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1.
Chem Biodivers ; 21(3): e202301950, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38258537

RESUMO

The increased expression of VEGFR-2 in a variety of cancer cells promotes a cascade of cellular responses that improve cell survival, growth, and proliferation. Heterocycles are common structural elements in medicinal chemistry and commercially available medications that target several biological pathways and induce cell death in cancer cells. Herein, the evaluation of indazolyl-acyl hydrazones as antioxidant and anticancer agents is reported. Compounds 4e and 4j showed inhibitory activity in free radical scavenging assays (DPPH and FRPA). The titled compounds were employed in cell viability studies using MCF-7 cells, and it was observed that compounds 4f and 4j exhibited IC50 values 15.83 µM and 5.72 µM, respectively. In silico docking revealed the favorable binding energies of -7.30 kcal/mol and -8.04 kcal/mol for these compounds towards Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), respectively. In conclusion, compounds with antioxidant activity and that target VEGFR-2 in breast cancer cells are reported.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Estrutura Molecular , Relação Estrutura-Atividade , Antioxidantes/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Neoplasias da Mama/tratamento farmacológico , Hidrazonas/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proliferação de Células , Desenho de Fármacos , Simulação de Acoplamento Molecular , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais
2.
Cell Commun Signal ; 21(1): 59, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36915147

RESUMO

BACKGROUND: Breast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population. METHODS: Co-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8. RESULTS: We identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden. CONCLUSION: Taken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes. Video Abstract.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Interleucina-8 , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Tamoxifeno/farmacologia , Células-Tronco Neoplásicas/patologia
3.
Int J Mol Sci ; 24(11)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37298108

RESUMO

Although DNA damage repair plays a critical role in cancer chemotherapy, the function of lncRNAs in this process remains largely unclear. In this study, in silico screening identified H19 as an lncRNA that potentially plays a role in DNA damage response and sensitivity to PARP inhibitors. Increased expression of H19 is correlated with disease progression and with a poor prognosis in breast cancer. In breast cancer cells, forced expression of H19 promotes DNA damage repair and resistance to PARP inhibition, whereas H19 depletion diminishes DNA damage repair and increases sensitivity to PARP inhibitors. H19 exerted its functional roles via direct interaction with ILF2 in the cell nucleus. H19 and ILF2 increased BRCA1 stability via the ubiquitin-proteasome proteolytic pathway via the H19- and ILF2-regulated BRCA1 ubiquitin ligases HUWE1 and UBE2T. In summary, this study has identified a novel mechanism to promote BRCA1-deficiency in breast cancer cells. Therefore, targeting the H19/ILF2/BRCA1 axis might modulate therapeutic approaches in breast cancer.


Assuntos
Neoplasias da Mama , RNA Longo não Codificante , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/uso terapêutico , Ubiquitina/metabolismo , Dano ao DNA , Proteína do Fator Nuclear 45/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
4.
Molecules ; 28(13)2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37446915

RESUMO

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Histona Desacetilases/metabolismo , Triazóis/química , Linhagem Celular Tumoral , Isoxazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores de Histona Desacetilases/química , Proliferação de Células , Antineoplásicos/química , Relação Estrutura-Atividade
5.
Molecules ; 28(8)2023 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-37110684

RESUMO

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.


Assuntos
Apoptose , Neoplasias da Mama , Humanos , Feminino , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Cumarínicos/farmacologia , Pirimidinas , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral
6.
Int J Mol Sci ; 23(5)2022 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-35269786

RESUMO

Patients with epithelial ovarian cancer (EOC) are often diagnosed at an advanced stage due to nonspecific symptoms and ineffective screening approaches. Although chemotherapy has been available and widely used for the treatment of advanced EOC, the overall prognosis remains dismal. As part of the intrinsic defense mechanisms against cancer development and progression, immune cells are recruited into the tumor microenvironment (TME), and this process is directed by the interactions between different chemokines and their receptors. In this review, the functional significance of CXC chemokine ligands/chemokine receptors (CXCL/CXCR) and their roles in modulating EOC progression are summarized. The status and prospects of CXCR/CXCL-based theranostic strategies in EOC management are also discussed.


Assuntos
Neoplasias Ovarianas , Receptores CXCR , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/terapia , Quimiocinas CXC , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Nanomedicina Teranóstica , Microambiente Tumoral
7.
Molecules ; 27(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163965

RESUMO

Novel PARP inhibitors with selective mode-of-action have been approved for clinical use. Herein, oxadiazole based ligands that are predicted to target PARP-1 have been synthesized and screened for the loss of cell viability in mammary carcinoma cells, wherein seven compounds were observed to possess significant IC50 values in the range of 1.4 to 25 µM. Furthermore, compound 5u, inhibited the viability of MCF-7 cells with an IC50 value of 1.4µM, when compared to Olaparib (IC50 = 3.2 µM). Compound 5s also decreased cell viability in MCF-7 and MDA-MB-231 cells with IC50 values of 15.3 and 19.2 µM, respectively. Treatment of MCF-7 cells with compounds 5u and 5s produced PARP cleavage, H2AX phosphorylation and CASPASE-3 activation comparable to that observed with Olaparib. Compounds 5u and 5s also decreased foci-formation and 3D Matrigel growth of MCF-7 cells equivalent to or greater than that observed with Olaparib. Finally, in silico analysis demonstrated binding of compound 5s towardsthe catalytic site of PARP-1, indicating that these novel oxadiazoles synthesized herein may serve as exemplars for the development of new therapeutics in cancer.


Assuntos
Desenho de Fármacos/métodos , Oxidiazóis/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Oxidiazóis/química , Poli(ADP-Ribose) Polimerase-1/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos
8.
Molecules ; 27(9)2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35566199

RESUMO

A number of uracil amides cleave poly (ADP-ribose) polymerase and therefore novel thiouracil amide compounds were synthesized and screened for the loss of cell viability in a human-estrogen-receptor-positive breast cancer cell line. The synthesized compounds exhibited moderate to significant efficacy against human breast cancer cells, where the compound 5e IC50 value was found to be 18 µM. Thouracil amide compounds 5a and 5e inhibited the catalytical activity of PARP1, enhanced cleavage of PARP1, enhanced phosphorylation of H2AX, and increased CASPASE 3/7 activity. Finally, in silico analysis demonstrated that compound 5e interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology.


Assuntos
Neoplasias da Mama , Poli(ADP-Ribose) Polimerases , Difosfato de Adenosina , Amidas , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Piperazina , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose , Tiouracila
9.
Proc Natl Acad Sci U S A ; 115(44): E10505-E10514, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30309962

RESUMO

Human BCL-2-associated death promoter (hBAD) is an apoptosis-regulatory protein mediating survival signals to carcinoma cells upon phosphorylation of Ser99, among other residues. Herein, we screened multiple small-molecule databases queried in a Laplacian-modified naive Bayesian-based cheminformatics platform and identified a Petasis reaction product as a site-specific inhibitor for hBAD phosphorylation. Based on apoptotic efficacy against mammary carcinoma cells, N-cyclopentyl-3-((4-(2,3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) benzamide (NPB) was identified as a potential lead compound. In vitro biochemical analyses demonstrated that NPB inhibited the phosphorylation of hBAD specifically on Ser99. NPB was observed to exert this effect independently of AKT and other kinase activities despite the demonstration of AKT-mediated BAD-Ser99 phosphorylation. Using a structure-based bioinformatics platform, we observed that NPB exhibited predicted interactions with hBAD in silico and verified the same by direct binding kinetics. NPB reduced phosphorylation of BAD-Ser99 and enhanced caspase 3/7 activity with associated loss of cell viability in various human cancer cell lines derived from mammary, endometrial, ovarian, hepatocellular, colon, prostatic, and pancreatic carcinoma. Furthermore, by use of a xenograft model, it was observed that NPB, as a single agent, markedly diminished BAD phosphorylation in tumor tissue and significantly inhibited tumor growth. Similar doses of NPB utilized in acute toxicity studies in mice did not exhibit significant effects. Hence, we report a site-specific inhibitor of BAD phosphorylation with efficacy in tumor models.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Piperazinas/farmacologia , Serina/química , Proteína de Morte Celular Associada a bcl/antagonistas & inibidores , Antineoplásicos/química , Apoptose , Benzamidas/química , Proliferação de Células , Bases de Dados Factuais , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos , Células MCF-7 , Fosforilação , Piperazinas/química , Interferência de RNA , Bibliotecas de Moléculas Pequenas , Ressonância de Plasmônio de Superfície
10.
Int J Mol Sci ; 22(20)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34681659

RESUMO

The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC50 values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development.


Assuntos
Nitrobenzenos/química , Proteína de Morte Celular Associada a bcl/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cristalografia por Raios X , Teoria da Densidade Funcional , Feminino , Humanos , Células MCF-7 , Conformação Molecular , Nitrobenzenos/farmacologia , Fosforilação/efeitos dos fármacos , Serina/metabolismo
11.
Molecules ; 26(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546391

RESUMO

Herein, the activity of adamantanyl-tethered-biphenyl amines (ATBAs) as oestrogen receptor alpha (ERα) modulating ligands is reported. Using an ERα competitor assay it was demonstrated that ATBA compound 3-(adamantan-1-yl)-4-methoxy-N-(4-(trifluoromethyl) phenyl) aniline (AMTA) exhibited an inhibitory concentration 50% (IC50) value of 62.84 nM and demonstrated better binding affinity compared to tamoxifen (IC50 = 79.48 nM). Treatment of ERα positive (ER+) mammary carcinoma (MC) cells (Michigan Cancer Foundation-7 (MCF7)) with AMTA significantly decreased cell viability at an IC50 value of 6.4 µM. AMTA treatment of MC cell-generated three-dimensional (3D) spheroids resulted in significantly decreased cell viability. AMTA demonstrated a superior inhibitory effect compared to tamoxifen-treated MC cell spheroids. Subsequently, by use of an oestrogen response element (ERE) luciferase reporter construct, it was demonstrated that AMTA treatment significantly deceased ERE transcriptional activity in MC cells. Concordantly, AMTA treatment of MC cells also significantly decreased protein levels of oestrogen-regulated CCND1 in a dose-dependent manner. In silico molecular docking analysis suggested that AMTA compounds interact with the ligand-binding domain of ERα compared to the co-crystal ligand, 5-(4-hydroxyphenoxy)-6-(3-hydroxyphenyl)-7- methylnaphthalen-2-ol. Therefore, an analogue of AMTA may provide a structural basis to develop a newer class of ERα partial agonists.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama , Receptor alfa de Estrogênio , Proteínas de Neoplasias , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo
12.
Pharmacol Res ; 156: 104686, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32068118

RESUMO

Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Currently, the efficacies of CDK4/6 inhibitors in other breast cancer subtypes and cancers are being actively explored. All three CDK4/6 inhibitors have demonstrated very similar clinical efficacies. However, being the least similar structurally, abemaciclib is the only CDK4/6 inhibitor with single agent activity in refractory metastatic ER + breast cancer, the ability to cross the blood brain barrier efficiently, and a distinct toxicity profile of lower myelosuppression such that it can be dosed continuously. Here, we further discuss the distinguishing features of abemaciclib as compared to the other two CDK4/6 inhibitors, palbociclib and ribociclib. Besides being the most potent inhibitor of CDK4/6, abemaciclib exhibits a wider selectivity towards other CDKs and kinases, and functions through additional mechanisms of action besides inducing G1 cell cycle arrest, in a dose dependent manner. Hence, abemaciclib has the potential to act independently of the CDK4/6-cyclin D-RB pathway, resulting in crucial implications on the possibly expanded clinical indications and predictive biomarkers of abemaciclib, in contrast to the other CDK4/6 inhibitors. The current status of preclinical evidence and clinical studies of abemaciclib as a single agent and in combination treatment in breast and other cancers, together with its potential predictive biomarkers, is also summarised in this review.


Assuntos
Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/efeitos adversos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de Sinais , Resultado do Tratamento
13.
J Biol Chem ; 293(11): 3949-3964, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29367342

RESUMO

Gastric cancer remains a malignancy with poor survival outcome. We herein report that GSE1, a proline-rich protein, possesses a role in the progression of human gastric cancer. The expression of GSE1 was observed to be much higher in human gastric cancer tissues compared with normal gastric tissues, and GSE1 expression correlated positively with lymph node metastasis, histological grade, depth of invasion, and clinical stage in gastric cancer patients. Moreover, GSE1 expression was also associated with decreased post-operative relapse-free survival and overall survival in the cohort. The forced expression of GSE1 in gastric cancer cell lines resulted in increased cell proliferation, increased colony formation, enhanced cell migration, and invasion. Furthermore, forced expression of GSE1 also increased tumor size and enhanced lung metastasis in xenograft models. The depletion of endogenous GSE1 with shRNAs decreased the oncogenicity and invasiveness of gastric cancer cells both in vitro and in vivo In addition, GSE1 was determined to be a direct target of miR-200b and miR-200c. Furthermore, GSE1 positively regulated the downstream gene SLC7A5 (also known as LAT-1), which was scanned and verified from mRNA sequencing. GSE1 therefore possesses an oncogenic role in human gastric cancer, and targeted therapeutic approaches to inhibit GSE1 function in gastric cancer warrant further consideration.


Assuntos
Adenocarcinoma/mortalidade , Movimento Celular , Proliferação de Células , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/mortalidade , Neoplasias Gástricas/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer ; 125(11): 1789-1798, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933320

RESUMO

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Desenvolvimento de Medicamentos , Neoplasias/tratamento farmacológico , Rotenona/análogos & derivados , Animais , Humanos , Rotenona/uso terapêutico
15.
Br J Cancer ; 120(7): 728-745, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816325

RESUMO

BACKGROUND: SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα- early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. RESULTS: As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc- [HR (95% CI) = 0.52 (0.34-0.78), p = 0.002]. Meanwhile, in ERα- patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto- [HR (95% CI) = 0.50 (0.34-0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc- or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28-27.03), p = 0.012], or SHON-Cyto- [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18-25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc- [HR (95% CI) = 0.41 (0.19-0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto- patients [HR (95% CI) = 4.63 (1.05-20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13-44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant. CONCLUSION: SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Proteínas Oncogênicas/metabolismo , Tamoxifeno/uso terapêutico , Adolescente , Adulto , Idoso , Antraciclinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Núcleo Celular/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Adulto Jovem
16.
Bioorg Chem ; 87: 142-154, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30884308

RESUMO

The formation of a thrombus is a key event in thromboembolic disorders, that contribute to high mortality and morbidity in affected patients. In the present study, we synthesized a library of novel substituted 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4(5H)-one derivatives which were tested for their platelet aggregation and thrombin inhibitory activity. Among the tested compounds, 3,3-dibutyl-7-(2-chlorophenyl)-8-methoxy-2,3-dihydrobenzo[b] [1,4]thiazepin-4(5H)-one (DCT) displayed the maximum thrombin inhibition with an IC50 value of 3.85 µM and thus DCT was chosen for further studies. Next, the effect of DCT on primary hemostasis was evaluated using agonist-induced platelet aggregation model. The lead compound inhibited the collagen- or ADP- or thrombin-induced platelet aggregation in a dose-dependent manner. Furthermore, DCT prolonged the process of clot formation when evaluating plasma re-calcification time (320 ±â€¯11 sec at 5 µg DCT), activated partial thromboplastin time (58.0 ±â€¯0.01 sec at 2 µg), and prothrombin time (14.7 ±â€¯0.01 sec at 5 µg). Molecular docking studies suggested that the benzothiazepinones evaluated here consistently display hydrogen bonding with Ser214 of thrombin, which is similar to that of the co-crystallized ligand (1-(2R)-2-amino-3-phenyl-propanoyl-N-(2,5dichlorophenyl)methylpyrrolidine-2-carboxamide). DCT displayed additional hydrogen bonding to Ser195 and π-π interactions between its methoxyphenyl groups and Trp60, thereby providing a structural rationale for the observed biological effect.


Assuntos
Inibidores de Serina Proteinase/farmacologia , Tiazepinas/farmacologia , Trombina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Tiazepinas/síntese química , Tiazepinas/química , Trombina/metabolismo
17.
Int J Mol Sci ; 20(24)2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31835445

RESUMO

Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas de Neoplasias , Nitrilas/farmacologia , Fator Trefoil-3/antagonistas & inibidores , Animais , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Fator Trefoil-3/metabolismo
18.
Carcinogenesis ; 39(12): 1506-1516, 2018 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-30084985

RESUMO

The dysregulation of micro RNAs (miRNAs) is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3' untranslated region of the DICER1 transcript and posttranscriptionally represses DICER1 expression, thereby impairing global miRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, whereas the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, high-mobility group AT-hook 2 (HMGA2). The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , MicroRNAs/genética , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Ribonuclease III/genética , Regiões 3' não Traduzidas/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes/genética
19.
J Biol Chem ; 292(33): 13551-13564, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28637868

RESUMO

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.


Assuntos
Regiões 3' não Traduzidas/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteína Semelhante a ELAV 1/metabolismo , MicroRNAs/metabolismo , Receptor ErbB-2/metabolismo , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Clivagem , Feminino , Humanos , MicroRNAs/antagonistas & inibidores , Mutação , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Poliadenilação/efeitos dos fármacos , Interferência de RNA , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/agonistas , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/química , RNA Mensageiro/metabolismo , RNA Neoplásico/agonistas , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/química , RNA Neoplásico/metabolismo , Proteínas de Ligação a RNA/agonistas , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptor ErbB-2/agonistas , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Elementos de Resposta/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Bioorg Med Chem Lett ; 28(13): 2314-2319, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29789259

RESUMO

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Reação de Cicloadição , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirimidinas/síntese química , Triazóis/síntese química , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
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