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1.
Cancer Treat Rev ; 86: 102021, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32311593

RESUMO

Ovarian cancer is the most lethal gynecological malignancy worldwide although exponential progress has been made in its treatment over the last decade. New agents and novel combination treatments are on the horizon. Among many new drugs, a series of PI3K/AKT/mTOR pathway (referred to as the PI3K pathway) inhibitors are under development or already in clinical testing. The PI3K pathway is frequently upregulated in ovarian cancer and activated PI3K signaling contributes to increased cell survival and chemoresistance. However, no significant clinical success has been achieved with the PI3K pathway inhibitor(s) to date, reflecting the complex biology and also highlighting the need for combination treatment strategies. DNA damage repair pathways have been active therapeutic targets in ovarian cancer. Emerging data suggest the PI3K pathway is also involved in DNA replication and genome stability, making DNA damage response (DDR) inhibitors as an attractive combination treatment for PI3K pathway blockades. This review describes an expanded role for the PI3K pathway in the context of DDR and cell cycle regulation. We also present the novel treatment strategies combining PI3K pathway inhibitors with DDR blockades to improve the efficacy of these inhibitors for ovarian cancer.


Assuntos
Dano ao DNA , Neoplasias Ovarianas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Animais , Replicação do DNA/efeitos dos fármacos , Feminino , Humanos , Terapia de Alvo Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Transdução de Sinais/efeitos dos fármacos
2.
Proc Natl Acad Sci U S A ; 117(14): 8013-8021, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32193335

RESUMO

AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell-cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell-cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell-cell adhesion and cancer metastasis.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Linhagem Celular Tumoral , Cromonas/farmacologia , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lapatinib/farmacologia , Camundongos , Morfolinas/farmacologia , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Análise Serial de Tecidos , Transcrição Genética/efeitos dos fármacos , Ativação Transcricional , Ensaios Antitumorais Modelo de Xenoenxerto
3.
BMC Complement Med Ther ; 20(1): 13, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32020862

RESUMO

BACKGROUND: Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. Buyang Huanwu Tang (BYHWT), a classical traditional Chinese medicine formula, has been widely utilized for the treatment of PF in China. This present study aimed to explore the mechanism of BYHWT in the treatment of PF in vitro. METHODS: TGF-ß1 stimulated human alveolar epithelial A549 cells were used as in vitro model for PF. Post the treatment of BYHWT, cell viability was measured by MTT assay, and cell morphology was observed under microscope. The epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, Vimentin) and collagen I (Col I) were detected by western blot, immunofluorescence staining and real-time quantitative polymerase chain reaction. With the co-administration of activators (IGF-1, SC79) and inhibitors (LY294002, MK2206), the effect of BYHWT on PI3K/Akt pathway was analyzed by western blot. RESULTS: BYHWT inhibited cell growth, and prevented cell morphology changed from epithelial to fibroblasts in TGF-ß1 induced A549 cells. BYHWT decreased Vimentin and Col I, while increased E-cadherin at both protein and mRNA levels. Moreover, phosphorylation of PI3K (p-PI3K) and phosphorylation of Akt (p-Akt) were significantly down-regulated by BYHWT in TGF-ß1 stimulated A549 cells. CONCLUSION: These results indicate that BYHWT suppressed TGF-ß1-induced collagen accumulation and EMT of A549 cells by inhibiting the PI3K/Akt signaling pathway. These findings suggest that BYHWT may have potential for the treatment of PF.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Humanos , Medicina Tradicional Chinesa , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Am J Respir Cell Mol Biol ; 62(5): 657-667, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922900

RESUMO

Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CF transmembrane conductance regulator (CFTR) expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is transforming growth factor (TGF) ß1, a genetic modifier of CF lung disease. Prior studies demonstrated that TGFß exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFß, with elevated PI3K signaling and greater increases in lung resistance compared with controls. Here, we show that TGFß drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR-deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFß1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared with non-CF mice. Furthermore, therapeutic inhibition of PI3K signaling mitigated the TGFß-induced AHR and goblet cell hyperplasia in CF mice. These results highlight a latent AHR phenotype in CFTR deficiency that is enhanced through TGFß-induced PI3K signaling.


Assuntos
Fibrose Cística/enzimologia , Fibrose Cística/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Hipersensibilidade Respiratória/enzimologia , Hipersensibilidade Respiratória/fisiopatologia , Transdução de Sinais , Fator de Crescimento Transformador beta/efeitos adversos , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Células Caliciformes/patologia , Hiperplasia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos
5.
Int J Mol Sci ; 21(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940823

RESUMO

Outdoor particulate matter (PM10) exposure is carcinogenic to humans. The cellular mechanism by which PM10 is associated specifically with lung cancer includes oxidative stress and damage to proteins, lipids, and DNA in the absence of apoptosis, suggesting that PM10 induces cellular survival. We aimed to evaluate the PI3K/AKT/FoxO3a pathway as a mechanism of cell survival in lung epithelial A549 cells exposed to PM10 that were subsequently challenged with hydrogen peroxide (H2O2). Our results showed that pre-exposure to PM10 followed by H2O2, as a second oxidant stimulus increased the phosphorylation rate of pAKTSer473, pAKTThr308, and pFoxO3aSer253 2.5-fold, 1.8-fold, and 1.2-fold, respectively. Levels of catalase and p27kip1, which are targets of the PIK3/AKT/FoxO3a pathway, decreased 38.1% and 62.7%, respectively. None of these changes had an influence on apoptosis; however, the inhibition of PI3K using the LY294002 compound revealed that the PI3K/AKT/FoxO3a pathway was involved in apoptosis evasion. We conclude that nontoxic PM10 exposure predisposes lung epithelial cell cultures to evade apoptosis through the PI3K/AKT/FoxO3a pathway when cells are treated with a second oxidant stimulus.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Apoptose , Estresse Oxidativo , Material Particulado/farmacologia , Transdução de Sinais , Células A549 , Células Epiteliais Alveolares/metabolismo , Proteína Forkhead Box O3/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Cancer Sci ; 111(5): 1500-1513, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31997489

RESUMO

The role of epithelial V-like antigen 1 (EVA1) has been well studied in thymic development and homostasis; however, its putative relationship with cancer remains largely unknown. Therefore, here we investigated the role of EVA1 in hepatocellular carcinoma. Interestingly, EVA1 expression was significantly increased in hepatocellular carcinoma (HCC) and was also associated with a poor prognosis and recurrence in HCC patients. Overexpression of EVA1 promoted cell growth, invasion and migration in vitro. Consistently, knockdown of EVA1 expression inhibited proliferation and migration in vitro, while repressing metastasis of HCC cells in vivo. RNA-seq analysis indicated that EVA1 is able to upregulate the expression of genes in the ERBB3-PI3K pathway. Accordingly, an increased level of AKT phosphorylation was detected in HCC cells after EVA1 overexpression. 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 the ERBB-PI3K-AKT signaling pathway, reiterating the potential use of EVA1 as a therapeutic target and/or prognostic marker for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/metabolismo , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais
7.
Int J Radiat Oncol Biol Phys ; 106(3): 564-570, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678634

RESUMO

PURPOSE: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. METHODS AND MATERIALS: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. RESULTS: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. CONCLUSIONS: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.


Assuntos
Cetuximab/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Radiossensibilizantes/administração & dosagem , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Tiazóis/administração & dosagem , Adulto , Idoso , Quimiorradioterapia/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/efeitos adversos
8.
J Med Chem ; 63(2): 638-655, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31855425

RESUMO

Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Animais , Ligação Competitiva , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Isoenzimas , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/toxicidade , Ratos , Relação Estrutura-Atividade
9.
Biochim Biophys Acta Mol Cell Res ; 1867(1): 118558, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525406

RESUMO

The sea urchin embryo develops a well-defined biomineralized endoskeleton, synthesized exclusively by the skeletogenic cells, supported by ectodermal cues for the correct skeleton patterning. The biomineralization process is tightly regulated via a hierarchical order of gene expression, including transcription and growth factors, biomineralization proteins. Recently, the role of kinases and intracellular signaling pathways in sea urchin skeletogenesis has been addressed, although the downstream components still remain unknown. In this study, we investigated the role of phosphatidylinositide 3-kinase (PI3K)-mediated signaling pathway in Paracentrotus lividus, to identify its genes/proteins targets. The effects of LY294002 (LY), a PI3K-specific inhibitor, were evaluated at morphological and molecular levels. Treatment with 40 µM LY from the blastula stage completely blocked skeleton deposition, which was reversed by wash out experiments. Besides, LY caused a slight delay in the tripartite gut development. Despite the skeleton absence, a few skeleton-specific proteins/mRNAs were regularly expressed and localized in LY-treated embryos, as shown for MSP130 and SM50 by immunofluorescence and in situ hybridization experiments. QPCR analyses showed that LY differently affected the expression of genes coding for other biomineralization proteins, transcription and growth factors. SM30 and carbonic anhydrase expression was severely downregulated, while almost all the transcription factors analyzed were upregulated. Based on the present results and in silico analyses, we propose an "interactomic" model simulating PI3K connections in P. lividus embryos. Our findings define a novel regulatory step in the embryonic skeletogenesis, and provide valuable molecular data for further studies on the role of PI3K signaling in invertebrate biomineralization.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Cromonas/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Morfolinas/farmacologia , Paracentrotus/embriologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Biologia Computacional , Embrião não Mamífero , Epistasia Genética/efeitos dos fármacos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Paracentrotus/efeitos dos fármacos , Paracentrotus/genética , Paracentrotus/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
10.
Gynecol Oncol ; 156(2): 301-307, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870556

RESUMO

OBJECTIVE: To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior. METHODS: Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events. RESULTS: Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation. CONCLUSIONS: Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Adulto Jovem
11.
Ann Oncol ; 30(Suppl_10): x3-x11, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31859348

RESUMO

One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.


Assuntos
Neoplasias da Mama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Estrogênicos/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Humanos , Epidemiologia Molecular , Terapia de Alvo Molecular , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
12.
Ann Oncol ; 30(Suppl_10): x12-x20, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31859349

RESUMO

The phosphoinositide 3 (PI3)-kinase/Akt signaling pathway has always been a focus of interest in breast cancer due to its role in cell growth, cell proliferation, cell migration and deregulated apoptosis. Its activation has been linked to endocrine resistance and worse prognosis in certain subgroups of breast cancer. In addition, deregulation of the PI3K/Akt pathway including PIK3CA activating mutation is frequently present in breast cancer. Multiple efforts have been carried out to target this pathway, initially with pan-PI3K inhibitors with some hint of activity but hampered by their limiting side-effects. A recent large randomized trial in patients with endocrine-resistant PIK3CA-mutant hormone receptor (HR)-positive tumors led to the approval of the first PI3K inhibitor, alpelisib, in combination with fulvestrant. The specificity of alpelisib against the p110α catalytic isoform provided additional efficacy and a better toxicity profile. In this review, we summarize the main research with PI3K inhibitors in breast cancer and we provide some insight of potential future combinations of this treatment in breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Animais , Neoplasias da Mama/enzimologia , Feminino , Humanos , Terapia de Alvo Molecular , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos
13.
Ann Oncol ; 30(Suppl_10): x27-x42, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31859350

RESUMO

In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18FFDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the α-selective PI3Ki alpelisib (SOLAR-1 trial) and the ß-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Med Sci Monit ; 25: 8660-8670, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31860631

RESUMO

BACKGROUND The C-terminus of E1A binding proteins (CTBPs) has recently been shown to stimulate tumorigenesis in several human tissues by participating in cell signal transduction. However, to date, the expression profile of CTBP isoforms in hepatocellular carcinoma (HCC) and the impact of CTBPs on HCC cell phenotype have not been fully explored. MATERIAL AND METHODS The expression level of CTBP1 was investigated in various HCC cell lines and HCC tissues by RT-qPCR, Western blotting, and immunohistochemistry assays. The phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 was utilized to treat hepatic astrocyte cells, and the impact of CTBP1 on proliferation and metastasis of hepatic astrocytes and HCC cells was accessed by CCK-8, clone-forming, Transwell chamber, and cell scratch assays. RESULTS Increased expression of CTBP1 was observed in HCC tissues and was a predictor of poor prognosis in HCC patients. CTBP1 modified proliferation and migratory activity of HCC cells via the PI3K/protein kinase B (Akt) signaling pathway in hepatic astrocytes. Moreover, genetic loss of CTBP1 significantly reduced the metastatic activity of HCC cells in vitro. CONCLUSIONS Our data suggest that the loss of CTBP1 suppresses cell proliferative and invasive activity of HCC cells via the PI3K/Akt pathway.


Assuntos
Oxirredutases do Álcool/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/metabolismo , Idoso , Apoptose/fisiologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Cromonas/farmacologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacologia , Invasividade Neoplásica , Metástase Neoplásica , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
15.
Asian Pac J Cancer Prev ; 20(11): 3377-3383, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759362

RESUMO

The activation of PI3K further activates subsequent regulatory pathways, which are activated via AKT phosphorylation. AKT is closely related to the Bcl-2 family, a protein known to be involved in cell survival. AKT also has a relationship with inflammatory and glycolytic mediators. The present work aimed to evaluate the relationship between the PI3K/AKT pathway, cell survival/proliferation, inflammatory mediators and the glycolytic pathway in oral squamous cell carcinoma. All experiments were performed in the SCC25 oral squamous cell carcinoma cell line. In the presence or absence of PI3K pathway inhibitors, we analyzed the protein expression of pAKT and AKT; X-linked inhibitor of apoptosis protein; Bcl-2-associated death promoter; Bcl-2-like protein two inhibitor; cyclooxygenase 1; cyclooxygenase-2; and glycoprotein-associated glucose transporter 1. For the functional characterization of treated or untreated cells, we also performed matrix invasion assays, cell migration assays, and cell proliferation assays. Our results demonstrated that activation of the PI3K/AKT pathway is directly related to members of the Bcl-2 family and GLUT1, but not the inflammatory mediators COX1 and COX2. Our data suggest that the PI3K/AKT pathway is related to cell survival and proliferation in oral squamous cell carcinoma through its interaction with Bcl-2 family members.
.


Assuntos
Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
16.
Science ; 366(6466): 714-723, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699932

RESUMO

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.


Assuntos
Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/química , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Feminino , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Ligação Proteica , Domínios Proteicos , Tiazóis/farmacologia
17.
Eur J Med Chem ; 183: 111718, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581005

RESUMO

Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.


Assuntos
Antineoplásicos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenho de Fármacos , Resistência a Múltiplos Medicamentos , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
18.
Phytomedicine ; 65: 153083, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31600690

RESUMO

BACKGROUND: Angiogenesis plays a critical role in ischemia disease like coronary heart disease. Shunxinyin formula has been developed for treating coronary heart disease according to the principle of traditional Chinese medicine while its underlying mechanism is not fully elucidated. PURPOSE: Here, we hypothesize Shuxinyin formula could promote angiogenesis and microcirculation, and the underlying mechanism is also investigated. METHODS: We established the chemical profile of Shuxinyin (SXY) extract utilizing a UHPLC-Q/Exactive analysis system and evaluated its pro-angiogenesis effect in zebrafish model. The underlying mechanisms were investigated by combination of pharmacological experiments with transcriptome analysis in zebrafish. Zebrafish treated with VEGF was served as the positive control in present study. RESULTS: We found SXY significantly enhanced the sub-intestinal vessel plexus (SIVs) growth in zebrafish. Co-treatment and post-treatment SXY attenuated VEGF receptor tyrosine kinase inhibitor II (VRI)-induced deficiency of intersegmental vessels (ISVs) in a concentration dependent manner. Post-treatment VEGF, which is a well-known angiogenesis driver, also partially ameliorated VRI-induced ISVs deficiency. In addition, SXY inhibited the down-regulation of VEGF receptors, including kdr, flt1 and kdrl, induced by VRI in zebrafish. The pro-angiogenesis effect of SXY on VRI-induced ISVs deficiency was suppressed by PI3K and JNK inhibitors, and Akt inhibitor abolished the pro-angiogenesis effect of SXY. The transcriptome profile of SXY preventing from VRI-induced vascular growth deficiency revealed that the underlying mechanisms were also co-related to cell junction, apoptosis and autophagy. CONCLUSION: We could conclude that SXY presented pro-angiogenesis effect and the action mechanisms were involved in VEGF/PI3K/Akt/MAPK signaling pathways, cell junction, apoptosis and autophagy.


Assuntos
Indutores da Angiogênese/química , Indutores da Angiogênese/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transcriptoma/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
19.
BMC Cancer ; 19(1): 936, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601188

RESUMO

BACKGROUND: The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients. METHODS: We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation. RESULTS: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects. CONCLUSIONS: IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-6/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/metabolismo , Terapia de Alvo Molecular/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Interleucina-6/genética , Isoquinolinas/farmacologia , Inibidores de Janus Quinases/farmacologia , Linfoma de Células B/patologia , Linfoma de Células T/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Purinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transfecção , Proteínas Supressoras de Tumor/metabolismo
20.
Int J Oncol ; 55(6): 1372-1384, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638167

RESUMO

Fibroblast growth factor receptor (FGFR)3 and phosphatidylinositol­4,5­bisphosphate 3­kinase, catalytic subunit alpha (PIK3CA) mutations are found in various types of cancer, such as urinary bladder cancer, human papillomavirus­positive tonsillar and base of the tongue squamous cell carcinoma, breast cancer and some childhood sarcomas. Several drugs can target these genes, some of which have been used for the treatment of urinary bladder cancer. Much less is known about childhood cancer. For this reason, the present study investigated the presence of such mutations in neuroblastomas (NBs) and tested NB cell lines for sensitivity to FGFR and phosphoinositide 3­kinase (PI3K) inhibitors. In total, 29 NBs were examined for the presence of the three most common FGFR3 and PIK3CA mutations using a competitive allele­specific TaqMan PCR (CAST­PCR). Furthermore, the SK­N­AS, SK­N­BE(2)­C, SK­N­DZ, SK­N­FI and SK­N­SH NB cell lines (where SK­N­DZ had a deletion of PIK3C2G, none had FGFR mutations according to the Cancer Program's Dependency Map, but some were chemoresistant), were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BKM120) inhibitors by viability, cytotoxicity, apoptosis and proliferation assays. CAST­PCR detected one FGFR3 mutation in 1/29 NBs. Following treatment with FGFR and PI3K inhibitors, a decrease in viability and proliferation was observed in the majority, but not all, the cell lines. Following combination treatment with both drugs, the sensitivity of all cell lines was increased. On the whole, the findings of this study demonstrate that FGFR3 and PIK3CA mutations are uncommon in patients with NB. However, certain NB cell lines are rather sensitive to both FGFR and PI3K inhibitors alone, and even more so when the different drugs are used in combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Neuroblastoma/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Lactente , Recém-Nascido , Masculino , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Mutação , Neuroblastoma/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores
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