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1.
Comput Math Methods Med ; 2022: 7864114, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36164613

RESUMO

A study to examine the efficacy and risk factors associated with pyrrotinib in the second- and third-line treatment of advanced breast cancer with Human epidermal growth factor receptor 2- (HER2-) positive cells was conducted. Progression-free survival (PFS) was assessed as the primary endpoint, and the objective response rate (ORR), overall survival (OS), and safety were secondary endpoints. Across all the patients, the ORR was 48.57%, and the disease control rate (DCR) was 94.29%. In the follow-up period, the median PFS was 15 months, and second-line treatment had significantly longer PFS than third-line treatment (P = 0.027). The OS among all the patients was up to 28 months, but the median OS has not yet been reached. Diarrhea (69.57%) was the most important AE, mainly in grades 1 and 2. According to the COX regression analysis, brain metastasis was a risk factor for PFS, while second-line treatment and capecitabine chemotherapy were relevant to a longer PFS correlation among patients. In the second- and third-line treatment, pyrrotinib is still highly effective and safe. Pyrrotinib is a potential ideal salvage treatment plan for patients who failed in first-line treatments.


Assuntos
Acrilamidas , Aminoquinolinas , Neoplasias da Mama , Inibidores Enzimáticos , Receptor ErbB-2 , Acrilamidas/efeitos adversos , Acrilamidas/uso terapêutico , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Fatores de Risco
2.
J Biol Chem ; 298(10): 102395, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35988642

RESUMO

The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that governs the pH of various intracellular compartments and also functions at the plasma membrane in certain cell types, including cancer cells. Membrane targeting of the V-ATPase is controlled by isoforms of subunit a, and we have previously shown that isoforms a3 and a4 are important for the migration and invasion of several breast cancer cell lines in vitro. Using CRISPR-mediated genome editing to selectively disrupt each of the four a subunit isoforms, we also recently showed that a4 is critical to plasma membrane V-ATPase localization, as well as in vitro migration and invasion of 4T1-12B murine breast cancer cells. We now report that a4 is important for the growth of 4T1-12B tumors in vivo. We found that BALB/c mice bearing a4-/- 4T1-12B allografts had significantly smaller tumors than mice in the control group. In addition, we determined that a4-/- allografts showed dramatically reduced metastases to the lung and reduced luminescence intensity of metastases to bone relative to the control group. Taken together, these results suggest that the a4 isoform of the V-ATPase represents a novel potential therapeutic target to limit breast cancer growth and metastasis.


Assuntos
Neoplasias da Mama , ATPases Vacuolares Próton-Translocadoras , Animais , Camundongos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Isoformas de Proteínas/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Metástase Neoplásica , Camundongos Endogâmicos BALB C , Movimento Celular
3.
Proc Natl Acad Sci U S A ; 119(29): e2110348119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858297

RESUMO

The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H2O2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.


Assuntos
Neoplasias da Mama , Núcleo Celular , Histona Desmetilases , Ferro , Células-Tronco Neoplásicas , Superóxido Dismutase , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Núcleo Celular/enzimologia , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Peróxido de Hidrogênio/metabolismo , Ferro/metabolismo , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Processamento de Proteína Pós-Traducional , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
4.
Biochemistry ; 61(13): 1286-1297, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35737372

RESUMO

Peptidylarginine deiminase 2 (PAD2) is a Ca2+-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. This kind of structural modification in histone molecules may affect gene regulation, leading to effects that may trigger several diseases, including breast cancer, which makes PAD2 an attractive target for anticancer drug development. To design new effective inhibitors to control activation of PAD2, improving our understanding of the molecular mechanisms of PAD2 using up-to-date computational techniques is essential. We have designed five different PAD2-substrate complex systems based on varying protonation states of the active site residues. To search the conformational space broadly, multiple independent molecular dynamics simulations of the complexes have been performed. In total, 50 replica simulations have been performed, each of 1 µs, yielding a total simulation time of 50 µs. Our findings identify that the protonation states of Cys647, Asp473, and His471 are critical for the binding and localization of the N-α-benzoyl-l-arginine ethyl ester substrate within the active site. A novel mechanism for enzyme activation is proposed according to near attack conformers. This represents an important step in understanding the mechanism of citrullination and developing PAD2-inhibiting drugs for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Simulação de Dinâmica Molecular , Proteína-Arginina Desiminase do Tipo 2 , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Citrulinação , Feminino , Humanos , Proteína-Arginina Desiminase do Tipo 2/química , Proteína-Arginina Desiminase do Tipo 2/metabolismo
5.
Zhonghua Zhong Liu Za Zhi ; 44(6): 540-549, 2022 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-35754228

RESUMO

Objective: To observe the platinum drugs resistance effect of N-acetyltransferase 10 (NAT10) overexpression in breast cancer cell line and elucidate the underlining mechanisms. Methods: The experiment was divided into wild-type (MCF-7 wild-type cells without any treatment) group, NAT10 overexpression group (H-NAT10 plasmid transfected into MCF-7 cells) and NAT10 knockdown group (SH-NAT10 plasmid transfected into MCF-7 cells). The invasion was detected by Transwell array, the interaction between NAT10 and PARP1 was detected by co-immunoprecipitation. The impact of NAT10 overexpression or knockdown on the acetylation level of PARP1 and its half-life was also determined. Immunostaining and IP array were used to detect the recruitment of DNA damage repair protein by acetylated PARP1. Flow cytometry was used to detect the cell apoptosis. Results: Transwell invasion assay showed that the number of cell invasion was 483.00±46.90 in the NAT10 overexpression group, 469.00±40.50 in the NAT10 knockdown group, and 445.00±35.50 in the MCF-7 wild-type cells, and the differences were not statistically significant (P>0.05). In the presence of 10 µmol/L oxaliplatin, the number of cell invasion was 502.00±45.60 in the NAT10 overexpression group and 105.00±20.50 in the NAT10 knockdown group, both statistically significant (P<0.05) compared with 219.00±31.50 in wild-type cells. In the presence of 10 µmol/L oxaliplatin, NAT10 overexpression enhanced the binding of PARP1 to NAT10 compared with wild-type cells, whereas the use of the NAT10 inhibitor Remodelin inhibited the mutual binding of the two. Overexpression of NAT10 induced PARP1 acetylation followed by increased PARP1 binding to XRCC1, and knockdown of NAT10 expression reduced PARP1 binding to XRCC1. Overexpression of NAT10 enhanced PARP1 binding to LIG3, while knockdown of NAT10 expression decreased PARP1 binding to LIG3. In 10 µmol/L oxaliplatin-treated cells, the γH2AX expression level was 0.38±0.02 in NAT10 overexpressing cells and 1.36±0.15 in NAT10 knockdown cells, both statistically significant (P<0.05) compared with 1.00±0.00 in wild-type cells. In 10 µmol/L oxaliplatin treated cells, the apoptosis rate was (6.54±0.68)% in the NAT10 overexpression group and (12.98±2.54)% in the NAT10 knockdown group, both of which were statistically significant (P<0.05) compared with (9.67±0.37)% in wild-type cells. Conclusion: NAT10 overexpression enhances the binding of NAT10 to PARP1 and promotes the acetylation of PARP1, which in turn prolongs the half-life of PARP1, thus enhancing PARP1 recruitment of DNA damage repair related proteins to the damage sites, promoting DNA damage repair and ultimately the survival of breast cancer cells.


Assuntos
Neoplasias da Mama , Acetiltransferases N-Terminal , Compostos Organoplatínicos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Acetiltransferases N-Terminal/metabolismo , Compostos Organoplatínicos/farmacologia , Oxaliplatina/farmacologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
6.
Int J Biol Sci ; 18(7): 3034-3047, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541910

RESUMO

5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or -suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.


Assuntos
Neoplasias da Mama , Ornitina Descarboxilase , Purina-Núcleosídeo Fosforilase , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação para Baixo , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Ornitina Descarboxilase/metabolismo , Purina-Núcleosídeo Fosforilase/genética , Purina-Núcleosídeo Fosforilase/metabolismo
7.
Int J Mol Med ; 49(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35234274

RESUMO

Myricetin, a flavonoid found in fruits and vegetables, is known to have antioxidant and anticancer effects. However, the anticancer effects of myricetin on SK­BR­3 human breast cancer cells have not been elucidated. In the present study, the anticancer effects of myricetin were confirmed in human breast cancer SK­BR­3 cells. As the concentration of myricetin increased, the cell viability decreased. DAPI (4',6­diamidino­2­phenylindole) and Annexin V/PI staining also revealed a significant increase in apoptotic bodies and apoptosis. Western blot analysis was performed to confirm the myricetin­induced expression of apoptosis­related proteins. The levels of cleaved PARP and Bax proteins were increased, and that of Bcl­2 was decreased. The levels of proteins in the mitogen­activated protein kinase (MAPK) pathway were examined to confirm the mechanism of myricetin­induced apoptosis, and it was found that the expression levels of phosphorylated c­Jun N­terminal kinase (p­JNK) and phosphorylated mitogen­activated protein kinases (p­p38) were increased, whereas that of phosphorylated extracellular­regulated kinase (p­ERK) was decreased. It was also demonstrated that myricetin induced autophagy by promoting autophagy­related proteins such as microtubule­associated protein 1A/1B­light chain 3 (LC 3) and beclin 1. In addition, 3­methyladenine (3­MA) was used to evaluate the association between cell viability and autophagy in cells treated with myricetin. The results showed that simultaneous treatment with 3­MA and myricetin promoted the apoptosis of breast cancer cells. Furthermore, treatment with a JNK inhibitor reduced cell viability, promoted Bax expression, and reduced the expression of p­JNK, Bcl­2, and LC 3­II/I. These results suggest that myricetin induces apoptosis via the MAPK pathway and regulates JNK­mediated autophagy in SK­BR­3 cells. In conclusion, myricetin shows potential as a natural anticancer agent in SK­BR­3 cells.


Assuntos
Apoptose , Flavonoides , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Flavonoides/farmacologia , Humanos
8.
Breast Cancer Res Treat ; 192(3): 529-539, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35124721

RESUMO

BACKGROUND: The Ubiquitin-conjugating enzyme 2C (UBE2C) is essential for the ubiquitin-proteasome system and is involved in cancer cell migration and apoptosis. This study aimed to determine the prognostic value of UBE2C in invasive breast cancer (BC). METHODS: UBE2C was evaluated using the Molecular Taxonomy of Breast Cancer International Consortium (n = 1980), The Cancer Genome Atlas (n = 854) and Kaplan-Meier Plotter (n = 3951) cohorts. UBE2C protein expression was assessed using immunohistochemistry in the BC cohort (n = 619). The correlation between UBE2C, clinicopathological parameters and patient outcome was assessed. RESULTS: High UBE2C mRNA and protein expressions were correlated with features of poor prognosis, including high tumour grade, large size, the presence of lymphovascular invasion, hormone receptor negativity and HER2 positivity. High UBE2C mRNA expression showed a negative association with E-cadherin, and a positive association with adhesion molecule N-cadherin, matrix metalloproteinases and cyclin-related genes. There was a positive correlation between high UBE2C protein expression and cell cycle-associated biomarkers, p53, Ki67, EGFR and PI3K. High UBE2C protein expression was an independent predictor of poor outcome (p = 0.011, HR = 1.45, 95% CI; 1.10-1.93). CONCLUSION: This study indicates that UBE2C is an independent prognostic biomarker in BC. These results warrant further functional validation for UBE2C as a potential therapeutic target in BC.


Assuntos
Neoplasias da Mama , Enzimas de Conjugação de Ubiquitina , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
9.
Br J Cancer ; 126(12): 1715-1724, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35194193

RESUMO

BACKGROUND: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. METHODS: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. RESULTS: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. CONCLUSION: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.


Assuntos
Neoplasias da Mama , Antraciclinas/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Taxoides/administração & dosagem
10.
Anticancer Res ; 42(3): 1199-1205, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35220209

RESUMO

BACKGROUND/AIM: Aldehyde dehydrogenase (ALDH) 1A1 is a well-known marker for cancer stem cells (CSCs), characterized by self-renewal capacity and multidrug resistance in breast cancer. We developed a near-infrared turn-on fluorescence probe for ALDH1A1, C5S-A, which is suitable for observing and analyzing viable cells. Here, we demonstrated the utility of C5S-A in CSC research using breast cancer cell lines. MATERIALS AND METHODS: To evaluate concordance between C5S-A and conventional stem cell markers, breast cancer cells sorted for ALDEFLUOR-positive cells and for CD44+/CD24- cell populations were stained with C5S-A. Tumorigenicity of C5S-A-positive cells was examined by mammosphere formation assay and subcutaneous transplantation to immunodeficient mice. Additionally, to determine how long fluorescence from a single staining remained observable, we cultured breast cancer cells for 5 days after C5S-A staining. We then evaluated whether C5S-A-positive cells possessed resistance to cytotoxic drugs by chronological imaging. RESULTS: C5S-A staining showed good concordance with conventional breast CSC markers, and good utility for research into CSC characteristics in breast cancer cell lines, including tumorigenesis. Additionally, C5S-A was observable for more than 3 days with a single staining. Using this property, we then confirmed that C5S-A-positive cells possessed resistance to cytotoxic drugs, which is one of the characteristics of CSCs. CONCLUSION: We showed that C5S-A is suitable for CSC research using breast cancer cell lines, and confirmed its utility in observing cells over time.


Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Corantes Fluorescentes , Células-Tronco Neoplásicas/enzimologia , Retinal Desidrogenase/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Separação Celular , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Citometria de Fluxo , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Microscopia de Fluorescência , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Paclitaxel/farmacologia , Fatores de Tempo
11.
Molecules ; 27(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35164236

RESUMO

Mahanimbine (MN) is a carbazole alkaloid present in the leaves of Murraya koenigii, which is an integral part of medicinal and culinary practices in Asia. In the present study, the anticancer, apoptotic and anti-invasive potential of MN has been delineated in vitro. Apoptosis cells determination was carried out utilizing the acridine orange/propidium iodide double fluorescence test. During treatment, caspase-3/7,-8, and-9 enzymes and mitochondrial membrane potentials (Δψm) were evaluated. Anti-invasive properties were tested utilizing a wound-healing scratch test. Protein and gene expression studies were used to measure Bax, Bcl2, MMP-2, and -9 levels. The results show that MN could induce apoptosis in MCF-7 cells at 14 µM concentration IC50. MN-induced mitochondria-mediated apoptosis, with loss in Δψm, regulation of Bcl2/Bax, and accumulation of ROS (p ≤ 0.05). Caspase-3/7 and -9 enzyme activity were detected in MCF-7 cells after 24 and 48 h of treatment with MN. The anti-invasive property of MN was shown by inhibition of wound healing at the dose-dependent level and significantly suppressed mRNA and protein expression on MMP-2 and -9 in MCF-7 cells treated with a sub-cytotoxic dose of MN. The overall results indicate MN is a potential therapeutic compound against breast cancer as an apoptosis inducer and anti-invasive agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Murraya/química , Neovascularização Patológica/prevenção & controle , Folhas de Planta/química , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Invasividade Neoplásica/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo
12.
J Clin Oncol ; 40(5): 449-458, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34995105

RESUMO

PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estadiamento de Neoplasias , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Fatores de Risco , Fatores de Tempo
13.
Eur J Cancer ; 163: 35-43, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35032815

RESUMO

BACKGROUND: Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications. METHODS: We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour. RESULTS: 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21-0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19-0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours. CONCLUSIONS: HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Feminino , Humanos , Imuno-Histoquímica , Prognóstico , Receptor ErbB-2/biossíntese , Receptor ErbB-2/metabolismo
14.
Mol Biol Rep ; 49(1): 363-372, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34714485

RESUMO

BACKGROUND: The present research was performed to assess N-heteroaryl acetic acid salts' anticancer activity against the breast cancer cell in order to introduce new inhibitory agents for histone deacetylase. METHODS AND RESULTS: A molecular docking simulation was performed to design the rational novel compounds. Afterward, the best compounds were selected for synthesis. The cytotoxic effects and mechanism of action have been studied via (Methyl Thiazol-Tetrazolium) MTT assay. Flow cytometry and gene expression analyses were performed to introduce an effective acetic acid derivative as an anticancer agent. Molecular docking simulations demonstrated that all compounds have the best interaction with histone deacetylase. The fold changes of Bcl-2, Bak, Bim, Caspase-3, and Caspase-8 gene expressions were investigated and compared with reference gene using real-time PCR. The cytotoxic studies showed the best anticancer activity of 4-benzyl-1-(carboxymethyl) pyridinium bromide (compound 2) with a low IC50 value (32 µM, p < 0.05). Also, the best anti HDAC activity was obtained for compound 2 with IC50 value of 1.1 µM. Furthermore, this compound showed a high percentage of apoptosis among all tested compounds after 72 h incubation which was associated with the significant increase in mRNA level of Bim, Bax, Bak, Caspase-3, and Caspase-8 and the considerable decrease in Bcl2 gene expression. CONCLUSION: These results suggest that compound 2 with the benzyl ring could be an effective anticancer compound for further investigation in breast cancer treatment.


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/enzimologia , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Compostos de Piridínio/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Humanos , Concentração Inibidora 50 , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Relação Estrutura-Atividade
15.
J Clin Oncol ; 40(5): 438-448, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34890214

RESUMO

PURPOSE: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1). METHODS: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing. RESULTS: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80). CONCLUSION: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Fatores de Tempo , Trastuzumab/efeitos adversos
16.
Am J Clin Dermatol ; 23(2): 247-255, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34699032

RESUMO

BACKGROUND: Cyclin-dependent kinase (CDK)-4/6 inhibitors have been associated with dermatologic reactions, especially alopecia, in pivotal trials. OBJECTIVE: We aimed to comprehensively describe skin toxicities with CDK4/6 inhibitors reported in the real world through the US FDA Adverse Event Reporting System (FAERS). METHODS: Cutaneous adverse events (AEs) were characterized in terms of spectrum and clinical features, including seriousness (with fatality proportion), latency, and discontinuation. Disproportionality analyses were performed through the reporting odds ratio (ROR) and 95% confidence interval (CI) by comparing CDK4/6 inhibitors with other anticancer drugs used in breast cancer. RESULTS: As of December 2020, a total of 7986 cutaneous events were reported with CDK4/6 inhibitors (15% of total AEs with CDK4/6 inhibitors), mainly by consumers (39.6%), with 43.5% classified as serious and 25% requiring discontinuation. In 49% of the cases, five or more noncutaneous events were co-reported. The most frequently reported cutaneous events were alopecia (N = 3528), rash (N = 1493), and pruritus (N = 1211): rashes were recorded in the first month (median onset 28 days), whereas alopecia and nail alterations were recorded after a median of 67 and 112 days, respectively. Several cutaneous AEs were associated with increased reporting, including vitiligo (N = 6; ROR 8.88; 95% CI 2.95-22.46) and bullous dermatitis with ribociclib (N = 7; ROR 2.90; 95% CI 1.13-6.27); erythema multiforme with abemaciclib (N = 9; ROR 5.80; 95% CI 2.57-11.48); onychoclasis (N = 142, ROR 2.27; 95% CI 1.83-2.79) and trichorrhexis (N = 22; ROR 3.27; 95% CI 1.78-5.93) with palbociclib. CONCLUSIONS: Although causality cannot be demonstrated, a diverse reporting pattern of cutaneous AEs emerged from FAERS, including dermal/epidermal conditions, hair/nail disorders, and serious bullous conditions, with variable onsets and a remarkable proportion of discontinuations. The potential differential reporting among CDK4/6 inhibitors deserves further investigation.


Assuntos
Neoplasias da Mama , Inibidores de Proteínas Quinases , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Razão de Chances , Farmacovigilância , Estados Unidos/epidemiologia , United States Food and Drug Administration
17.
J Cell Biochem ; 123(2): 359-374, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34751461

RESUMO

Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule-affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure-based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence-based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change (∆H) and entropy change (∆S) delineated electrostatic interactions as a dominant force in the MARK4-myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 µM. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF-7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.


Assuntos
Neoplasias da Mama , Flavonoides , Neoplasias Pulmonares , Proteínas de Neoplasias , Células A549 , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Feminino , Flavonoides/química , Flavonoides/farmacologia , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , /química , /metabolismo
18.
Arch Toxicol ; 96(2): 511-524, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34783865

RESUMO

Arylamine N-acetyltransferase 1 (NAT1) plays a pivotal role in the metabolism of carcinogens and is a drug target for cancer prevention and/or treatment. A protein-ligand virtual screening of 2 million chemicals was ranked for predicted binding affinity towards the inhibition of human NAT1. Sixty of the five hundred top-ranked compounds were tested experimentally for inhibition of recombinant human NAT1 and N-acetyltransferase 2 (NAT2). The most promising compound 9,10-dihydro-9,10-dioxo-1,2-anthracenediyl diethyl ester (compound 10) was found to be a potent and selective NAT1 inhibitor with an in vitro IC50 of 0.75 µM. Two structural analogs of this compound were selective but less potent for inhibition of NAT1 whereas a third structural analog 1,2-dihydroxyanthraquinone (a compound 10 hydrolysis product also known as Alizarin) showed comparable potency and efficacy for human NAT1 inhibition. Compound 10 inhibited N-acetylation of the arylamine carcinogen 4-aminobiphenyl (ABP) both in vitro and in DNA repair-deficient Chinese hamster ovary (CHO) cells in situ stably expressing human NAT1 and CYP1A1. Compound 10 and Alizarin effectively inhibited NAT1 in cryopreserved human hepatocytes whereas inhibition of NAT2 was not observed. Compound 10 caused concentration-dependent reductions in DNA adduct formation and DNA double-strand breaks following metabolism of aromatic amine carcinogens beta-naphthylamine and/or ABP in CHO cells. Compound 10 inhibited proliferation and invasion in human breast cancer cells and showed selectivity towards tumorigenic versus non-tumorigenic cells. In conclusion, our study identifies potent, selective, and efficacious inhibitors of human NAT1. Alizarin's ability to inhibit NAT1 could reduce breast cancer metastasis particularly to bone.


Assuntos
Arilamina N-Acetiltransferase/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Animais , Antraquinonas/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Simulação por Computador , Cricetinae , Cricetulus , Adutos de DNA/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Hepatócitos/enzimologia , Humanos , Concentração Inibidora 50
19.
Oncol Rep ; 47(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34751415

RESUMO

The platelet isoform of phosphofructokinase (PFKP) is one of the key enzymes in the glycolytic pathway. PFKP is highly expressed in several cancers, and it has been reported to be involved in the progression of cancer cells. However, its oncological role in breast cancer (BC) remains unclear. The present study aimed to evaluate the function of PFKP in BC cells and its expression level in patients with BC. Firstly, the mRNA and protein expression of PFKP was evaluated in BC and non­cancerous mammary cell lines. Polymerase chain reaction (PCR) array analysis was conducted to evaluate the correlation between PFKP and 84 cancer­related genes. Then, PFKP knockdown was conducted using small interfering RNA, and cell proliferation, invasiveness and migration were analyzed. Furthermore, the association between PFKP mRNA expression and clinicopathological factors was investigated in 167 patients with BC. PFKP was highly expressed in estrogen receptor­negative and human epidermal growth factor receptor 2­negative BC cell lines. PCR array analysis demonstrated that the expression level of PFKP was significantly correlated with that of transforming growth factor­ß1 and MYC proto­oncogene. PFKP knockdown significantly decreased the proliferation and invasiveness of MCF7, SK­BR­3, and MDA­MB­231 cells. Furthermore, cell migration was inhibited in SK­BR­3 and MDA­MB­231 cells. In the clinical specimens, patients with T2/T3/T4, lymph node metastasis, or stage II/III/IV exhibited higher expression of PFKP mRNA than patients with less severe disease. In conclusion, the present findings indicated that PFKP is involved in promoting tumor­progressive oncological roles in BC cells across different subtypes and is considered a possible novel therapeutic target for BC.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Fosfofrutoquinase-1 Tipo C/genética , Fosfofrutoquinases/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade
20.
Cancer Res ; 82(4): 615-631, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34903604

RESUMO

Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a similar extent as truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group [OR 2.23; 95% confidence interval (CI), 1.62-3.07; P < 0.0001] and intermediate variants (OR 1.63; 95% CI, 1.21-2.20; P = 0.0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1.13; 95% CI, 0.87-1.46; P = 0.378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which cosegregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer. SIGNIFICANCE: Quantitative assessment of the functional consequences of CHEK2 variants of uncertain significance identifies damaging variants associated with increased cancer risk, which may aid in the clinical management of patients and carriers.


Assuntos
Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Células Cultivadas , Quinase do Ponto de Checagem 2/metabolismo , Feminino , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Neoplasias/enzimologia , Linhagem , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Fatores de Risco
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