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1.
Carcinogenesis ; 41(12): 1648-1659, 2020 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32747956

RESUMO

Emerging evidence suggests the role of environmental chemicals, in particular endocrine-disrupting chemicals (EDCs), in progression of breast cancer and treatment resistance, which can impact survival outcomes. However, most research tends to focus on tumor etiology and the effect of single chemicals, offering little insight into the effects of realistic complex mixture exposures on tumor progression. Herein, we investigated the effect of a polycyclic aromatic hydrocarbon (PAH)-enriched EDC mixture in a panel of normal and breast cancer cells and in a tumor organoid model. Cells or organoids in culture were treated with EDC mixture at doses estimated from US adult intake of the top four PAH compounds within the mixture from the National Health and Nutrition Examination Survey database. We demonstrate that low-dose PAH mixture (6, 30 and 300 nM) increased aryl hydrocarbon receptor (AhR) expression and CYP activity in estrogen receptor (ER) positive but not normal mammary or ER-negative breast cancer cells, and that upregulated AhR signaling corresponded with increased cell proliferation and expression of antiapoptotic and antioxidant proteins XIAP and SOD1. We employed a mathematical model to validate PAH-mediated increases in AhR and XIAP expression in the MCF-7 ER-positive cell line. Furthermore, the PAH mixture caused significant growth increases in ER-negative breast cancer cell derived 3D tumor organoids, providing further evidence for the role of a natural-derived PAH mixture in enhancing a tumor proliferative phenotype. Together, our integrated cell signaling, computational and phenotype analysis reveals the underlying mechanisms of EDC mixtures in breast cancer progression and survival.


Assuntos
Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Disruptores Endócrinos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Humanos , Receptores de Hidrocarboneto Arílico/genética , Células Tumorais Cultivadas
2.
Carcinogenesis ; 38(3): 252-260, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28426875

RESUMO

Emerging evidence from epidemiological studies suggests a link between environmental chemical exposure and progression of aggressive breast cancer subtypes. Of all clinically distinct types of breast cancers, the most lethal phenotypic variant is inflammatory breast cancer (IBC). Overexpression of epidermal growth factor receptors (EGFR/HER2) along with estrogen receptor (ER) negativity is common in IBC tumor cells, which instead of a solid mass present as rapidly proliferating diffuse tumor cell clusters. Our previous studies have demonstrated a role of an adaptive response of increased antioxidants in acquired resistance to EGFR-targeting drugs in IBC. Environmental chemicals are known to induce oxidative stress resulting in perturbations in signal transduction pathways. It is therefore of interest to identify chemicals that can potentiate EGFR mitogenic effects in IBC. Herein, we assessed in ER-negative IBC cells a subset of chemicals from the EPA ToxCast set for their effect on EGFR activation and in multiple cancer phenotypic assays. We demonstrated that endocrine-disrupting chemicals such as bisphenol A (BPA) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane can increase EGFR/ERK signaling. BPA also caused a corresponding increase in expression of SOD1 and anti-apoptotic Bcl-2, key markers of antioxidant and anti-apoptotic processes. BPA potentiated clonogenic growth and tumor spheroid formation in vitro, reflecting IBC-specific pathological characteristics. Furthermore, we identified that BPA was able to attenuate the inhibitory effect of an EGFR targeted drug in a longer-term anchorage-independent growth assay. These findings provide a potential mechanistic basis for environmental chemicals such as BPA in potentiating a hyperproliferative and death-resistant phenotype in cancer cells by activating mitogenic pathways to which the tumor cells are addicted for survival.


Assuntos
Compostos Benzidrílicos/toxicidade , Carcinógenos Ambientais/toxicidade , Receptores ErbB/genética , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Fenóis/toxicidade , Compostos Benzidrílicos/farmacologia , Carcinógenos Ambientais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos
3.
Org Biomol Chem ; 14(33): 7864-8, 2016 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-27492274

RESUMO

The ß-amino carboxylic acid moiety is a key feature of numerous important biologically active compounds. We describe a syn-selective direct Mannich addition reaction that uses α-iodo thioesters and sulfonyl imines and produces ß-amino thioesters. Enolate formation is achieved by reductive soft enolization. The products of the reaction provide straightforward access to biologically important ß-lactams through a variety of known reactions.

4.
Breast Cancer Res Treat ; 137(2): 359-71, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23225169

RESUMO

X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K (d) > 1 µM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment.


Assuntos
Apoptose/efeitos dos fármacos , Dipeptídeos/farmacologia , Indóis/farmacologia , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Proteínas Inibidoras de Apoptose/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Proteínas Reguladoras de Apoptose , Caspase 8/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/química , Relação Dose-Resposta a Droga , Técnicas de Silenciamento de Genes , Humanos , Indóis/química , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Mitocondriais/química , Quinolinas/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
5.
Cancers (Basel) ; 15(8)2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37190189

RESUMO

Inflammatory breast cancer (IBC), an understudied and lethal breast cancer, is often misdiagnosed due to its unique presentation of diffuse tumor cell clusters in the skin and dermal lymphatics. Here, we describe a window chamber technique in combination with a novel transgenic mouse model that has red fluorescent lymphatics (ProxTom RFP Nu/Nu) to simulate IBC clinicopathological hallmarks. Various breast cancer cells stably transfected to express green or red fluorescent reporters were transplanted into mice bearing dorsal skinfold window chambers. Intravital fluorescence microscopy and the in vivo imaging system (IVIS) were used to serially quantify local tumor growth, motility, length density of lymph and blood vessels, and degree of tumor cell lymphatic invasion over 0-140 h. This short-term, longitudinal imaging time frame in studying transient or dynamic events of diffuse and collectively migrating tumor cells in the local environment and quantitative analysis of the tumor area, motility, and vessel characteristics can be expanded to investigate other cancer cell types exhibiting lymphovascular invasion, a key step in metastatic dissemination. It was found that these models were able to effectively track tumor cluster migration and dissemination, which is a hallmark of IBC clinically, and was recapitulated in these mouse models.

6.
J Am Chem Soc ; 132(40): 13997-9, 2010 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-20849119

RESUMO

The direct addition of enolizable aldehydes and α-halo thioesters to produce ß-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used.


Assuntos
Aldeídos/química , Carbono/química , Ésteres/química , Cinética , Oxirredução
7.
Org Lett ; 9(22): 4663-5, 2007 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-17902688

RESUMO

A facile and efficient four-component anti-selective direct aldol addition of thioester enolates has been developed that is fully compatible with enolizable aldehydes and able to be conducted using untreated reagent-grade CH2Cl2 open to the air. The thioester enolates are generated in situ via an acylation/conjugate addition sequence using commercially available PhSLi and acryloyl chloride, thus avoiding prior enolate formation while maintaining complete chemoselectivity. The organosulfur products are convertible into various polyketide-based structures.

8.
Oncotarget ; 8(16): 25848-25863, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28460441

RESUMO

Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/patologia , Células Neoplásicas Circulantes/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores Tumorais , Técnicas de Cultura de Células , Sobrevivência Celular/genética , Cobre/farmacologia , Dissulfiram/farmacologia , Feminino , Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Inflamatórias Mamárias/metabolismo , Mitocôndrias/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Esferoides Celulares , Células Tumorais Cultivadas , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
9.
Cancer Lett ; 411: 136-149, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-28965853

RESUMO

Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of GLI antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines. In addition, GANT61 and JK184 significantly down-regulated GLI1 targets that regulate cell cycle (cyclin D and E) and apoptosis (Bcl2). GANT61 reduced SUM149 spheroid growth and emboli formation, and in orthotopic SUM149 tumor models significantly decreased tumor growth. We successfully utilized phenotypic profiling to identify a subset of GLI1 antagonists that were prioritized for testing in in vivo models. Our results indicated that GLI1 activation in TN-IBC as in TNBC, plays a vital role in promoting cell proliferation, motility, tumor growth, and formation of tumor emboli.


Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Piridinas/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Proteína GLI1 em Dedos de Zinco/biossíntese , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Org Lett ; 13(12): 3118-21, 2011 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-21615091

RESUMO

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Carbamatos/química , Hidrazonas/química , Mefloquina/síntese química , Mefloquina/farmacologia , Antimaláricos/química , Mefloquina/química , Estrutura Molecular , Estereoisomerismo
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