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1.
PLoS One ; 9(9): e107142, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25216266

RESUMEN

OBJECTIVE: Aldehyde dehydrogenase (ALDH) expressing cells have been characterized as possessing stem cell-like properties. We evaluated ALDH+ ovarian cancer stem cell-like properties and their role in platinum resistance. METHODS: Isogenic ovarian cancer cell lines for platinum sensitivity (A2780) and platinum resistant (A2780/CP70) as well as ascites from ovarian cancer patients were analyzed for ALDH+ by flow cytometry to determine its association to platinum resistance, recurrence and survival. A stable shRNA knockdown model for ALDH1A1 was utilized to determine its effect on cancer stem cell-like properties, cell cycle checkpoints, and DNA repair mediators. RESULTS: ALDH status directly correlated to platinum resistance in primary ovarian cancer samples obtained from ascites. Patients with ALDHHIGH displayed significantly lower progression free survival than the patients with ALDHLOW cells (9 vs. 3 months, respectively p<0.01). ALDH1A1-knockdown significantly attenuated clonogenic potential, PARP-1 protein levels, and reversed inherent platinum resistance. ALDH1A1-knockdown resulted in dramatic decrease of KLF4 and p21 protein levels thereby leading to S and G2 phase accumulation of cells. Increases in S and G2 cells demonstrated increased expression of replication stress associated Fanconi Anemia DNA repair proteins (FANCD2, FANCJ) and replication checkpoint (pS317 Chk1) were affected. ALDH1A1-knockdown induced DNA damage, evidenced by robust induction of γ-H2AX and BAX mediated apoptosis, with significant increases in BRCA1 expression, suggesting ALDH1A1-dependent regulation of cell cycle checkpoints and DNA repair networks in ovarian cancer stem-like cells. CONCLUSION: This data suggests that ovarian cancer cells expressing ALDH1A1 may maintain platinum resistance by altered regulation of cell cycle checkpoint and DNA repair network signaling.


Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Puntos de Control del Ciclo Celular , Reparación del ADN , Células Madre Neoplásicas/patología , Neoplasias Ováricas/patología , Transducción de Señal , Familia de Aldehído Deshidrogenasa 1 , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Reparación del ADN/efectos de los fármacos , Supervivencia sin Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Isoenzimas/metabolismo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Neoplasias Ováricas/tratamiento farmacológico , Fenotipo , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Retinal-Deshidrogenasa , Transducción de Señal/efectos de los fármacos
2.
PLoS One ; 9(6): e98370, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24896091

RESUMEN

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly diverse group that is associated with an aggressive phenotype. Its treatment has been challenging due to its heterogeneity and absence of well-defined molecular targets. Thus, there is an urgent need to identify novel agents with therapeutic application. NF-κB is over-expressed in many breast cancers; thus, inactivation of the NF-κB pathway could serve as a therapeutic target. Here we report for the first time the anti-tumor activity of panepoxydone (PP), a NF-κB inhibitor isolated from an edible mushroom, in several breast cancer cell lines. METHODS: We investigated the effects of PP on cell growth, migration-invasion, apoptosis and EMT-related proteins expression in MCF-7 and TNBC cell lines MDA-MB-231, MDA-MB-468 and MDA-MB-453. RESULTS: Significant antitumor activity was seen in all cell lines, with differential responses noted in cell-line specific manner. Treatment with PP resulted in significant cytotoxicity, decreased invasion, migration and increased apoptosis in all cell lines tested. Up-regulation of Bax and cleaved PARP and down-regulation of Bcl-2, survivin, cyclin D1 and caspase 3 were noted in PP-treated breast cancer cells. The antitumor effect of PP appeared related to its ability to inhibit the phosphorylation of inhibitor of NF-κB (IκBα) with cytoplasmic accumulation. PP treatment also down-regulated FOXM1 which resulted in a reversal of EMT. Similar results were obtained after silencing of NF-kB and FOXM1. CONCLUSION: Altogether, these studies show, for the first time the antitumor activity of PP against breast cancer cells, in particular TNBC cells. Furthermore, it highlights the concept that optimal treatment of TNBC warrants attention to the differential sensitivity of various TNBC subtypes to therapeutic agents. These results suggest that the PP may be a potentially effective chemopreventive or therapeutic agent against breast cancer. However, additional studies are required to more fully elucidate the mechanism of antitumor effect of PP.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , FN-kappa B/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Proteína Forkhead Box M1 , Humanos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos
3.
Oncol Rep ; 32(2): 469-74, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24926795

RESUMEN

Cellular resistance to platinum anticancer compounds is governed by no less than two molecular processes; DNA repair and cellular accumulation of drug. Gli1 is an upstream regulator of nucleotide excision repair, effecting this process through c-jun. We, therefore, investigated whether Gli1 plays a role in cellular accumulation of cisplatin. Using a Gli1-specific shRNA, we explored the role of Gli1 in the cellular accumulation and efflux of cisplatin, in cisplatin-resistant A2780-CP70 human ovarian cancer cells. When Gli1 is inhibited, cellular uptake of cisplatin was approximately 33% of the level of uptake under control conditions. When Gli1 is inhibited, cellular efflux of cisplatin was completely abrogated, over a 12-h period of observation. We assayed nuclear lysates from these cells, for the ability to bind the DNA sequence that is the Gli-binding site (GBS) in the 5'UTR for each of five known cisplatin transmembrane transporters. Four of these transporters are active in cisplatin uptake; and, one is active in cisplatin efflux. In each case, nuclear lysate from A2780-CP70 cells binds the GBS of the respective cisplatin transport gene. We conclude that Gli1 plays a strong role in total cellular accumulation of cisplatin in these cells; and, that the combined effects on cellular accumulation of drug and on DNA repair may indicate a role for Gli1 in protecting cellular DNA from lethal types of DNA damage.


Asunto(s)
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Resistencia a Antineoplásicos , Neoplasias Ováricas/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Sitios de Unión , Proteínas de Transporte de Catión/metabolismo , Línea Celular Tumoral , Transportador de Cobre 1 , Daño del ADN , Femenino , Humanos , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteína con Dedos de Zinc GLI1
4.
Gynecol Oncol ; 134(1): 160-3, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24796634

RESUMEN

OBJECTIVES: Gynecologic oncology patients undergoing surgery are at an increased risk for venous thromboembolism (VTE). We attempted to validate a VTE risk assessment model in gynecologic oncology patients. METHODS: All gynecologic oncology patients who underwent a laparotomy for the diagnosis or suspicion of gynecologic malignancy from 2004 to 2010 were included. Demographic, surgicopathologic, and complication data were collected. VTE was based on the symptomatic diagnosis. Data for the Caprini risk assessment model (RAM) was used to score and stratify patients on their risk for VTE. RESULTS: 1123 gynecologic oncology patients were included within this study. Ovarian cancer was the most common diagnosis (39%) with a median age of 56.1. All patients received SCDs with 40% receiving double prophylaxis. The overall incidence of VTE was 3.3%, with lower extremity deep venous thrombosis (DVT) n=17 and pulmonary embolism (PE) n=20. Complication rates were similar in each group. Based on the Caprini scoring model 92% of patients scored in the "Highest Risk" category. The Caprini RAM accurately predicted all 37 VTEs, all of which scored in the "Highest Risk" category. The percentage of patients that received double prophylaxis increased with time from 12% in 2004 to 63% in 2010. Importantly, 25 of the 37 VTEs (68%) did not receive double prophylaxis. CONCLUSIONS: The use of the Caprini RAM accurately predicted patients at the highest risk of experiencing VTE. Considering accurate identification of patients allows proper administration of double prophylaxis, we recommend the use of this scoring model preoperatively in patients undergoing surgery for gynecologic malignancies.


Asunto(s)
Neoplasias de los Genitales Femeninos/sangre , Neoplasias de los Genitales Femeninos/cirugía , Modelos Estadísticos , Medición de Riesgo/métodos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/prevención & control , Adulto , Femenino , Neoplasias de los Genitales Femeninos/patología , Humanos , Laparotomía/métodos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Medición de Riesgo/normas , Tromboembolia Venosa/patología
5.
Int J Oncol ; 44(3): 655-61, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24366538

RESUMEN

The Hedgehog pathway is molecularly linked to increased resistance to cisplatin and increased repair of platinum-DNA damage, through C-JUN. GLI1, which has five known isoforms, is a positive transcriptional regulator in Hedgehog. Southwestern blot assay, EMSA and ChIP assays indicate that only one of five isoforms of GLI1 may be responsible for the Hedgehog link with C-JUN and thus, increased platinum-DNA adduct repair. Cancer tissues express this 130-kDa isoform at levels 6-fold higher than non-malignant tissues; and this isoform exists in abundance in six of seven ovarian cancer cell lines examined.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Cisplatino/uso terapéutico , Daño del ADN/efectos de los fármacos , Femenino , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Proteína con Dedos de Zinc GLI1
6.
Int J Oncol ; 43(3): 721-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23817665

RESUMEN

ß-Elemene is a promising new plant-derived drug with broad-spectrum anticancer activity. It also increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human carcinoma cells. However, little is known about the mechanism of its action. To explore the potential therapeutic application of ß-elemene as a drug-resistance modulator, this study investigated the underlying mechanism of ß-elemene activity in cisplatin-resistant ovarian cancer cells. ß-Elemene enhanced cisplatin sensitivity to a much greater extent in chemoresistant A2780/CP70 and MCAS human ovarian carcinoma cells compared to the chemosensitive parental cell line A2780. The dose-modifying factors for cisplatin were between 35 and 60 for A2780/CP70 cells and between 1.6 and 2.5 for A2780 cells. In the cisplatin-resistant ovarian carcinoma cells, ß-elemene abrogated cisplatin­induced expression of excision repair cross-complementation group­1 (ERCC-1), a marker gene in the nucleotide excision repair pathway that repairs cisplatin-caused DNA damage. In addition, ß-elemene not only reduced the level of X-linked inhibitor of apoptosis protein (XIAP), but also downregulated cisplatin-mediated XIAP expression in chemoresistant cells. Furthermore, ß-elemene blocked the cisplatin-stimulated increase in the level of phosphorylated c-Jun NH2-terminal kinase (JNK) in these cells. These novel findings suggest that the ß-elemene enhancement of cisplatin sensitivity in human chemoresistant ovarian cancer cells is mediated at least in part through the impairment of DNA repair activity and the activation of apoptotic signaling pathways, thereby making resistant ovarian cancer cells susceptible to cisplatin-induced cell death.


Asunto(s)
Carcinoma/tratamiento farmacológico , Proteínas de Unión al ADN/biosíntesis , Endonucleasas/biosíntesis , Proteínas Quinasas JNK Activadas por Mitógenos/biosíntesis , Neoplasias Ováricas/tratamiento farmacológico , Proteína Inhibidora de la Apoptosis Ligada a X/biosíntesis , Apoptosis/efectos de los fármacos , Carcinoma/genética , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Endonucleasas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Sesquiterpenos/administración & dosificación , Proteína Inhibidora de la Apoptosis Ligada a X/genética
7.
Anticancer Res ; 33(4): 1421-8, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23564782

RESUMEN

Cisplatin-based combination treatment is the most effective systemic chemotherapy for bladder cancer; however, resistance to cisplatin remains a significant problem in the treatment of this disease. ß-Elemene is a new natural compound that blocks cell-cycle progression and has a broad spectrum of antitumor activity. This study was conducted to explore the potential of ß-elemene as a chemosensitizer for enhancing the therapeutic efficacy and potency of cisplatin in bladder cancer and other solid carcinomas. ß-Elemene not only markedly inhibited cell growth and proliferation but also substantially increased cisplatin cytotoxicity towards human bladder cancer 5637 and T-24 cells. Similarly, ß-elemene also enhanced cisplatin sensitivity and augmented cisplatin cytotoxicity in small-cell lung cancer and carcinomas of the brain, breast, cervix, ovary, and colorectal tract in vitro, with dose-modifying factors ranging from 5 to 124. ß-Elemene-enhanced cisplatin cytotoxicity was associated with increased apoptotic cell death, as determined by DNA fragmentation, and increased activities of caspase-3, -7, -8, -9, and -10 in bladder cancer cell lines. Collectively, these results suggest that ß-elemene augments the antitumor activity of cisplatin in human bladder cancer by enhancing the induction of cellular apoptosis via a caspase-dependent mechanism. Cisplatin combined with ß-elemene as a chemosensitizer warrants further pre-clinical therapeutic studies and may be useful for the treatment of cisplatin-resistant bladder cancer and other types of carcinomas.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Sesquiterpenos/farmacología , Neoplasias de la Vejiga Urinaria/patología , Protocolos de Quimioterapia Combinada Antineoplásica , Western Blotting , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo
8.
J Hum Lact ; 29(4): 469-72, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23492761

RESUMEN

Cisplatin, a platinum-based chemotherapy agent, is commonly used in treating cancers that may affect women of childbearing age, including cervical cancer, triple-negative breast cancer, and pediatric tumors in adolescents. The authors found that platinum was undetectable in breast milk at 66 hours and beyond following a 70-mg dose of intravenous cisplatin. Relative infant dose of platinum was calculated to be between 0.29% and 0.40% of the maternal dose corrected for body weight. This case demonstrates minimal exposure to platinum via breast milk, following a single 70-mg intravenous dose of cisplatin.


Asunto(s)
Lactancia Materna , Cisplatino/análisis , Cisplatino/farmacocinética , Leche Humana/química , Adenocarcinoma/tratamiento farmacológico , Adulto , Cisplatino/uso terapéutico , Femenino , Humanos , Lactante , Factores de Tiempo , Neoplasias del Cuello Uterino/tratamiento farmacológico
9.
Anticancer Res ; 33(3): 929-40, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23482764

RESUMEN

ß-Elemene, originally derived from plants, has been recently investigated as a new anticancer agent. The purpose of this study was to explore the efficacy and mechanisms of action of the combined use of ß-elemene plus a taxane as an antitumor therapeutic strategy for ovarian cancer and other carcinomas. The interaction of ß-elemene with paclitaxel or docetaxel produced additive to moderately synergistic effects against the platinum-resistant ovarian cancer cell line A2780/CP70 and its parental cell line A2780, and showed moderately synergistic activity against PC-3 prostate cancer cells. In addition, the co-administration of ß-elemene and a taxane at low-micromolar concentrations dramatically increased the rate of micronucleus formation and the percentage of mitotic arrest in both ovarian cancer cell lines, as compared with treatment with either agent alone. The highest synergy towards the ovarian cancer cells was observed with ß-elemene plus docetaxel. Consistent with these data, treatment of A2780/CP70 cells with ß-elemene plus a taxane strikingly reduced cell viability and increased cell apoptosis, as assessed by annexin V binding. Moreover, ß-elemene plus docetaxel induced elevated levels of caspase-9 and p53 proteins in A2780/CP70 cells, and the combination of ß-elemene plus a taxane caused marked cell-cycle arrest at the G2/M phase in these cells. One possible mechanism to account for the enhanced cytotoxic efficacy of this combination treatment is a ß-elemene-induced increase in taxane influx into cancer cells. These observations indicate that combination therapy with ß-elemene and taxanes has synergistic antitumor activity against ovarian and prostate carcinomas in vitro. This promising new therapeutic combination warrants further pre-clinical exploration for the treatment of chemoresistant ovarian cancer and other types of tumors.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Sesquiterpenos/farmacología , Taxoides/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Docetaxel , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Ováricas/patología , Paclitaxel/farmacología
10.
Med Oncol ; 30(1): 488, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23397083

RESUMEN

The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that ß-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether ß-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. ß-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, ß-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G(2)/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, ß-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21(Cip1/Waf1), p27(Kip1), and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the ß-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G(2)/M. A comparison of the cytotoxic efficacies of ß-elemene and three synthetic analogs (ß-elemenol, ß-elemenal, and ß-elemene fluoride) in the two lung cancer cell lines revealed that ß-elemenol and ß-elemene fluoride had the same antitumor efficacy as ß-elemene, whereas ß-elemenal was appreciably more potent than ß-elemene. Thus, although all three synthetic analogs of ß-elemene considerably suppressed NSCLC cell growth and proliferation, ß-elemenal may have greater potential as an anticancer alternative to ß-elemene in treating lung cancer and other tumors.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sesquiterpenos/farmacología , Proteína Quinasa CDC2 , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa de Punto de Control 2 , Ciclina B/metabolismo , Quinasas Ciclina-Dependientes , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo
11.
Cancer Chemother Pharmacol ; 71(4): 965-72, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23370663

RESUMEN

PURPOSE: This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1-7) for reduction in Grade 3-4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1-7) in platelet production and retention of scheduled dose intensity were also determined. METHODS: Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle. RESULTS: There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo. CONCLUSIONS: A 100 mcg/kg dose of A(1-7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3-4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1-7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.


Asunto(s)
Angiotensina I/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Trombocitopenia/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/efectos de los fármacos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Gemcitabina
12.
BMJ Open ; 3(1)2013 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-23293248

RESUMEN

OBJECTIVES: Although it does not alter the ERCC1 phenotype, the ERCC1 500C>T (rs11615) polymorphism has undergone a myriad of investigations into its role as a marker for nucleotide excision repair (NER) function in different races, diseases and treatment outcomes. The goal of our study was to test the hypothesis that 500C>T is in linkage disequilibrium (LD) with causative alleles, and that these haplotypes are more frequent in Caucasians with melanoma than in healthy Caucasians or African Americans. DESIGN: In this case-control study, we selected race-specific ERCC1 single-nucleotide polymorphism (SNPs), conducted LD analysis with ERCC1 500C>T and compared the frequency of ERCC1 diplotypes in Caucasians with melanoma (n=165), healthy Caucasians (n=150) and healthy African Americans (n=159). The haplotype was further studied using a fusion gene containing multiple ERCC1 SNPs. SETTING: Large cancer institute in the USA. PARTICIPANTS: A total of 165 Caucasian melanoma patients, 159 healthy Caucasian controls and 159 African American healthy controls. Men and women were enrolled in the clinical trial; however, since the screening trial included prostate cancer screening in addition to screening for other cancers, only male controls were available. OUTCOME MEASURES: The outcome measures were melanoma risk in Caucasians, and LD between ERCC1 SNP, N118N and other race-specific allelic variants. RESULTS: When compared to ERCC1 500C>T alone, a race-specific three-SNP variant haplotype in ERCC1 (comprised of rs11615, rs3212950 and rs3212948) was even more frequent in Caucasians with melanoma than in healthy Caucasians (p=0.0034) or African Americans (p<0.0001). A plasmid containing the variant haplotype was not differentially expressed. CONCLUSIONS: We demonstrate that ERCC1 500C>T participates in a previously characterised cancer-risk haplotype found more frequently in Caucasians, while LD is weak in African Americans; this haplotype appears to also be related to melanoma. It is therefore likely that ERCC1 500C>T is only a valid NER, disease or treatment outcome marker in Caucasians.

13.
Med Oncol ; 30(1): 424, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23277286

RESUMEN

ß-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that ß-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether ß-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that ß-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose- and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, ß-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated with both agents. Furthermore, ß-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (ΔΨ (m)) and increased the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-X(L) in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that ß-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of ß-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria- and caspase-dependent cell death pathway.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Ováricas , Sesquiterpenos/farmacología , Western Blotting , Línea Celular Tumoral , Cisplatino/farmacología , Sinergismo Farmacológico , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Potencial de la Membrana Mitocondrial/efectos de los fármacos
14.
Anticancer Res ; 32(8): 3103-13, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22843880

RESUMEN

The development of cisplatin drug resistance remains a chief concern in ovarian cancer chemotherapy. ß-Elemene is a natural plant product with broad-spectrum antitumor activity towards many types of carcinomas. This study aimed to define the biological and therapeutic significance of ß-elemene in chemoresistant ovarian cancer. In the present study, ß-elemene significantly inhibited cell growth and proliferation of both the cisplatin-sensitive human ovarian cancer cell line A2780 and its cisplatin-resistant counterpart A2780/CP. ß-Elemene also suppressed the growth of several other chemosensitive and chemoresistant ovarian cancer cell lines, including ES-2, MCAS, OVCAR-3, and SKOV-3, with the half maximal inhibitory concentration (IC(50)) values ranging from 54 to 78 µg/ml. In contrast, the IC(50) values of ß-elemene for the human ovarian epithelial cell lines IOSE-386 and IOSE-397 were 110 and 114 µg/ml, respectively, which are almost two-fold those for the ovarian cancer cell lines. Cell cycle analysis demonstrated that ß-elemene induced a persistent block of cell cycle progression at the G(2)/M phase in A2780 and A2780/CP cells. This was mediated by alterations in cyclin and cyclin-dependent kinase expression, including the down-regulation of CDC2, cyclin A, and cyclin B1, and the up-regulation of p21(WAF1/CIP1) and p53 proteins. Moreover, ß-elemene triggered apoptosis and irreversible cell death in both sensitive and resistant ovarian cancer cells via the activation of caspase-3, -8 and 9; the loss of mitochondrial membrane potential (δΨm); the release of cytochrome c into the cytosol; and changes in the expression of BCL-2 family proteins. All of these molecular changes were associated with ß-elemene-induced growth inhibition and cell death of ovarian cancer cells. Our results demonstrate that ß-elemene has antitumor activity against both platinum-sensitive and resistant ovarian cancer cells, and thus has the potential for development as a chemotherapeutic agent for cisplatin-resistant ovarian cancer.


Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Resistencia a Antineoplásicos , Neoplasias Ováricas/patología , Sesquiterpenos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ
15.
J Cancer Educ ; 27(4): 687-94, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22829231

RESUMEN

In order to inform efforts to increase screening rates for colorectal cancer (CRC), we conducted a survey of Alabama primary care physicians regarding CRC screening practices, educational preferences, and perceptions of obstacles to screening. A mail survey of 2,378 Alabama physicians in Family Medicine, Internal Medicine, and Obstetrics & Gynecology was conducted. Many physicians are not fully up-to-date with current CRC screening practices that could improve patient compliance with screening guidelines. One example is the potential use of high-sensitivity stool tests, such as the fecal immunochemical test, instead of the no longer recommended low-sensitivity guaiac fecal occult blood tests. In addition, enhanced multimedia and web-based approaches to educating physicians and patients could be more fully utilized. Further, greater use of health information technologies could increase screening rates. Enhancing primary care physicians' knowledge of screening modalities and increasing their use of electronic technology could significantly improve colorectal cancer screening outcomes.


Asunto(s)
Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/estadística & datos numéricos , Adhesión a Directriz , Pautas de la Práctica en Medicina/estadística & datos numéricos , Atención Primaria de Salud/normas , Actitud del Personal de Salud , Neoplasias Colorrectales/prevención & control , Humanos , Atención Primaria de Salud/tendencias , Encuestas y Cuestionarios
16.
Int J Gynecol Cancer ; 22(5): 786-91, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22552832

RESUMEN

OBJECTIVE: Considering the paucity of data relating erythropoiesis-stimulating agent (ESA) use to ovarian cancer survival, our objective was to evaluate the effect of ESA as used for the treatment of chemotherapy-induced anemia (CIA) on survival in ovarian cancer patients. MATERIALS AND METHODS: A multi-institution retrospective chart review was performed on ovarian cancer patients. Data collection included patient demographic, surgicopathologic, chemotherapy, ESA, and survival data. Patients were stratified by ever-use of ESA and were compared using appropriate statistical methods. RESULTS: A total of 581 patients were eligible for analysis with 39% (n = 229) patients with ever-use of ESA (ESA-YES) and 61% (n = 352) never-use ESA (ESA-NO). Mean age was 60.4 years with most patients having stage IIIC (60%) of papillary serous histological diagnosis (64%) with an optimal cytoreduction (67%). Median follow-up for the cohort was 27 months. Both ESA-YES and ESA-NO groups were similar regarding age, body mass index, race, stage, histological diagnosis, and debulking status. Compared with the ESA-NO group, ESA-YES patients were significantly more likely to experience recurrence (56% vs 80%, P < 0.001) and death (46% vs 59%, P = 0.002). Kaplan-Meier curves demonstrated a significant reduction in progression-free survival for ESA-YES patients (16 vs 24 months, P < 0.001); however, overall survival was statistically similar between the 2 groups (38 vs 46 months, P = 0.10). When stratifying by ever experiencing a CIA, ESA-YES patients demonstrated a significantly worse progression-free survival (17 vs 24 months, P = 0.02) and overall survival (37 vs 146 months, P < 0.001). CONCLUSIONS: Our data evaluating the use of ESA as a treatment of CIA in ovarian cancer patients are similar to reports in other tumor sites. Considering that patients who used ESA were more likely to experience recurrence and death and to have decreased survival, the use of ESA in ovarian cancer patients should be limited.


Asunto(s)
Anemia/inducido químicamente , Anemia/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Hematínicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Anemia/tratamiento farmacológico , Carcinoma Papilar/tratamiento farmacológico , Carcinoma Papilar/mortalidad , Carcinoma Papilar/patología , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/mortalidad , Neoplasias de las Trompas Uterinas/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
17.
Clin Exp Metastasis ; 29(8): 939-48, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22610780

RESUMEN

Cancer cells with the surface marker profile CD44+/CD24- have previously been described to possess cancer stem cell-like properties. This manuscript evaluates those properties in ovarian cancer cell lines. The proportion of CD44+/CD24- cells corresponded to the clinical aggressiveness of each ovarian cancer cell line histologic subtype. CD44+/CD24- cells demonstrated enhanced progressive differentiation as well as showing a 60-fold increase in Matrigel invasion in both SKOV3 and OV90 cell lines (p < 0.001 each) compared to other phenotypes. CD44+/CD24- demonstrated significant resistance to all chemotherapy agents used in all cell lines, with a 71-93 % increase in resistance compared with baseline. Using a threshold of 25 % CD44+/CD24- ovarian cancer cells found in ascites, patients with >25 % CD44+/CD24- were significantly more likely to recur (83 vs. 14 %, p = 0.003) and had shorter median progression-free survival (6 vs. 18 months, p = 0.01). In conclusion, the CD44+/CD24- phenotype in ovarian cancer cells demonstrate cancer stem cell-like properties of enhanced differentiation, invasion, and resistance to chemotherapy. This CD44+/CD24- phenotype correlates to clinical endpoints with increased risk of recurrence and shorter progression-free survival in patients with ovarian cancer.


Asunto(s)
Antígeno CD24/metabolismo , Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/fisiología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Antígenos de Superficie/metabolismo , Biomarcadores de Tumor/metabolismo , Antígeno CD24/inmunología , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Humanos , Receptores de Hialuranos/inmunología , Invasividad Neoplásica , Neoplasias Ováricas/inmunología , Fenotipo , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/metabolismo
18.
Carcinogenesis ; 33(6): 1149-57, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22431717

RESUMEN

Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4-2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (>60-fold) and protein (>15-fold) levels, in castration-resistant (C4-2) cells as compared with androgen-dependent (LNCaP) prostate cancer cells of the same genotypic lineage. Using loss and gain of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and -deprived conditions, respectively, through induction of cyclins (A1, D1 and E1), Bcl-xL and Bcl2 and downregulation of p27 and Bax. Interestingly, Myb overexpression is also associated with enhanced prostate-specific antigen expression. Furthermore, our data show a role of Myb in enhanced motility and invasion and decreased homotypic interactions of prostate cancer cells. Myb overexpression is also associated with actin reorganization leading to the formation of filopodia-like cellular protrusions. Immunoblot analyses demonstrate gain of mesenchymal and loss of epithelial markers and vice versa, in Myb-overexpressing LNCaP and -silenced C4-2 cells, respectively, indicating a role of Myb in epithelial to mesenchymal transition. Altogether, our studies provide first experimental evidence for a functional role of Myb in growth and malignant behavior of prostate cancer cells and suggest a novel mechanism for castration resistance.


Asunto(s)
Andrógenos/metabolismo , Proteínas Oncogénicas v-myb/biosíntesis , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Andrógenos/deficiencia , Apoptosis , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Ciclina A1/metabolismo , Ciclina D1/metabolismo , Ciclina E/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Masculino , Invasividad Neoplásica , Proteínas Oncogénicas/metabolismo , Proteínas Oncogénicas v-myb/genética , Orquiectomía , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Próstata/metabolismo , Próstata/patología , Antígeno Prostático Específico/biosíntesis , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Seudópodos , Interferencia de ARN , ARN Interferente Pequeño , Transcripción Genética , Regulación hacia Arriba , Proteína X Asociada a bcl-2/biosíntesis , Proteína Letal Asociada a bcl/metabolismo , Proteína bcl-X/metabolismo
19.
Oncol Rep ; 27(1): 286-92, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21971700

RESUMEN

The aim of this study was to better understand the mechanisms of tumor development and disease progression in human epithelial ovarian cancer. Fifty genes were screened for gene signature; 20 expressed genes were assessed in tumor and normal samples of EOC patients by RT-PCR. Expression of UBE2I, EGF, TAL2 and ILF3 was validated by qPCR on the ABI Prism 7000 Detection System. ERCC1 and XPB expression was previously determined by RT-PCR in these specimens. Statistical analyses include two-sided Kruskal-Wallis test, pairwise comparison, Pearson correlation coefficient and paired t-test. In comparison to normal samples, 6 genes demonstrated distinct expression patterns in tumor tissues, with high expression observed for ERCC1, XPB and ILF3 (p=0.001, 0.0007 and 0.002, respectively) and low expression observed for TAL2 and EGF (both p<0.0001). This differential expression pattern between normal and tumor tissues may reflect in part the development of ovarian cancer. Significant differences in expression patterns of these genes in clear cell, endometrioid, mucinous and serous ovarian cancer were observed. Comparison of expression of any two EOC subtypes revealed multiple gene involvement in histopathological differentiation and cancer progression. A positive association was found between ERCC1 and XPB expression (r=0.53, p<0.0001) and between TAL2 and EGF expression (r=0.817, p<0.0001) suggesting the existence of gene linkage in these tumors. The differences in expression patterns of studied genes between tumors and normal specimens, between histological subtypes and correlations among studied genes, may indicate their involvement in tumor growth and disease progression in human epithelial ovarian cancer. Further investigation of these genes may enable better understanding of the molecular mechanism of tumorigenesis and identification of potential biomarkers.


Asunto(s)
Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma Epitelial de Ovario , ADN Helicasas/biosíntesis , ADN Helicasas/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Endonucleasas/biosíntesis , Endonucleasas/genética , Factor de Crecimiento Epidérmico/biosíntesis , Factor de Crecimiento Epidérmico/genética , Femenino , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias Glandulares y Epiteliales/metabolismo , Proteínas del Factor Nuclear 90/biosíntesis , Proteínas del Factor Nuclear 90/genética , Neoplasias Ováricas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Enzimas Ubiquitina-Conjugadoras/biosíntesis , Enzimas Ubiquitina-Conjugadoras/genética
20.
Int J Gynecol Cancer ; 21(6): 1131-4, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21792016

RESUMEN

OBJECTIVE: Double prophylaxis for deep venous thrombosis (DVT) with thromboprophylaxis plus sequential compression devices (SCDs) is recommended for high-risk surgical patients with gynecologic oncology. Despite the use of preoperative thromboprophylaxis in clinical trials, the schedule of perioperative low molecular-weight heparin varies widely. We sought to determine the effectiveness and adverse effects of a preoperative dose of anticoagulation in patients with gynecologic oncology. METHODS: A multi-institutional chart review from January 2006 to July 2008 was performed. Patients with gynecologic oncology who received double prophylaxis for laparotomy were eligible. The patients were grouped according to whether they received preoperative anticoagulation (YES PREOP vs NO PREOP). All patients received postoperative low molecular-weight heparin for thromboprophylaxis and SCDs until discharge. Demographic, surgicopathologic, and complication data were collected. RESULTS: A total of 239 patients were identified: YES PREOP (n = 101) and NO PREOP (n = 138). Groups were similar with respect to demographics, diagnosis, and length of hospital stay. There were 2 DVTs in the YES PREOP group compared with 11 in the NO PREOP group (P = 0.04; relative risk, 0.77). There were also fewer DVT-attributable deaths in the YES PREOP group (0 vs 2; P < 0.001). Postoperative hematocrit (30.2% vs 31.4%; P = 0.42) and number of transfusions (26 vs 14; P = 0.31) were similar. CONCLUSION: The use of preoperative anticoagulation seems to significantly decrease the risk of DVT in this patient population, and complication rates are not increased. Patients receiving double prophylaxis should receive a preoperative dose of anticoagulation for maximum benefit.


Asunto(s)
Anticoagulantes/administración & dosificación , Neoplasias de los Genitales Femeninos/cirugía , Laparotomía/efectos adversos , Complicaciones Posoperatorias/prevención & control , Trombosis de la Vena/prevención & control , Alabama , Esquema de Medicación , Femenino , Humanos , Aparatos de Compresión Neumática Intermitente , Persona de Mediana Edad , Cuidados Preoperatorios , Estudios Retrospectivos , Resultado del Tratamiento
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