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1.
Anticancer Res ; 39(10): 5231-5259, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570421

RESUMO

BACKGROUND/AIM: Prostate cancer is one of the most common cancers in men which remains a global public health issue. Treatment of prostate cancer is becoming increasingly intensive and aggressive, with a corresponding increase in resistance, toxicity and side effects. This has revived an interest in nontoxic and cost-effective preventive strategies including dietary compounds due to the multiple effects they have been shown to have in various oncogenic signalling pathways, with relatively few significant adverse effects. MATERIALS AND METHODS: To identify such dietary components and micronutrients and define their prostate cancer-specific actions, we systematically reviewed the current literature for the pertinent mechanisms of action and effects on the modulation of prostate carcinogenesis, along with relevant updates from epidemiological and clinical studies. RESULTS: Evidence from various recent experimental, clinical and epidemiological studies indicates that select dietary micronutrients (i.e., lycopene, epigallocatechin gallate, sulforaphane, indole-3-carbinol, resveratrol, quercetin, curcumin & piperine) and zinc play a key role in prostate cancer prevention and progression and therefore hold great promise for the future overall management of prostate cancer. CONCLUSION: A formulation that comprises these micronutrients using the optimal, safest form and dosing should be investigated in future prostate cancer chemoprevention studies and as part of standard prostate cancer therapy.


Assuntos
Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/prevenção & controle , Animais , Quimioprevenção/métodos , Dieta/métodos , Estudos Epidemiológicos , Humanos , Masculino , Micronutrientes/farmacologia , Micronutrientes/uso terapêutico
2.
Anticancer Res ; 39(10): 5417-5425, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570436

RESUMO

BACKGROUND/AIM: Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate. MATERIALS AND METHODS: We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis. RESULTS: TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo. CONCLUSION: The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Autofagia/efeitos dos fármacos , Docetaxel/administração & dosagem , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Sirolimo/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células PC-3 , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/administração & dosagem
3.
Cancer Radiother ; 23(6-7): 496-499, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31471251

RESUMO

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias/radioterapia , Radiocirurgia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Terapia Combinada/métodos , Previsões , França , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
4.
Arch Esp Urol ; 72(7): 712-715, 2019 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31475684

RESUMO

OBJECTIVE: Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer. METHODS: We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase. RESULTS: To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate. CONCLUSIONS: We recognize that these clinical cases do not translate that estramustine acetate is a first line treatment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetate.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Estramustina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Humanos , Masculino
5.
Cancer Invest ; 37(9): 478-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31557062

RESUMO

Hypertension is associated with enzalutamide in the treatment of prostate cancer. We performed a meta-analysis of randomized clinical trials to determine the risk of hypertension. Databases including Pubmed and Google scholar were searched to identify randomized clinical trials with enzalutamide. A total of seven studies including 7347 patients were selected. The overall incidences of all-grade and high-grade hypertension were 11.9% (95%% CI: 8.8-16.0%) and 4.9% (95%% CI: 3.5-6.8%) respectively, with a relative risk of 2.82 (95%% CI: 2.34-3.38, p < 0.001) for all-grade and 2.27 (95%% CI: 1.73-2.96, p < 0.001) for high-grade. There was a significant risk of developing hypertension with enzalutamide.


Assuntos
Hipertensão/epidemiologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Humanos , Hipertensão/induzido quimicamente , Incidência , Masculino , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
BMJ ; 366: l5214, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554611

RESUMO

OBJECTIVE: To compare the risk and severity of prostate cancer between men achieving fatherhood by assisted reproduction and men conceiving naturally. DESIGN: National register based cohort study. SETTING: Sweden from January 1994 to December 2014. PARTICIPANTS: 1 181 490 children born alive in Sweden during 1994-2014 to the same number of fathers. Fathers were grouped according to fertility status by mode of conception: 20 618 by in vitro fertilisation (IVF), 14 882 by intra-cytoplasmic sperm injection (ICSI), and 1 145 990 by natural conception. MAIN OUTCOME MEASURES: Prostate cancer diagnosis, age of onset, and androgen deprivation therapy (serving as proxy for advanced or metastatic malignancy). RESULTS: Among men achieving fatherhood by IVF, by ICSI, and by non-assisted means, 77 (0.37%), 63 (0.42%), and 3244 (0.28%), respectively, were diagnosed as having prostate cancer. Mean age at onset was 55.9, 55.1, and 57.1 years, respectively. Men who became fathers through assisted reproduction had a statistically significantly increased risk of prostate cancer compared with men who conceived naturally (hazard ratio 1.64, 95% confidence interval 1.25 to 2.15, for ICSI; 1.33, 1.06 to 1.66, for IVF). They also had an increased risk of early onset disease (that is, diagnosis before age 55 years) (hazard ratio 1.86, 1.25 to 2.77, for ICSI; 1.51, 1.09 to 2.08, for IVF). Fathers who conceived through ICSI and developed prostate cancer received androgen deprivation therapy to at least the same extent as the reference group (odds ratio 1.91; P=0.07). CONCLUSIONS: Men who achieved fatherhood through assisted reproduction techniques, particularly through ICSI, are at increased risk for early onset prostate cancer and thus constitute a risk group in which testing and careful long term follow-up for prostate cancer may be beneficial.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Fertilização In Vitro/estatística & dados numéricos , Infertilidade Masculina/epidemiologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologia , Adulto , Idade de Início , Estudos de Coortes , Fertilização , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricos , Análise de Sobrevida , Suécia/epidemiologia
7.
Anticancer Res ; 39(9): 4811-4816, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519583

RESUMO

BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is highly expressed in many forms of cancer, and is a promising therapeutic target. The present study investigated whether inhibition of GGCT enhanced the antiproliferative effects of the drug docetaxel in prostate cancer cells. MATERIALS AND METHODS: Immunohistochemistry and western blot analysis were conducted to measure GGCT expression in prostate cancer tissue samples and cell lines. GGCT was inhibited using RNAi and a novel enzymatic inhibitor, pro-GA, and cell proliferation was evaluated with single and combination treatments of GGCT inhibitors and docetaxel. RESULTS: GGCT was highly expressed in cultured prostate cancer cells and patient samples. GGCT inhibition alone inhibited prostate cancer cell line proliferation and induced cellular senescence. GGCT inhibition in combination with apoptosis-inducing docetaxel had more potent antiproliferative effects than either drug used alone. CONCLUSION: GGCT inhibition may potentiate anticancer drug efficacy.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Inibidores Enzimáticos/farmacologia , gama-Glutamilciclotransferase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/genética , gama-Glutamilciclotransferase/genética , gama-Glutamilciclotransferase/metabolismo
8.
Medicine (Baltimore) ; 98(35): e17060, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464967

RESUMO

BACKGROUND: To evaluate the effectiveness and safety of neoadjuvant chemotherapy (NAC) for locally advance prostate patients undergoing radical prostatectomy. METHODS: PubMed/Medline, EMBASE, Web of Science, Ovid, Web of Knowledge, and Cochrane Library will be searched for studies related to the topic. The identification, inclusion and exclusion flow charts will be conducted according to PRISMA guidelines. The identified reports will be critically appraised using GRADE approach. Bias and heterogeneity of included studies will be assessed, and outcome measurements from individual studies will be combined with 95% confidence interval using a fixed- or random-effects model if qualified. RESULTS: This study will provide evidence and data on the tolerance and efficacy of NAC followed by radical prostatectomy (RP). CONCLUSION: The application of taxanes-based chemotherapy has been widened to metastatic hormone sensitive prostate cancer in recent years. To be more vigorous, whether neoadjuvant administration of these cytotoxic agents can improve the outcome of RP in locally advance prostate cancer patients has been explored. This study aims to synthesis data regarding the adverse effect, response rate, recurrence, and survival from multiple trials, and to guide the healthcare practitioners using an evidence-based approach.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Fatores Etários , Quimioterapia Adjuvante , Humanos , Masculino , Projetos de Pesquisa , Fatores Socioeconômicos
9.
Life Sci ; 235: 116791, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31465732

RESUMO

AIMS: Prostate cancer (PCa) incidence rates are rising in China currently. Cancer-associated fibroblasts (CAFs), as a major component of tumor microenvironment, are crucial for tumor progression. This study was aimed to explore the promotion effect of patient-derived CAFs on the proliferation and migration of prostate cancer cells. MAIN METHODS: CAFs were isolated from tumor tissues of PCa patients. The promotion effect of CAFs on the proliferation and migration of PC-3 and LNCaP cells were evaluated in vitro and in vivo. The concentration of TGF-ß1 was measured by Luminex assay. The blocking activity of LY2109761 on the promotion effect of CAFs was also evaluated. KEY FINDINGS: CAFs could significantly promote the proliferation and migration of PC-3 and LNCaP cells both in vitro and in vivo. TGF-ß1 was identified as a highly increased factor in CAFs-CM compared with the normal culture medium of these two cancer cell lines. TGF-ß receptor inhibitor LY2109761 could suppress the CAFs-induced cellular proliferation and migration of PC-3 cells but not LNCaP cells. SIGNIFICANCE: Our study suggested a crucial role for CAFs and TGF-ß signaling in the progression of PCa. Zebrafish xenograft model was an ideal animal model for the study of CAFs and cancer cell interaction.


Assuntos
Fibroblastos Associados a Câncer , Movimento Celular , Proliferação de Células , Embrião não Mamífero/patologia , Neoplasias da Próstata/patologia , Pirazóis/farmacologia , Pirróis/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
10.
Bratisl Lek Listy ; 120(8): 601-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379184

RESUMO

Gonadotropin-releasing hormone agonists were described as anti-angiogenic factors in tumors. Simultaneously they were associated with increased cardiovascular risk in patients treated for prostate cancer, especially in those with preexisting cardiac disease. Studies aiming to elucidate the mechanisms by which androgen deprivation therapy causes cardiovascular effects are rare. We believe that gonadotropin-releasing hormone agonists can impair myocardial angiogenesis. That, in patients with myocardial disease can deepen hypoxia, significantly worsen the condition of the myocardium, and therefore increase the risk of cardiac failure. Careful assessment of the myocardial status and consequent timing and typing of therapy can minimalize the adverse effects. Ideally through close cooperation between cardiologists and oncologists (Fig. 1, Ref. 25). Keywords: angiogenesis, cardiovascular risk, follicle stimulating hormone, GnRH agonist, testosterone.


Assuntos
Antagonistas de Androgênios/farmacologia , Hormônio Liberador de Gonadotropina/agonistas , Cardiopatias/induzido quimicamente , Antagonistas de Androgênios/efeitos adversos , Humanos , Masculino , Miocárdio , Neoplasias da Próstata/tratamento farmacológico
11.
Life Sci ; 233: 116730, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31390552

RESUMO

AIMS: Dihydroartemisinin (DHA) exhibits potential anticancer activity. However, the biological functions of DHA in prostate cancer remain largely unexplored. In this study, we aim to investigate the anti-proliferative effect and glycolysis regulation of DHA on prostate cancer cell LNCaP. MAIN METHODS: Cell proliferative activity and apoptosis inducing were detected. The gene expression was detected by mRNA microarray and results were analyzed by GO and KEGG pathway database. Expressions of glycolysis key enzymes and PI3K/AKT/HIF-1α were detected by Western blot. KEY FINDINGS: Results indicated that DHA could inhibit the LNCaP cell proliferation considerably and induce cell apoptosis. mRNA microarray showed 1293 genes were upregulated and 2322 genes were downregulated. GO and KEGG enrichment analysis suggested that glycolysis pathway was correlated with DHA inhibited the proliferation on the LNCaP cell. Western blot results showed that DHA can decrease GLUT1 and regulatory enzymes of glycolytic pathway expression probably by suppressing the activity of the intracellular Akt/mTOR and HIF-1 α. SIGNIFICANCE: Experimental validation results indicate that DHA treatment can inhibit the LNCaP cell proliferation and induce apoptosis, which may be related to glycolysis inhibition.


Assuntos
Artemisininas/farmacologia , Biomarcadores Tumorais/metabolismo , Glicólise/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Antimaláricos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
13.
Eur J Med Chem ; 179: 660-666, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279298

RESUMO

Prostate cancer is the most diagnosed type of cancer in men in Canada. One out of eight men will be stricken with this disease during the course of his life. It is noteworthy that, at initial diagnoses 80-90% of cancers are androgen dependent. Hence, the androgen receptor is a viable biological target to be considered for drug targeting. We have developed a new generation of testosterone-Pt(II) hybrids for site-specific treatment of hormone-dependent prostate cancer. The hybrid molecules are made from testosterone using an eight-step reaction sequence with about 7% overall yield. They are linked with a stronger tether chain between the testosterone moiety and the Pt(II) moiety in comparison to our first generation hybrids. The new hybrids were tested on hormone-dependent and -independent prostate cancer cell lines. The hybrid 3a presents the best antiproliferative activity and was selective on hormone-dependent prostate cancer with IC50 of 2.2 µM on LNCaP (AR+) in comparison to 13.3 µM on PC3 (AR-) and 8.8 µM on DU145 (AR-) prostate cancer cells. On the same cell lines, CDDP displayed IC50 of 2.1 µM, 0.5 µM and 1.0 µM, respectively. Remarkably, hybrid 3a was inactive on both colon carcinoma (HT-29) and normal human adult keratinocyte cells (HaCat) with an IC50 of >25 µM. This is not the case for CDDP showing IC50 of 1.3 µM and 5.1 µM on HT-29 and HaCat cells, respectively. The potential for selective activity on androgen-receptor positive prostate cancer cells is confirmed with hybrid 3a giving new hope for an efficient and less toxic platinum-based treatment of prostate cancer patients.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Testosterona/química
14.
Eur J Med Chem ; 180: 1-14, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31288149

RESUMO

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Nitrilos/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/farmacologia , Anilidas/síntese química , Anilidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nitrilos/síntese química , Nitrilos/química , Feniltioidantoína/síntese química , Feniltioidantoína/química , Feniltioidantoína/farmacologia , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Compostos de Tosil/síntese química , Compostos de Tosil/química
15.
Eur J Med Chem ; 179: 483-492, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271960

RESUMO

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.


Assuntos
Androstadienos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Androstadienos/síntese química , Androstadienos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade
16.
Planta Med ; 85(11-12): 997-1007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288278

RESUMO

Silymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.


Assuntos
Doxorrubicina/uso terapêutico , Cardo Mariano/química , Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Silimarina/uso terapêutico , Western Blotting , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Masculino , Células PC-3/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Silimarina/isolamento & purificação
17.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 283-288, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257814

RESUMO

OBJECTIVE: To investigate the effects of tectochrysin on prostate cancer cell line 22Rv.1 and reveal its molecular mechanism. METHODS: Tectochrysin at the concentrations of 0~20 µg/ml was applied to 22Rv.1 cells and normal prostate cell RWPE-1. The proliferation activity of the cells was detected by MTS assay. Flow cytometry and hoechst 33342 staining were used to analyze the effects of drugs on cell apoptosis, death, cell cycle and nuclear type changes. LDH release test was used to analyze the cytotoxicity of the drug to 22Rv.1 cells. QPCR and Western blot were used to analyze the effects of the drug on the expressions of genes in 22Rv.1 cells. Finally, the tumor inhibited effect of the drug on the bearing tumor BALB/c mice were confirmed though anti-tumor experiment. RESULTS: Tectochrysin could significantly inhibit the proliferation activity of 22Rv.1 cells and induced their apoptosis, and promoted the expressions of genes dr4, dr5, trail, p53, caspase-3, caspase-8, caspase-9, bid, bax and foxo3, inhibited the expressions of anti-apoptotic genes akt, pi3k and bcl-2. CONCLUSION: Tectochrysin can induce prostate cancer cells apoptosis through affecting TRAIL and PI3K/AKT signaling pathways, and has anti-prostate cancer effect.


Assuntos
Apoptose , Flavonoides/farmacologia , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias da Próstata/tratamento farmacológico , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
18.
J Nanobiotechnology ; 17(1): 83, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291948

RESUMO

BACKGROUND: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. RESULTS: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. CONCLUSIONS: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.


Assuntos
Antineoplásicos/química , Materiais Biomiméticos/química , Portadores de Fármacos/química , Macrófagos/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Grafite/química , Humanos , Hipertermia Induzida , Raios Infravermelhos , Lasers , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Distribuição Tecidual
19.
Expert Opin Drug Saf ; 18(9): 759-767, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31353982

RESUMO

Introduction: To evaluate the safety profile characteristics of abiraterone acetate (AA) in the treatment of metastatic prostate cancer (mPCa). Areas covered: In this literature review the authors evaluate safety data from phase III trials investigating the combination of abiraterone acetate plus prednisone (AAP) in patients with metastatic prostate cancer. In particular, the aim was to clarify its toxicity profile, long-term exposure impact, and the correlation with general health-related quality of life (HRQoL). Expert opinion: Based on the studies reviewed, it appears that abiraterone acetate has favourable outcomes, is effective and well tolerated, mostly in asymptomatic or slightly symptomatic patients, and has recognised toxicity profile characteristics. Incidence of adverse events (AEs), such as mineralocorticoid- and corticosteroid-releated AEs, and hepatotoxicity is well known and widely described. Understanding the toxicity profile of AA could assist decision-making in clinical practice.


Assuntos
Acetato de Abiraterona/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Acetato de Abiraterona/efeitos adversos , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Masculino , Metástase Neoplásica , Prednisona/administração & dosagem , Neoplasias da Próstata/patologia , Qualidade de Vida
20.
Anticancer Res ; 39(7): 3469-3485, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262871

RESUMO

BACKGROUND/AIM: Isothiocyanates (ITCs) are phytochemicals with potential cancer-preventative properties derived from the breakdown of glucosinolates that exist in cruciferous vegetables. Studies, to date, have demonstrated that various ITCs possess the ability to act as anticancer agents in different cancer types. This study investigated the anticancer properties of dietary ITCs (allyl-ITC, benzyl-ITC, phenylethyl-ITC) and synthetic (phenylbutyl-ITC and phenylhexyl-ITC) on liver and prostate carcinoma cells in vitro. MATERIALS AND METHODS: The effects of ITCs on cellular viability, migration, invasion, clonogenicity, apoptosis induction and reactive oxygen species generation were assessed in HepG2, DU145 and 22Rv1 cells. RESULTS: All ITCs reduced metabolic activity in each cell line with the most significant being phenylethyl-ITC. Both dietary and synthetic ITCs suppressed the migratory and invasive potential of all cell lines, inhibited colony-forming capability and induced apoptosis. Phenylethyl-ITC exposure resulted in the significant generation of reactive oxygen species. CONCLUSION: These data highlight the potential advantages of utilizing ITCs to delay the carcinogenic process and the potential for dietary and synthetic ITCs to act as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Isotiocianatos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Neoplasias da Próstata/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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