Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.850
Filtrar
1.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878797

RESUMO

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Survivina/genética , Taxoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Prostate ; 80(12): 926-937, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542812

RESUMO

BACKGROUND: Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer. METHODS: To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days. RESULTS: Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner. CONCLUSIONS: Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Di-Hidrotestosterona/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Orquiectomia , Neoplasias da Próstata/cirurgia , Distribuição Aleatória , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS One ; 15(6): e0234078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484838

RESUMO

BACKGROUND: Despite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms. METHODS: Du145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies. RESULTS: While age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial cross-resistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression level altered the sensitivity of prostate cancer cells to both drugs identifying a possible new target for taxane resistance. CONCLUSION: Our study represents the first demonstration that while Wnt pathway seems to play an important role in taxanes resistance, Wnt effectors responsible for taxane specificity remain un-identified prompting the need for more studies.


Assuntos
Antineoplásicos/farmacologia , Taxoides/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
4.
Mol Pharmacol ; 98(2): 156-167, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32591477

RESUMO

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anticancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and taxane-resistant cancer cell models, diminished risk of chemotherapy-mediated senescence, and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to ß-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.


Assuntos
Alcanos/química , Carbamatos/química , Lactonas/síntese química , Neoplasias Ovarianas/metabolismo , Pironas/química , Neoplasias de Mama Triplo Negativas/metabolismo , Moduladores de Tubulina/síntese química , Células A549 , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lactonas/química , Lactonas/farmacologia , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
5.
Cancer Res ; 80(8): 1693-1706, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32054769

RESUMO

A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of NEK2 was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, in vitro. In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple in vivo models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Paclitaxel/farmacologia , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Senescência Celular , Centrossomo/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Mitose/genética , Quinases Relacionadas a NIMA/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
6.
Cancer Res ; 80(7): 1564-1577, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32029552

RESUMO

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of prostate cancer. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat prostate cancer and CRPC.Significance: Merging mathematical modeling with experimental data, this study presents the "TRAMP-based platform" as a novel experimental tool to study the in vitro and in vivo evolution of prostate cancer resistance to enzalutamide.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Camundongos , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia , Taxoides/uso terapêutico
7.
Anticancer Res ; 40(1): 335-339, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892584

RESUMO

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Docetaxel/farmacologia , Terapia de Alvo Molecular , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Idoso , Antagonistas de Receptores de Andrógenos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Masculino , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Resultado do Tratamento
8.
Gynecol Oncol ; 156(3): 654-661, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31973910

RESUMO

OBJECTIVE: The first-line chemotherapy for ovarian cancer is based on a combination of platinum and taxane. To date, no reliable predictive biomarker has been recognized that is capable of identifying patients with pre-existing resistance to these agents. Here, we have established an integrated database and identified the most significant biomarker candidates for chemotherapy resistance in serous ovarian cancer. METHODS: Gene arrays were collected from the GEO and TCGA repositories. Treatment response was defined based on pathological response or duration of relapse-free survival. The responder and nonresponder cohorts were compared using the Mann-Whitney and receiver operating characteristic tests. An independent validation set was established to investigate the correlation between chemotherapy response for the top 8 genes. Statistical significance was set at p < 0.05. RESULTS: The entire database included 1816 tumor samples from 12 independent datasets. From analyzing all the genes for platinum + taxane response, we identified the eight strongest genes correlated to chemotherapy resistance: AKIP1 (p = 1.60E-08, AUC = 0.728), MARVELD1 (p = 2.70E-07, AUC = 0.712), AKIRIN2 (p = 2.60E-07, AUC = 0.704), CFL1 (p = 8.10E-08, AUC = 0.694), SERBP1 (p = 8.10E-07, AUC = 0.684), PDXK (p = 1.30E-04, AUC = 0.634), TFE3 (p = 7.90E-05, AUC = 0.631) and NCOR2 (p = 1.90E-03, AUC = 0.611). Of these, the independent validation confirmed TFE3 (p = 0.012, AUC = 0.718), NCOR2 (p = 0.048, AUC = 0.671), PDXK (p = 0.019, AUC = 0.702), AKIP1 (p = 0.002, AUC = 0.773), MARVELD1 (p = 0.044, AUC = 0.675) and AKIRIN2 (p = 0.042, AUC = 0.676). An online interface was set up to enable future validation and ranking of new biomarker candidates in an automated manner (www.rocplot.org/ovar). CONCLUSIONS: We compiled a large integrated database with available treatment and response information and used this to uncover new biomarkers of chemotherapy response in serous ovarian cancer.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Taxoides/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas Nucleares/genética , Correpressor 2 de Receptor Nuclear/genética , Valor Preditivo dos Testes , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética
9.
Prostate ; 80(2): 214-224, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31799745

RESUMO

BACKGROUND: Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. METHODS: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3 . Two cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole-genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. RESULTS: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. CONCLUSIONS: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.


Assuntos
Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Taxoides/farmacologia , Antagonistas de Androgênios/farmacologia , Androstenos/farmacologia , Animais , Antineoplásicos/farmacologia , Castração , Linhagem Celular Tumoral , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Isoformas de Proteínas , Receptores Androgênicos/genética , Taxoides/administração & dosagem , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncogene ; 39(2): 454-468, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492900

RESUMO

The nuclear transport receptor importin-ß/karyopherin-ß1 is overexpressed in cancers that display genomic instability. It is regarded as a promising cancer target and inhibitors are being developed. In addition to its role in nucleo-cytoplasmic transport, importin-ß regulates mitosis, but the programmes and pathways in which it operates are defined only in part. To unravel importin-ß's mitotic functions we have developed cell lines expressing either wild-type or a mutant importin-ß form in characterised residues required for nucleoporin binding. Both forms similarly disrupted spindle pole organisation, while only wild-type importin-ß affected microtubule plus-end function and microtubule stability. A proteome-wide search for differential interactors identified a set of spindle regulators sensitive to mutations in the nucleoporin-binding region. Among those, HURP (hepatoma up-regulated protein) is an importin-ß interactor and a microtubule-stabilising factor. We found that induction of wild type, but not mutant importin-ß, under the same conditions that destabilise mitotic microtubules, delocalised HURP, indicating that the spatial distribution of HURP along the spindle requires importin-ß's nucleoporin-binding residues. Concomitantly, importin-ß overexpression sensitises cells to taxanes and synergistically increases mitotic cell death. Thus, the nucleoporin-binding domain is dispensable for importin-ß function in spindle pole organisation, but regulates microtubule stability, at least in part via HURP, and renders cells vulnerable to certain microtubule-targeting drugs.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Microtúbulos/metabolismo , Mitose/efeitos dos fármacos , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Taxoides/farmacologia , beta Carioferinas/química , beta Carioferinas/metabolismo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Microtúbulos/efeitos dos fármacos , Paclitaxel/farmacologia , Ligação Proteica
11.
Prostate ; 80(1): 88-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31661167

RESUMO

BACKGROUND: Prostate cancer (PCa) remains the second leading cause of cancer-related death among men. Taxanes, such as docetaxel and cabazitaxel are utilized in standard treatment regimens for chemotherapy naïve castration-resistant PCa. However, tumors often develop resistance to taxane chemotherapeutics, highlighting a need to identify additional therapeutic targets. Fatty acid-binding protein 5 (FABP5) is an intracellular lipid carrier whose expression is upregulated in metastatic PCa and increases cell growth, invasion, and tumor formation. Here, we assessed whether FABP5 inhibitors synergize with semi-synthetic taxanes to induce cytotoxicity in vitro and attenuate tumor growth in vivo. METHODS: PC3, DU-145, and 22Rv1 PCa cells were incubated with FABP5 inhibitors Stony Brook fatty acid-binding protein inhibitor 102 (SBFI-102) or SBFI-103 in the presence or absence of docetaxel or cabazitaxel, and cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Cytotoxicity of SBFI-102 and SBFI-103 was also evaluated in noncancerous cells. For the in vivo studies, PC3 cells were subcutaneously implanted into BALB/c nude mice, which were subsequently treated with FABP5 inhibitors, docetaxel, or a combination of both. RESULTS: SBFI-102 and SBFI-103 produced cytotoxicity in the PCa cells. Coincubation of the PCa cells with FABP5 inhibitors and docetaxel or cabazitaxel produced synergistic cytotoxic effects in vitro. Treatment of mice with FABP5 inhibitors reduced tumor growth and a combination of FABP5 inhibitors with a submaximal dose of docetaxel reduced tumor growth to a larger extent than treatment with each drug alone. CONCLUSIONS: FABP5 inhibitors increase the cytotoxic and tumor-suppressive effects of taxanes in PCa cells. The ability of these drugs to synergize could permit more efficacious antitumor activity while allowing for dosages of docetaxel or cabazitaxel to be lowered, potentially decreasing taxane-resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Docetaxel/farmacologia , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Taxoides/farmacologia , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Docetaxel/administração & dosagem , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Anticancer Res ; 39(12): 6673-6684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810932

RESUMO

BACKGROUND/AIM: The aim of the study was to evaluate the antitumor potential and combination effects of chemotherapeutic drugs. MATERIALS AND METHODS: The cytotoxicity of 20 drip-type classical and molecular-targeted anticancer drugs was examined against 4 human oral squamous cell carcinoma cell lines and 5 human oral normal mesenchymal and epithelial cells. Cell cycle progression was monitored by a cell sorter. Combination effect was evaluated by combination index. RESULTS: Most of the classical anticancer drugs showed much higher antitumor activity than molecular-targeted drugs, except bortezomib. Among 12 classical anticancer drugs, taxanes and gemsitabine showed the highest tumor-specificity (TS) and potency-selectivity expression (PSE) values, whereas platinum analogs showed the least TS value. Combination of two classical or a classical and a molecular-targeted drug showed mostly additive or antagonistic effect. 5-FU and cisplatin did not produce a subG1 population, but induced G2/M or G1/S arrest, regardless of the addition of cetuximab. Cetuximab, nibolumab and bortezomib showed potent keratinocyte toxicity. CONCLUSION: The present TS monitoring system may provide useful information for building up the treatment regimens of anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias Bucais/tratamento farmacológico , Bortezomib/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cetuximab/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Fluoruracila/farmacologia , Hormese , Humanos , Técnicas In Vitro , Queratinócitos/efeitos dos fármacos , Mucosa Bucal/citologia , Nivolumabe/farmacologia , Compostos de Platina/farmacologia , Taxoides/farmacologia
13.
Proc Natl Acad Sci U S A ; 116(47): 23691-23697, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685623

RESUMO

Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.


Assuntos
Aneuploidia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/fisiologia , Paclitaxel/farmacologia , Proteínas Supressoras de Tumor/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Citocinese/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/fisiologia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Terapia Neoadjuvante , Invasividade Neoplásica/genética , Transplante de Neoplasias , Interferência de RNA , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/ultraestrutura , Taxoides/farmacologia , Imagem com Lapso de Tempo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
14.
Anticancer Res ; 39(10): 5505-5513, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570444

RESUMO

BACKGROUND/AIM: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood. PATIENTS AND METHODS: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined. RESULTS: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression. CONCLUSION: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteína 1 Homóloga a MutL/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Taxoides/farmacologia , Idoso , Antígeno Ca-125/metabolismo , Claudina-4/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão
15.
Life Sci ; 234: 116768, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445027

RESUMO

In prostate cancer development, the androgen receptor (AR) signaling plays a crucial role during both formation of early prostate lesions and progression to the lethal, incurable castration resistant stage. Accordingly, numerous approaches have been developed to inhibit AR activity including androgen deprivation therapy, application of the AR antagonists as well as the use of taxanes. However, these treatments, although effective initially, resistance inevitably occur for most of the patients within several years and limiting the therapeutic efficacy. Of note, alterations and reactivation of the AR signaling pathway have been demonstrated as the major reasons for the observed resistance. Accumulating evidences have suggested that synthesis of AR splicing variants, in particular, the constitutively active AR-V7, is one of the most important mechanisms that contribute to the abnormal AR signaling. In addition, clinical data also highlight the potential of using AR-V7 as a predictive biomarker and a therapeutic target in metastatic castration resistant prostate cancer (mCRPC). In this review, we summarize the recent findings concerning the specific role of AR-V7 in CRPC progression, drug resistance and its potential value in clinical assessment.


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Taxoides/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Antineoplásicos/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxoides/farmacologia
16.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412591

RESUMO

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Próstata/genética , Taxoides/farmacologia , Tubulina (Proteína)/genética , Linhagem Celular Tumoral , Cromonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Morfolinas/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Ligação Proteica , Tubulina (Proteína)/metabolismo
17.
Cancer Chemother Pharmacol ; 84(3): 487-499, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31309254

RESUMO

Enzymes of the cytochrome P450 (CYP) subfamily 3A and 2C play a major role in the metabolism of taxane anticancer agents. While their function in hepatic metabolism of taxanes is well established, expression of these enzymes in solid tumors may play a role in the in situ metabolism of drugs as well, potentially affecting the intrinsic taxane susceptibility of these tumors. This article reviews the available literature on intratumoral expression of docetaxel- and paclitaxel-metabolizing enzymes in mammary, prostate, lung, endometrial, and ovarian tumors. Furthermore, the clinical implications of the intratumoral expression of these enzymes are reviewed and the potential of concomitant treatment with protease inhibitors (PIs) as a method to inhibit CYP3A4-mediated metabolism is discussed.


Assuntos
Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Taxoides/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Neoplasias/enzimologia , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
18.
Molecules ; 24(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181726

RESUMO

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.


Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/química
19.
Biomed Pharmacother ; 116: 109001, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146114

RESUMO

Renal cell carcinoma (RCC) has always been considered resistant to chemotherapy. IR-780 is a near-infrared fluorescent (NIRF) dye that can be efficiently taken up by RCC cells. Cabazitaxel is a cytotoxic drug that interferes with mitosis by acting on tubulin. We chemically fused IR-780 and cabazitaxel into a new drug, Caba-780, which is expected to increase the sensitivity of RCC to chemotherapy. Infrared spectrum, nuclear magnetic resonance spectra, high-resolution mass spectra, and IR spectra were used for detecting structural characterization of the new synthetic drug Caba-780. The RCC cells lines ACHN and 786-O, as well as the non-cancerous human embryonic kidney cell line HEK293, were used to assess the cytotoxicity and tumor-efficient uptake of Caba-780 in vitro. The xenograft tumor-bearing mice and C57 mice were used to estimate the tumor-efficient imaging of Caba-780 as well as the safety and efficacy of its anti-tumor effects in vivo. The new synthetic drug Caba-780 retains the NIRF properties of IR-780. In vitro, Caba-780 was efficiently absorbed by the RCC cell lines ACHN and 786-O, and had an inhibitory effect on their growth, clonogenicity migration, and invasion. At the same time, Caba-780 retained the anti-tumor effect of cabazitaxel, which can inhibit the growth of tumor cells and promote apoptosis by inhibiting mitosis. In vivo experiments showed that Caba-780 can be taken up and imaged in tumor tissue, whereby it inhibits tumor growth. The novel fused molecule Caba-780 has application prospects in the diagnosis and treatment of RCC and makes RCC chemotherapy possible.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Raios Infravermelhos , Neoplasias Renais/tratamento farmacológico , Taxoides/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias Renais/patologia , Camundongos , Invasividade Neoplásica , Transportadores de Ânions Orgânicos/metabolismo , Frações Subcelulares/metabolismo , Taxoides/síntese química , Taxoides/química , Taxoides/farmacologia , Testes de Toxicidade Aguda
20.
Nat Commun ; 10(1): 2189, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097698

RESUMO

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Inibidores de Janus Quinases/farmacologia , Leucemia Experimental/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Linhagem Celular Tumoral , Criança , Pré-Escolar , Citarabina/farmacologia , Citarabina/uso terapêutico , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Lactente , Inibidores de Janus Quinases/uso terapêutico , Leucemia Experimental/etiologia , Leucemia Experimental/mortalidade , Leucemia Experimental/patologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Taxoides/farmacologia , Taxoides/uso terapêutico , Irradiação Corporal Total/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA