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1.
Oncol Res ; 32(7): 1197-1207, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948022

RESUMO

Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.


Assuntos
Autofagia , Neoplasias da Mama , Piperazinas , Piridinas , Piridonas , Pirimidinonas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Feminino , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camundongos Nus , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Células MCF-7
2.
Signal Transduct Target Ther ; 9(1): 181, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992067

RESUMO

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.


Assuntos
Bortezomib , Proteínas de Ciclo Celular , Mitose , Complexo de Endopeptidases do Proteassoma , Proteínas Tirosina Quinases , Piroptose , Piroptose/efeitos dos fármacos , Humanos , Camundongos , Animais , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Mitose/efeitos dos fármacos , Mitose/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteassoma/farmacologia , Pirimidinas/farmacologia , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Gasderminas , Pirimidinonas
3.
Taiwan J Obstet Gynecol ; 63(4): 471-478, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39004472

RESUMO

Platinum-resistant ovarian cancer (PROC) refers to disease progression within 6 months after the completion of platinum-based chemotherapy. Historically, treatment options for PROC were limited with a poor prognosis and non-platinum single agent plus bevacizumab has been the mainstay of treatment. Fortunately, there have been notable advancements in recent years, leading to an advance in treatment paradigms for this challenging disease. Various combinations of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy are being explored for an improved treatment outcome. Antibody-drug conjugates targeting folate receptor alpha, which deliver a cytotoxic payload directly to cancer cells, have emerged as a promising therapeutic approach for PROC. WEE1 inhibitors, such as adavosertib, function by inhibiting the WEE1 kinase activity, leading to premature entry of a cell into mitosis phase and thus increased DNA damage. It has been observed that cancer cells with TP53 mutations may be more sensitive to WEE1 inhibitors. Biomarker testing such as analysis of the expression level of folate receptor alpha or mutation in TP53 may be applicable for identifying patients who are more likely to respond to the specific therapy, enabling a more personalized treatment approach. This overview summarizes key clinical findings on the efficacy and safety of theses novel biomarker-driven therapeutic approaches.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Receptor 1 de Folato/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Imunoconjugados/uso terapêutico , Pirazóis/uso terapêutico , Proteína Supressora de Tumor p53 , Pirimidinonas/uso terapêutico
4.
Low Urin Tract Symptoms ; 16(4): e12529, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38956950

RESUMO

OBJECTIVES: This study aimed to evaluate the efficacy and safety of Vibegron for the treatment of residual overactive bladder (OAB) symptoms after laser vaporization of the prostate (photo-selective vaporization of the prostate, contact laser vaporization of the prostate, and thulium laser vaporization). METHODS: This randomized, open-label, parallel-group, single-center superiority trial with a 12-week observation (jRCTs071190040) enrolled male patients with OAB aged 40 years or older who had undergone laser vaporization of the prostate for not less than 12 weeks and not more than 1 year earlier. Patients were allocated to receive Vibegron 50 mg once daily or follow-up without treatment for 12 weeks. RESULTS: Forty-seven patients were enrolled between January 2020 and March 2023. The median age (interquartile range) was 75.5 (72.5-78.5) years for the Vibegron group and 76.5 (71.0-81.0) years for the control group. The intergroup difference in the mean change (95% confidence interval) in the 24-hour urinary frequency at 12 weeks after randomization was -3.66 (-4.99, -2.33), with a significant decrease for the Vibegron group. The Overactive Bladder Symptom Score, International Prostate Symptom Score, IPSS storage score, and Overactive Bladder Questionnaire score significantly improved for the Vibegron group. Voided volume per micturition also increased for the Vibegron group. CONCLUSIONS: The administration of 50 mg of Vibegron once daily for 12 weeks showed significant improvement compared with follow-up without treatment in bladder storage (OAB) symptoms after laser vaporization of the prostate for symptomatic benign prostatic hyperplasia.


Assuntos
Terapia a Laser , Bexiga Urinária Hiperativa , Humanos , Masculino , Idoso , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Estudos Prospectivos , Terapia a Laser/métodos , Terapia a Laser/efeitos adversos , Hiperplasia Prostática/cirurgia , Hiperplasia Prostática/complicações , Resultado do Tratamento , Idoso de 80 Anos ou mais , Pirimidinonas , Pirrolidinas
5.
J Urol ; 212(2): 267-279, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38979756

RESUMO

PURPOSE: We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). MATERIALS AND METHODS: A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. RESULTS: In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. CONCLUSIONS: Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).


Assuntos
Incontinência Urinária por Estresse , Humanos , Método Duplo-Cego , Feminino , Incontinência Urinária por Estresse/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Qualidade de Vida , Idoso , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Pirimidinonas
6.
Genome Biol ; 25(1): 143, 2024 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822412

RESUMO

BACKGROUND: Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence. RESULTS: Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers. CONCLUSIONS: Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Histona-Lisina N-Metiltransferase/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Proteína de Leucina Linfoide-Mieloide/genética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/genética
7.
Molecules ; 29(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38930946

RESUMO

Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.


Assuntos
Injúria Renal Aguda , Cisplatino , Modelos Animais de Doenças , Inflamação , Estresse Oxidativo , Piridonas , Pirimidinonas , Animais , Cisplatino/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Piridonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Pirimidinonas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Morte Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Túbulos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
8.
Nat Commun ; 15(1): 4893, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849340

RESUMO

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.


Assuntos
Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases , Camundongos Transgênicos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Humanos , Feminino , Animais , Masculino , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Proteína FUS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/genética , Córtex Pré-Frontal/metabolismo , Transcriptoma , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Pessoa de Meia-Idade , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Caracteres Sexuais , Idoso , Fatores Sexuais , Pirimidinonas
9.
Cell Commun Signal ; 22(1): 324, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867255

RESUMO

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Omeprazol , Proteínas Proto-Oncogênicas c-met , Proteínas Proto-Oncogênicas p21(ras) , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Animais , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Camundongos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Feminino , Triazinas/farmacologia , Triazinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Piperazinas , Piperidinas , Piridazinas , Piridonas
10.
Cancer Res Commun ; 4(7): 1793-1801, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38920407

RESUMO

We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.


Assuntos
Proteínas de Ciclo Celular , Histona-Lisina N-Metiltransferase , Proteínas Tirosina Quinases , Pirazóis , Humanos , Pessoa de Meia-Idade , Histona-Lisina N-Metiltransferase/genética , Masculino , Idoso , Feminino , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , Mutação
11.
Bioorg Med Chem ; 109: 117799, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38897138

RESUMO

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.


Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Alcaloides Indólicos , Quinazolinas , Humanos , Quinazolinas/química , Quinazolinas/farmacologia , Quinazolinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Linhagem Celular Tumoral , Pirimidinonas/química , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Relação Dose-Resposta a Droga , Quinazolinonas
12.
Eur J Med Chem ; 275: 116568, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38889606

RESUMO

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.


Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pirimidinonas , Humanos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Pirimidinonas/farmacologia , Pirimidinonas/química , Pirimidinonas/síntese química , Estrutura Molecular , Camundongos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Proteases Específicas de Ubiquitina/metabolismo
13.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731855

RESUMO

The thermo- and pain-sensitive Transient Receptor Potential Melastatin 3 and 8 (TRPM3 and TRPM8) ion channels are functionally associated in the lipid rafts of the plasma membrane. We have already described that cholesterol and sphingomyelin depletion, or inhibition of sphingolipid biosynthesis decreased the TRPM8 but not the TRPM3 channel opening on cultured sensory neurons. We aimed to test the effects of lipid raft disruptors on channel activation on TRPM3- and TRPM8-expressing HEK293T cells in vitro, as well as their potential analgesic actions in TRPM3 and TRPM8 channel activation involving acute pain models in mice. CHO cell viability was examined after lipid raft disruptor treatments and their effects on channel activation on channel expressing HEK293T cells by measurement of cytoplasmic Ca2+ concentration were monitored. The effects of treatments were investigated in Pregnenolone-Sulphate-CIM-0216-evoked and icilin-induced acute nocifensive pain models in mice. Cholesterol depletion decreased CHO cell viability. Sphingomyelinase and methyl-beta-cyclodextrin reduced the duration of icilin-evoked nocifensive behavior, while lipid raft disruptors did not inhibit the activity of recombinant TRPM3 and TRPM8. We conclude that depletion of sphingomyelin or cholesterol from rafts can modulate the function of native TRPM8 receptors. Furthermore, sphingolipid cleavage provided superiority over cholesterol depletion, and this method can open novel possibilities in the management of different pain conditions.


Assuntos
Esfingomielina Fosfodiesterase , Canais de Cátion TRPM , beta-Ciclodextrinas , Animais , Humanos , Camundongos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , beta-Ciclodextrinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células CHO , Colesterol/metabolismo , Cricetulus , Modelos Animais de Doenças , Células HEK293 , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/metabolismo , Pregnenolona/farmacologia , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielina Fosfodiesterase/farmacologia , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Pirimidinonas/farmacologia
14.
Microbes Infect ; 26(5-6): 105353, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38763478

RESUMO

The obligate intracellular parasite Leishmania binds several receptors to trigger uptake by phagocytic cells, ultimately resulting in visceral or cutaneous leishmaniasis. A series of signaling pathways in host cells, which are critical for establishment and persistence of infection, are activated during Leishmania internalization. Thus, preventing Leishmania uptake by phagocytes could be a novel therapeutic strategy for leishmaniasis. However, the host cellular machinery mediating promastigote and amastigote uptake is not well understood. Here, using small molecule inhibitors of Mitogen-activated protein/Extracellular signal regulated kinases (MAPK/ERK), we demonstrate that ERK1/2 mediates Leishmania amazonensis uptake and (to a lesser extent) phagocytosis of beads by macrophages. We find that inhibiting host MEK1/2 or ERK1/2 leads to inefficient amastigote uptake. Moreover, using inhibitors and primary macrophages lacking spleen tyrosine kinase (SYK) or Abl family kinases, we show that SYK and Abl family kinases mediate Raf, MEK, and ERK1/2 activity and are necessary for uptake. Finally, we demonstrate that trametinib, a MEK1/2 inhibitor used to treat cancer, reduces disease severity and parasite burden in Leishmania-infected mice, even if it is started after lesions develop. Our results show that maximal Leishmania infection requires MAPK/ERK and highlight potential for MAPK/ERK-mediated signaling pathways to be novel therapeutic targets for leishmaniasis.


Assuntos
Macrófagos , Animais , Macrófagos/parasitologia , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos , Fagocitose , Piridonas/farmacologia , Leishmaniose/parasitologia , Leishmaniose/imunologia , Quinase Syk/metabolismo , Quinase Syk/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Leishmania mexicana/enzimologia , Leishmania , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Pirimidinonas
15.
J Agric Food Chem ; 72(23): 12925-12934, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38809684

RESUMO

Potato virus Y (PVY) relies on aphids and tubers to spread in the field and causes serious economic losses in the potato industry. Here, we found that pyrido[1,2-α] pyrimidinone mesoionic compounds with insecticidal activity against aphids possessed a good inhibitory effect on PVY. Among them, compound 35 had the best inhibitory activity against PVY (EC50 = 104 µg/mL), even superior to that of ningnanmycin (125 µg/mL). The fluorescence and qPCR results confirmed that compound 35 could inhibit the proliferation of PVY in Nicotiana benthamiana. Preliminary experiments on the mechanism of action indicated that compound 35 had good binding affinity with the coat protein (CP), which plays an essential role in aphid-PVY interactions. Molecular docking revealed that compound 35 could bind to the pocket of CP formed by Ser52, Glu204, and Arg208. Compound 35 had substantially lower binding affinity (Kd) values with CPS52A (219 µM), CPE204A (231 µM), and CPR208A (189 µM) than those with CPWT (5.80 µM). A luciferase assay confirmed that mutating Ser52, Glu204, and Arg208 significantly affected the expression level of CP and further reduced virus proliferation. Therefore, the broad-spectrum activity of compound 35 provides a unique strategy for the prevention and treatment of PVY.


Assuntos
Antivirais , Afídeos , Simulação de Acoplamento Molecular , Nicotiana , Doenças das Plantas , Potyvirus , Afídeos/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Animais , Doenças das Plantas/virologia , Doenças das Plantas/prevenção & controle , Potyvirus/efeitos dos fármacos , Potyvirus/genética , Potyvirus/química , Nicotiana/virologia , Pirimidinonas/farmacologia , Pirimidinonas/química , Inseticidas/química , Inseticidas/farmacologia , Solanum tuberosum/química , Solanum tuberosum/virologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/química , Relação Estrutura-Atividade
16.
J Med Chem ; 67(11): 9150-9164, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38753759

RESUMO

The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of ß-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aß peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.


Assuntos
Fármacos Neuroprotetores , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/agonistas , Receptores sigma/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ratos , Humanos , Masculino , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Transtornos da Memória/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Ratos Wistar , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo
18.
Cell Biol Int ; 48(8): 1185-1197, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38773713

RESUMO

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.


Assuntos
Neoplasias da Mama , Movimento Celular , Transição Epitelial-Mesenquimal , Ácido Láctico , Transportadores de Ácidos Monocarboxílicos , Neoplasias Bucais , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Feminino , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/tratamento farmacológico , Ácido Láctico/metabolismo , Movimento Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Simportadores/metabolismo , Simportadores/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Pirimidinonas , Tiofenos
19.
J Urol ; 212(2): 256-266, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38708869

RESUMO

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Hiperplasia Prostática , Bexiga Urinária Hiperativa , Humanos , Masculino , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Método Duplo-Cego , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirrolidinas/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/administração & dosagem , Inibidores de 5-alfa Redutase/uso terapêutico , Inibidores de 5-alfa Redutase/efeitos adversos , Antagonistas Adrenérgicos alfa/uso terapêutico , Quimioterapia Combinada
20.
Thorac Cancer ; 15(18): 1454-1456, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38766698

RESUMO

Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Imidazóis , Neoplasias Pulmonares , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Idoso , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Imidazóis/uso terapêutico , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oximas/uso terapêutico , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem
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