFR, poly (ADP-ribose) polymerase or WEE1 inhibitors (BYL719, PD-0332991, JNJ-42756493, BMN-673 and MK-1775, respectively), or cisplatin. The cell lines were then assessed for 72 h after treatment for viability, proliferation and cytotoxicity. RESULTS: Curcumin led to dose-dependent responses with reduced viability and proliferation; upon combining it with BYL719, additional positive effects were found for most OPSCC lines grown as monolayers, and these effects were validated in CU-OP-2 cells grown as spheroids. Curcumin with MK-1775 or PD-0332991 also elicited some positive effects on CU-OP-2 and CU-OP-17 cells. CONCLUSION: Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.


Subject(s)
Curcumin , Oropharyngeal Neoplasms , Humans , Curcumin/pharmacology , Cell Line, Tumor , Oropharyngeal Neoplasms/virology , Oropharyngeal Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Cell Proliferation/drug effects , Papillomavirus Infections/virology , Papillomavirus Infections/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Papillomaviridae/drug effects , Cisplatin/pharmacology
14.
Microbiol Spectr ; 12(5): e0183923, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38564670

ABSTRACT

Solid organ transplantation is a crucial treatment for patients who have reached the end stage of heart, lung, kidney, or liver failure. However, the likelihood of developing cancer post-transplantation increases. Additionally, primary malignant tumors remain a major obstacle to the long-term survival of transplanted organs. Therefore, it is essential to investigate effective therapies that can boost the immune system's ability to combat cancer and prevent allograft rejection. We established a mouse orthotopic liver tumor model and conducted allogeneic heterotopic heart transplantation. Various treatments were administered, and survival curves were generated using the Kaplan-Meier method. We also collected graft samples and measured inflammatory cytokine levels in the serum using an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. We administered a combination therapy of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 to primary liver cancer model mice with cardiac allografts. Consistent with our prior findings, L. rhamnosus HN001 alleviated the intestinal flora imbalance caused by BEZ235. Our previous research confirmed that the combination of BEZ235 and L. rhamnosus HN001 significantly prolonged cardiac transplant survival. IMPORTANCE: We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.


Subject(s)
Heart Transplantation , Lacticaseibacillus rhamnosus , TOR Serine-Threonine Kinases , Animals , Male , Mice , Disease Models, Animal , Graft Rejection/prevention & control , Graft Survival/drug effects , Liver Neoplasms , Mice, Inbred BALB C , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
15.
Mol Immunol ; 170: 110-118, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38653076

ABSTRACT

Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis.


Subject(s)
Class I Phosphatidylinositol 3-Kinases , Lipopolysaccharides , Mice, Inbred C57BL , Pyroptosis , Sepsis , T-Lymphocytes, Regulatory , Th17 Cells , Animals , Pyroptosis/drug effects , Sepsis/immunology , Sepsis/drug therapy , Lipopolysaccharides/pharmacology , Mice , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/drug effects , Th17 Cells/immunology , Th17 Cells/drug effects , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Macrophages/immunology , Macrophages/drug effects , Macrophages/metabolism , Male , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Signal Transduction/drug effects
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 643-646, 2024 Apr.
Article in Chinese | MEDLINE | ID: mdl-38660880

ABSTRACT

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new drugs, chemotherapy has been gradually replaced by targeted therapy, which significantly prolongs the survival of patients and reduces the side effects of treatment. At present, BTK inhibitors, PI3K inhibitors, spleen tyrosine kinase (SYK) inhibitors and BCL-2 inhibitors are the most studied targeted therapeutic drugs for CLL/SLL. This article reviews the research progress of different types of targeted therapeutic drugs in the treatment of CLL/SLL.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Molecular Targeted Therapy , Syk Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2 , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Phosphoinositide-3 Kinase Inhibitors
17.
Cell Rep ; 43(5): 114132, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38656871

ABSTRACT

Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion in vivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kß activities are functionally redundant in adipocyte insulin signaling. PI3Kß-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.


Subject(s)
Adipocytes , Fasting , Insulin Secretion , Insulin , Mice, Knockout , Phosphatidylinositol 3-Kinases , Animals , Adipocytes/metabolism , Insulin/metabolism , Mice , Fasting/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , Fatty Acids, Nonesterified/metabolism , Fatty Acids, Nonesterified/blood , Lipolysis , Male , Proto-Oncogene Proteins c-akt/metabolism , Mice, Inbred C57BL , Phosphorylation , Phosphoinositide-3 Kinase Inhibitors/pharmacology
18.
Life Sci ; 347: 122662, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38670450

ABSTRACT

AIMS: PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds. MAIN METHODS: We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo. KEY FINDINGS: We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model. SIGNIFICANCE: Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.


Subject(s)
Antineoplastic Agents , Class I Phosphatidylinositol 3-Kinases , Lymphoma, B-Cell , Phosphoinositide-3 Kinase Inhibitors , Xenograft Model Antitumor Assays , Humans , Animals , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Mice , Antineoplastic Agents/pharmacology , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Indazoles/pharmacology , Indazoles/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Female , Signal Transduction/drug effects , Mice, Nude
19.
J Neurooncol ; 168(1): 139-149, 2024 May.
Article in English | MEDLINE | ID: mdl-38662151

ABSTRACT

PURPOSE: Medulloblastoma (MB), a common and heterogeneous posterior fossa tumor in pediatric patients, presents diverse prognostic outcomes. To advance our understanding of MB's intricate biology, the development of novel patient tumor-derived culture MB models with necessary data is still an essential requirement. METHODS: We continuously passaged PUMC-MB1 in vitro in order to establish a continuous cell line. We examined the in vitro growth using Cell Counting Kit-8 (CCK-8) and in vivo growth with subcutaneous and intracranial xenograft models. The xenografts were investigated histopathologically with Hematoxylin and Eosin (HE) staining and immunohistochemistry (IHC). Concurrently, we explored its molecular features using Whole Genome Sequencing (WGS), targeted sequencing, and RNA sequecing. Guided by bioinformatics analysis, we validated PUMC-MB1's drug sensitivity in vitro and in vivo. RESULTS: PUMC-MB1, derived from a high-risk MB patient, displayed a population doubling time (PDT) of 48.18 h and achieved 100% tumor growth in SCID mice within 20 days. HE and Immunohistochemical examination of the original tumor and xenografts confirmed the classification of PUMC-MB1 as a classic MB. Genomic analysis via WGS revealed concurrent MYC and OTX2 amplifications. The RNA-seq data classified it within the Group 3 MB subgroup, while according to the WHO classification, it fell under the Non-WNT/Non-SHH MB. Comparative analysis with D283 and D341med identified 4065 differentially expressed genes, with notable enrichment in the PI3K-AKT pathway. Cisplatin, 4-hydroperoxy cyclophosphamide/cyclophosphamide, vincristine, and dactolisib (a selective PI3K/mTOR dual inhibitor) significantly inhibited PUMC-MB1 proliferation in vitro and in vivo. CONCLUSIONS: PUMC-MB1, a novel Group 3 (Non-WNT/Non-SHH) MB cell line, is comprehensively characterized for its growth, pathology, and molecular characteristics. Notably, dactolisib demonstrated potent anti-proliferative effects with minimal toxicity, promising a potential therapeutic avenue. PUMC-MB1 could serve as a valuable tool for unraveling MB mechanisms and innovative treatment strategies.


Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Mice, SCID , TOR Serine-Threonine Kinases , Xenograft Model Antitumor Assays , Humans , Animals , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Medulloblastoma/drug therapy , Medulloblastoma/pathology , Medulloblastoma/genetics , Medulloblastoma/metabolism , Mice , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Cell Proliferation/drug effects , Cell Line, Tumor , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics
20.
Expert Opin Ther Pat ; 34(3): 141-158, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38557273

ABSTRACT

INTRODUCTION: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. AREA COVERED: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. EXPERT OPINION: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.


Subject(s)
Antineoplastic Agents , Drug Design , Drug Development , Neoplasms , Patents as Topic , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Signal Transduction/drug effects , Antineoplastic Agents/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Animals , Neoplasms/drug therapy , Neoplasms/pathology , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Drug Resistance, Neoplasm , Phosphatidylinositol 3-Kinases/metabolism , Cell Proliferation/drug effects , Molecular Targeted Therapy
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