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1.
Int J Cancer ; 146(1): 123-136, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31090219

RESUMO

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.


Assuntos
Anticorpos/uso terapêutico , Auranofina/uso terapêutico , Antígeno B7-H1/imunologia , Inibidores Enzimáticos/uso terapêutico , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Auranofina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Cancer ; 146(1): 262-271, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162838

RESUMO

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proliferação de Células/genética , Pesquisa Médica Translacional , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Relação Dose-Resposta a Droga , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia
3.
Bioelectrochemistry ; 131: 107350, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31518962

RESUMO

Curcumin (Cur), the yellow pigment of well-known turmeric (Curcuma longa L.) is effective in multiple cancers including triple negative breast cancer (TNBC). In combination with electrical pulses (EP), enhanced effects of curcumin (Cur + EP) are observed in TNBC cells. To gain insights into the mechanisms of enhanced anticancer effects of Cur + EP, we studied the proteins involved in the anticancer activity of Cur + EP in MDA-MB-231, human TNBC cells using high-throughput global proteomics. A curcumin dose of 50 µM was applied with eight, 1200 V/cm, 100 µs pulses, the most commonly used electrochemotherapy (ECT) parameter in clinics. Results show that the Cur + EP treatment reduced the clonogenic ability in MDA-MB-231 cells, with the induction of apoptosis. Proteomic analysis identified a total of 1456 proteins, of which 453 proteins were differentially regulated, including kinases, heat shock proteins, transcription factors, structural proteins, and metabolic enzymes. Eight key glycolysis proteins (ALDOA, ENO2, LDHA, LDHB, PFKP, PGM1, PGAM1 and PGK1) were downregulated in Cur + EP from Cur. There was a switch in the metabolism with upregulation of 10 oxidative phosphorylation pathway proteins and 8 tricarboxylic acid (TCA) cycle proteins in the Cur + EP sample, compared to curcumin. These results provide novel systematic insights into the mechanisms of ECT with curcumin.


Assuntos
Antineoplásicos/uso terapêutico , Curcumina/uso terapêutico , Eletroquimioterapia/métodos , Proteínas de Neoplasias/metabolismo , Proteômica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Curcumina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Glicólise , Humanos , Fosforilação Oxidativa , Via de Pentose Fosfato/efeitos dos fármacos , Reprodutibilidade dos Testes , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
4.
Drugs Today (Barc) ; 55(9): 575-585, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584574

RESUMO

Patients with metastatic triple-negative breast cancer (mTNBC) that has progressed on first-line therapy have a poor prognosis with limited therapeutic options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate (ADC) that has shown promising efficacy in mTNBC. SG is comprised of SN-38, the active metabolite of irinotecan, conjugated via a hydrolyzable linker to the humanized RS7 antibody targeting trophoblast cell surface antigen 2 (Trop-2), a glycoprotein that is expressed at high levels in many epithelial solid tumors. It has received breakthrough therapy status by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pretreated mTNBC. In this review, we summarize available data regarding the pharmacology, pharmacokinetics, safety and efficacy of SG and describe ongoing and future clinical studies investigating this agent.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antígenos de Neoplasias , Camptotecina/uso terapêutico , Moléculas de Adesão Celular , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
5.
Neoplasma ; 66(6): 963-970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607128

RESUMO

Triple negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer (BC) for which limited therapeutic options are available. Recently, ß-blockers (BBs) have been suggested to have favorable effects in the treatment of BC. The aim of this systematic review was to collect evidence from preclinical and clinical studies concerning the scientific evidence for the repurposing of BBs in TNBC treatment. PubMed database was searched to retrieve studies of interest published up to 30/01/2018. All preclinical studies using TNBC in vitro and in vivo models and assessing the effect of any molecule with sympatholytic or sympathomimetic activity on adrenergic receptors were included. Clinical studies concerning BBs were considered eligible. The Newcastle-Ottawa scale was used for the quality assessment of clinical studies. A total of 614 study references were retrieved. Forty-six preclinical studies were included. In in vitro studies, propranolol, a non-selective BB, significantly decreased proliferation, migration and invasion of TNBC cells. Consistently, in in vivo studies, propranolol inhibited metastasis, angiogenesis and tumor growth. Clinical studies, reporting evidence from a total of four distinct retrospective observational cohort studies, showed a beneficial effect of BBs in TNBC treatment. The overall quality of the clinical evidence collected was low. Preclinical evidence collected in this systematic review are in line with the results reported in the clinical studies retrieved, pointing towards a beneficial effect of BB in the treatment of TNBC. However, given the overall low quality of available evidence, no definite conclusion may be drawn.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neovascularização Patológica , Estudos Observacionais como Assunto , Estudos Retrospectivos
6.
Anticancer Res ; 39(10): 5285-5296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570423

RESUMO

Triple-negative breast cancer (TNBC) is characterized by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and unfortunately is not associated with good prognosis. Treatment of breast cancer mainly depends on chemotherapy, due to the lack of specifically approved targeted therapies for TNBC. It is of paramount importance to find new therapeutic approaches, as resistance to chemotherapy frequently occurs. Herein, we present clinical studies published within the last five years, in order to reveal possible targeted therapies against TNBC. We aimed to discuss factors against TNBC, such as tyrosine kinase inhibitors, anti-androgens, poly ADP-ribose polymerase-1 (PARP-1) inhibitors, anti-angiogenic factors, immune checkpoints and histone deacetylase inhibitors (HDACI). Furthermore, the PI3K/AKT/mTOR pathway seems to be a promising field for the development of new anti-TNBC targeted therapies. Data from 18 clinical trials with patients suffering from TNBC were summarized and presented descriptively.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto Jovem
8.
Int J Radiat Oncol Biol Phys ; 105(3): 471-472, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31540590
9.
Cancer Sci ; 110(11): 3543-3552, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541611

RESUMO

Poly ADP-ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple-negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage-recognition factor, could protect TNBC cells from PARPi by regulating DNA double-strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway-induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC.


Assuntos
Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Rad51 Recombinase/metabolismo , Reparo de DNA por Recombinação , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Proteínas de Ligação a DNA/deficiência , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Ubiquitinação
10.
Eur J Med Chem ; 183: 111720, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553933

RESUMO

At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT5 and integrin αvß3 were designed and prepared in this work. Firstly, a Y-shaped Fru-RGD-chol ligand, where a fructose and peptide Arg-Gly-Asp (RGD) were covalently attached to cholesterol, was designed and synthesized. Then, the Fru-RGD-Lip was constructed by inserting Fru-RGD-chol into liposomes, while Fru+RGD-Lip was obtained by inserting both Fru-chol and RGD-chol (with the molar ratio of 1:1) into liposomes. The particle size, zeta potential, encapsulation efficiency and serum stability of the paclitaxel-loaded liposomes were characterized. The results indicated that the paclitaxel-loaded Fru-RGD-Lip had the strongest growth inhibition against GLUT5 and αvß3 overexpressed MDA-MB-231 and 4T1 cells. The cellular uptake of Fru-RGD-Lip on MDA-MB-231 cells and 4T1 cells was 3.19- and 3.23-fold more than that of the uncoated liposomes (Lip). The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively. The mechanism study demonstrated that the cellular uptake of both dual-targeting liposomes was likely to be recognized and mediated by GLUT5 and αvß3 firstly, then endocytosed through comprehensive pathways in an energy-dependent manner. Moreover, Fru-RGD-Lip displayed the maximum accumulation, which was 2.62-fold higher than that of Lip for instance, at the tumor sites compared to other liposomes using in vivo imaging. Collectively, the liposomes co-modified by fructose and RGD have enormous potential in the development of targeted TNBC treatment, especially the covalently modified Fru-RGD-Lip, making it a promising multifunctional liposome.


Assuntos
Antineoplásicos Fitogênicos , Transportador de Glucose Tipo 5/metabolismo , Integrina alfaVbeta3/metabolismo , Lipossomos , Paclitaxel , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Feminino , Frutose/química , Humanos , Lipossomos/química , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Oligopeptídeos/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/química , Neoplasias de Mama Triplo Negativas/metabolismo
11.
BMC Complement Altern Med ; 19(1): 216, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412862

RESUMO

BACKGROUND: Breast cancer is still the most common malignant tumor that threatens the female's life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. Lack of targeted therapies brings about urgent demand for novel treatments. In this study we aim to investigate the anti-tumor activity of Berberine (BBR), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 and elucidate its mechanism referring to anti-inflammation. METHODS: Cell inhibition rate was measured by Cell Proliferation Assay, the cytotoxic effects was detected by Lactate dehydrogenase (LDH) leakage assay, the colony formation and migration potential were evaluated by colony formation assay and wound healing assay, the release of inflammatory cytokines was detected by EMD multifactor detection, and alterations of proteins and genes related to the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway were analyzed using western blotting and real-time Polymerase Chain Reaction (PCR). RESULTS: BBR reduce the viability of MDA-MB-231 cells and increased the release of LDH from the cells in a dose-dependent manner, with and inhibition of colony formation potential and migration of the cells. BBR also caused a marked reduction in the secretion of proinflammatory cytokines, Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Besides, a down-regulated behavior was observed with the expression of P2X purinoceptor 7 (P2X7), NLRP3, pro-caspase-1, apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1 p20, Interleukin-18 (IL-18), IL-1ß proteins and NLRP3, Caspase-1 and ASC mRNAs in the NLRP3 inflammasome cascade. CONCLUSIONS: Our results confirmed that BBR can effectively affect both tumor outgrowth and spontaneous metastasis in TNBC, and that we identified a new mechanism associated with inhibition the NLRP3 inflammasome pathway, suggesting its potential therapeutic relevance in clinical use.


Assuntos
Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Apoptose/efeitos dos fármacos , Caspase 1/genética , Caspase 1/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
Breast Cancer Res ; 21(1): 87, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383035

RESUMO

BACKGROUND: Approximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development. METHODS: We assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes. RESULTS: Analysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2. CONCLUSIONS: We conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.


Assuntos
Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Variações do Número de Cópias de DNA , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Mutação , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Neoplasia Residual , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Transdução de Sinais , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Proteína Supressora de Tumor p53/genética
13.
Adv Exp Med Biol ; 1152: 311-334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456192

RESUMO

Triple negative breast cancer (TNBC) is a more aggressive subtype of breast cancer and is characteristic of the absence of the expressions of estrogen receptor, progesterone receptor, and human epithelial growth factor receptor 2 in breast tumor tissues. This subtype of breast cancer has the poorest prognosis, compared to other subtypes of breast cancer. TNBC is heterogeneous by showing several different histo-pathological and molecular subtypes with different prognosis and is more commonly found in younger age of women, especially African-American and Hispanic women. Recent epidemiological data indicate that TNBC is highly associated with overweight/obesity. Due to the absence of the common tumor biomarkers of breast cancer, the current molecular target therapy is not effective. TNBC patients have a shorter survival rate and an increased tumor recurrence. The concept of cancer stem cells (CSC), also called tumor initiating cells (TIC) has been more and more accepted and considered to contribute to aggressive phenotypes of many tumors including breast cancer. Moreover, CSC/TIC has been identified in the tumor tissues of breast cancer including TNBC. These rare subpopulations of CSC/TIC cells might be one of the key contributors to the aggressive phenotypes of TNBC such as drug treatment resistance, metastasis, and tumor recurrence. Therefore, targeting these CSC/TIC cells will provide a new therapeutic strategy for the treatment of TNBC.


Assuntos
Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Humanos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia
14.
Adv Exp Med Biol ; 1152: 377-399, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456195

RESUMO

The mortality from breast cancer has steadily decreased due in part to early detection and advances in therapy. The treatment options for breast cancer vary considerably depending on the histological subtype. There are a number of very effective targeted therapies available for estrogen receptor-positive disease and for human epidermal growth factor receptor 2-positive disease. However, triple-negative breast cancer is a particularly aggressive subtype. This subtype represents an unmet need for improved therapies. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Here we review the recent advances in the treatment of TNBC with emphasis on the many emerging novel targeted therapies.


Assuntos
Terapia de Alvo Molecular , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Feminino , Humanos
15.
Life Sci ; 234: 116783, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31442552

RESUMO

Breast cancer (BCa) is the most commonly diagnosed lethal cancer in women worldwide. Notch signaling pathway is directly linked to BCa recurrence and aggressiveness. Natural remedies are becoming a prime choice to overcome against cancer due to lesser side effect and cost-effectiveness. Bulbine frutescens (Asphodelaceae), a traditional medicinal plant in South Africa possess bioactive flavonoids and terpenoids. Polar (methanol) and non-polar (hexane) B. frutescens plant extracts were prepared. GC-MS analysis revealed the differential presence of secondary metabolites in both methanolic and hexane extracts. We hereby first time evaluated the anticancer potential of B. frutescens methanolic and hexane extract in triple-negative and luminal BCa cells. B. frutescens extracts significantly decreased cell viability (IC50 4.8-28.4 µg/ml) and induced cell cycle arrest at G1 phase in MDA-MB-231 and T47D cells as confirmed by spectrophotometry and flow cytometry technique. RT-PCR analysis of cell cycle (cyclin D1, CDK4, and p21) and apoptosis modulating genes (caspase 3, Bcl2 and survivin) revealed upexpression of p21, and caspase 3, and down expression of cyclin D1, CDK4, Bcl2 and survivin genes in extract-treated BCa cells. Fluorescence spectrophotometry and confocal microscopy showed B. frutescens induced nuclear morphology and mitochondrial integrity disruption, and increased reactive oxygen species production in MDA-MB-231 and T47D cells. Flow cytometric apoptosis analysis of B. frutescens extracts treated MDA-MB-231 cells showed ≈13% increase in early apoptotic population in comparison to non-treated cells. Dual-Luciferase Reporter assay confirmed notch promoter inhibitory activity of B. frutescens extracts. Moreover, RTPCR analysis showed down regulation of notch responsive genes (Hes1 and Hey1) at transcription levels in extract-treated BCa cells. Western Blot analysis showed increased procaspase 3 protein expression in extract-treated BCa cells. In all the assays methanolic extract showed better anti-cancer properties. Literature-based identification of methanol soluble phytochemicals in B. frutescens and in silico docking study revealed Bulbineloneside D as a potent ϒ-secretase enzyme inhibitor. In comparison to standard notch inhibitor, lead phytochemical showed two additional hydrophobic interactions with Ala80 and Leu81 amino acids. In conclusion, B. frutescens phytochemicals have cell cycle arrest, ROS production, apoptosis induction, and mitochondria membrane potential disruption efficacy in breast cancer cells. B. frutescens phytochemicals have the ability to downregulate the notch signaling pathway in triple-negative and luminal breast cancer cells.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Xanthorrhoeaceae/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
16.
Asian Pac J Cancer Prev ; 20(8): 2267-2273, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450894

RESUMO

Objective: The present study aimed to investigate the possible role of IL-6 and 1α,25-dihydroxyvitamin D3 (1,25D) signaling in epithelial-mesenchymal transition (EMT) and stemness in triple-negative breast cancer (TNBC) cell line. Methods: TNBC cell line, HCC 1806, was treated with IL-6 and 1,25D for three and six days. Also, the role of vitamin D receptor (VDR) was studied by transfection of TNBC cell line with VDR gene and transfection efficiency was assessed using Human VDR enzyme-linked immunosorbent assay (ELISA). Changes in E-cadherin gene expression were analyzed by quantitative real-time PCR (qRT-PCR). Also, changes in CD44+ cells were analyzed by flow cytometry. Finally, morphological changes were investigated by light microscopy after 6 days. Results: Treatment of HCC1806 cells with IL-6 has no significant effect either on E-cadherin gene expression or CD44+ cells, (p > 0.05). However, E-cadherin gene expression was significantly up-regulated after treatment with 1,25D for 6 days, (p < 0.05). Also, CD44+ cells were significantly reduced after treatment with 1,25D either for 3 or 6 days, (p < 0.05). Transfection of TNBC cell line with VDR gene significantly up-regulated VDR protein expression, (p < 0.05). In addition, overexpression of VDR in TNBC cells and treatment with 1,25D significantly up-regulated E-cadherin gene expression, (p < 0.05) and reduced CD44+ cells, (p < 0.05). Moreover, transfection with VDR and treatment with a combination of 1,25D and IL-6 significantly down-regulated E-cadherin gene expression and increased CD44+ cells compared with transfected cells with VDR treated with 1,25D alone, (p < 0.05). No significant morphological changes were observed in treated cells, 6 days post-treatment. Conclusion: The presence of IL-6 in the breast tumor microenvironment may impair the activity of vitamin D3 signaling, limiting its anti-tumor effects in TNBC.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Interleucina-6/administração & dosagem , Receptores de Calcitriol/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Vitamina D/análogos & derivados , Antígenos CD/genética , Caderinas/genética , Feminino , Humanos , Receptores de Calcitriol/genética , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem
17.
Int J Pharm ; 569: 118605, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31400433

RESUMO

A promising strategy for treatment of EGFR-dependent tumours is EGFR signal transduction suppression via inhibition of HMG-CoA reductase using high doses of statins, popular cholesterol-lowering drugs. The main purpose of this study was to obtain targeted long circulating immunoliposomes containing simvastatin (tLCLS) with anti-EGFR antibody attached to their surface and to test whether they can be effective in treatment of TNBC. The designed tLCLS were characterized in terms of physicochemical properties and long-term stability. In vitro experiments conducted on MDA-MB-231 cells demonstrated that tLCLS induced apoptosis and are characterized by IC50 of 7.5 µM. Treatment of studied cells with tLCLS led to a decrease in membrane order and inhibited PI3K/Akt signalling. Analyses of efficacy of the tLCLS in in vivo experiments in model animals indicate that immunoliposomes were effectively delivered to tumours. Our results showed that regardless of whether tLCLS were administered before or after tumour formation, at the tested dose they inhibited tumour growth by an average of 25% in comparison to the control. However, the results were not statistically significant. The experiments described above allowed us to test the possibility of using immunoliposomes as simvastatin carriers delivering increased amounts of the drug to tumour cells.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Cetuximab/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Sinvastatina/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Feminino , Humanos , Lipossomos , Neoplasias Mamárias Experimentais/imunologia , Camundongos SCID , Neoplasias de Mama Triplo Negativas/imunologia
18.
Cancer Sci ; 110(10): 3173-3182, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464035

RESUMO

Ferroptosis is an iron-dependent, lipid peroxide-driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple-negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin-loaded exosomes labeled with folate (FA) to form FA-vectorized exosomes loaded with erastin (erastin@FA-exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti-tumor effect in vitro of erastin@FA-exo were determined. Erastin@FA-exo could increase the uptake efficiency of erastin into MDA-MB-231 cells; compared with erastin@exo and free erastin, erastin@FA-exo has a better inhibitory effect on the proliferation and migration of MDA-MB-231 cells. Furthermore, erastin@FA-exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA-exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome-based erastin preparations provide an innovative and powerful delivery platform for anti-cancer therapy.


Assuntos
Exossomos/química , Ácido Fólico/química , Piperazinas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Morte Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína Dioxigenase/metabolismo , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Piperazinas/química , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
19.
Anticancer Res ; 39(8): 4043-4053, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366486

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is the most aggressive subtype, predominant in African American women. In this study, the antioxidant/anticancer activity of muscadine grape extracts and the role of their phenolic and flavonoid contents in exerting these properties were investigated in TNBC cells. MATERIALS AND METHODS: Berry extracts from muscadine genotypes were investigated for total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity, and anticancer effects using breast cancer cell lines, representing Caucasians and African Americans. RESULTS: The antioxidant activity was associated with high TPC content. Extracts showed cytotoxicity up to 78.6% in Caucasians and 90.7% in African American cells, with an association with high antioxidant capacity. There was a strong correlation between TPC and anticancer/antioxidant activities. CONCLUSION: The anticancer and antioxidant effects of muscadine grapes are attributed to the TPC of extracts, which showed a stronger positive correlation with growth inhibition of African American breast cancer cells compared to Caucasians.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitis/química , Afro-Americanos/genética , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
20.
Mater Sci Eng C Mater Biol Appl ; 103: 109716, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349431

RESUMO

Improved therapeutic effects can be achieved by the delivery of combination of drugs through multifunctional cell targeted nanocarrier systems. The present investigation reports the preparation of Poly (D,L-lactic-co-glycolic acid) (PLGA) nanospheres loaded with the novel combination such as Rutin (R) and Benzamide (B) as drugs using water-oil-water (w/o/w) emulsion method. Dual drug loaded PLGA nanospheres (R/B@PLGA) were stabilized by poly (vinyl alcohol) (PVA) coating and characterized in terms of morphology, size, surface charge, and structural chemistry by Scanning electron microscopy (SEM), Dynamic light scattering (DLS), Zeta potential analysis, UV-vis and Fourier transform infrared (FT-IR) spectroscopy. The inhibitory effects of rutin and benzamide on MDA-MB-231 (triple negative breast cancer-TNBC) cells using the drug loaded PLGA nanospheres as well as their non-toxic features were evaluated in vivo. The anticancer activity of the R/B@PLGA nanospheres through cell cycle disruption and apoptotic induction was assessed in vitro by flow cytometry analysis. Further, the in vitro antioxidant capacity, pH-based drug release and hemocompatible property were also investigated. It was shown that the R/B@PLGA nanospheres lacked genotoxic potential and they did not alter the antioxidant enzyme activities and histological features of zebrafish. Hence, this dual drug delivery system (DDS) not only actively targets multidrug-resistance (MDR) associated phenotype but also improves the therapeutic efficiency by its non-toxic nature towards enhanced cancer cell focused delivery and sustained release of therapeutic agents.


Assuntos
Benzamidas , Portadores de Fármacos , Nanosferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Rutina , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Humanos , Nanosferas/química , Nanosferas/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Rutina/química , Rutina/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Peixe-Zebra
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