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1.
Oncotarget ; 14: 302-315, 2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-37036756

RESUMEN

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.


Asunto(s)
Neoplasias , Neoplasias Pancreáticas , Humanos , Sorafenib/uso terapéutico , Riluzol/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/etiología , Neoplasias Pancreáticas/tratamiento farmacológico , Dosis Máxima Tolerada
2.
J Enzyme Inhib Med Chem ; 37(1): 542-553, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34986722

RESUMEN

Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated. The results showed that ROB and DOC in combination synergistically inhibited the growth of prostate cancer cells. The combination also strongly induced apoptosis, and suppressed cell migration, invasion and sphere formation. Mechanistic study showed that the combined effects of ROB and DOC on prostate cancer cells were associated with inhibition of NF-κB activation, down regulation of Bcl-2 and up regulation of Bax. Knockdown of NF-κB by small interfering RNA (siRNA) significantly decreased the combined effect of ROB and DOC. Moreover, we found that esomeprazole (ESOM), a proton pump inhibitor (PPI), strongly enhanced the effectiveness of ROB and DOC on prostate cancer cells in acidic culture medium. Since acidic micro environment is known to impair the efficacy of current anticancer therapies, ESOM combined with ROB and DOC may be an effective approach for improving the treatment of prostate cancer patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Neoplasias de la Próstata , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Docetaxel/química , Docetaxel/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Esomeprazol/química , Esomeprazol/farmacología , Estructura Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas
3.
Antioxidants (Basel) ; 10(12)2021 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-34943122

RESUMEN

Zingiber striolatum Diels (Z. striolatum), a widely popular vegetable in China, is famous for its medicinal and nutritional values. However, the anti-inflammatory effects of essential oil from Z. striolatum (EOZS) remain unclear. In this study, EOZS from seven regions in China were extracted and analyzed by GC-MS. LPS-induced RAW264.7 cells and 12-O-Tetradecanoylphorbol 13-acetate (TPA)-stimulated mice were used to evaluate the anti-inflammatory effects of EOZS. Results show that 116 compounds were identified in EOZS from seven locations. Samples 2, 4 and 5 showed the best capability on DPPH radical scavenging and NO inhibition. They also significantly reduced the production of ROS, pro-inflammatory cytokines, macrophage morphological changes, migration and phagocytic capability. Transcriptomics revealed MAPK and NF-κB signaling pathways may be involved in the anti-inflammatory mechanism, and the predictions were proven by Western blotting. In TPA-induced mice, EOZS reduced the degree of ear swelling and local immune cell infiltration by blocking the activation of MAPK and NF-κB signaling pathways, which was consistent with the in vitro experimental results. Our research unveils the antioxidant capability and potential molecular mechanism of EOZS in regulating inflammatory response, and suggests the application of EOZS as a natural antioxidant and anti-inflammatory agent in the pharmaceutical and functional food industries.

4.
Nutr Cancer ; 73(11-12): 2740-2750, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33319628

RESUMEN

The vitamin E forms γ- and δ-tocopherols (T) inhibit carcinogenesis in animal models; nevertheless, their cancer preventive activities in humans are uncertain. As an initial step to address this issue, we conducted a pilot phase 0 trial to determine the levels of tocopherols and their metabolites in prostate cancer patients undergoing radical prostatectomy. The patients were randomized to no supplementation or two capsules of a γ-T-rich vitamin E mixture daily for 7 or 14 day prior to prostatectomy. Blood and urine samples were collected before supplementation and on the day of surgery, along with prostate tissue, for analysis of tocopherols and their metabolites. Estimated blood loss during surgery was not significantly different across treatment arms and there were no reported adverse events. Prostate tissue levels of γ-T and δ-T were increased after 14 day of supplementation. Their side-chain degradation metabolites (CEHCs and CMBHCs) were significantly elevated in plasma, prostate and urine samples after supplementation for 7 or 14 day. In conclusion, supplementation with γ-T-rich vitamin E increased the prostate levels of γ-T and δ-T. The use of pure γ-T, δ-T or tocopherol mixtures with higher ratio of γ-T or δ-T to α-T is recommended for future studies.


Asunto(s)
Neoplasias de la Próstata , gamma-Tocoferol , Animales , Suplementos Dietéticos , Humanos , Masculino , Próstata/metabolismo , Neoplasias de la Próstata/cirugía , Tocoferoles/farmacología , Vitamina E , alfa-Tocoferol/farmacología
5.
Eur J Pharmacol ; 893: 173840, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33359649

RESUMEN

Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study, we investigated the effect atorvastatin, celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells. The sphere-forming cells were isolated from Panc-1 cells by sphere-forming method. These sphere-forming cells showed CSC properties. The levels of CD44, CD133 and ALDH1A1 in the sphere-forming cells were increased. Moreover, Panc-1 sphere-forming cells were resistant to chemotherapeutic drug gemcitabine. Combined atorvastatin with celecoxib and tipifarnib synergistically decreased the sphere forming ability of Panc-1 cells and the drug combination also strongly inhibited cell proliferation and promoted apoptosis in the sphere-forming cells. The effects of the drug combination on the Panc-1 sphere-forming cells were associated with decreases in the levels of CD44, CD133 and ALDH1A1, and suppression of Akt and NF-κB activation. Results of the present study indicate that the combination of atorvastatin, celecoxib and tipifarnib may represent an effective approach for inhibiting pancreatic CSCs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Atorvastatina/farmacología , Celecoxib/farmacología , Proliferación Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Quinolonas/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal , Esferoides Celulares
6.
Int J Med Sci ; 17(12): 1795-1802, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32714082

RESUMEN

Background/Aim: Pancreatic adenocarcinoma is a highly malignant tumor. Synergistic combinations of anticancer agents for the effective treatment of pancreatic cancer patients are urgently needed. Here, we investigated the combined effect of celecoxib (CEL) and salirasib (SAL) on pancreatic cancer cells. Methods: Cell viability and apoptosis were measured by the trypan blue assay, three-dimensional cultures, propidium iodide staining, and caspase-3 assay. NF-κB activation and the protein levels of Akt, pAkt, and Bcl-2 were determined by the luciferase reporter assay and western blot. Results: Co-treatment with CEL and SAL had stronger effects on decreasing cell viability and inducing apoptosis in Panc-1 cells as compared with each agent individually. This combination strongly inhibited NF-κB activity and reduced pAkt and Bcl-2 levels in Panc-1 cells. Conclusion: SAL in combination with CEL may represent a new approach for effective inhibition of pancreatic cancer.


Asunto(s)
Celecoxib/farmacología , Farnesol/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Salicilatos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Farnesol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , FN-kappa B/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transducción de Señal
7.
Biosci Biotechnol Biochem ; 84(10): 2069-2076, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32640883

RESUMEN

12-O-tetradecanoylphorbol-13-acetate (TPA), is a major active constituent of the seed oil of Croton tiglium L., has pharmacological activity for the treatment of acute myeloid leukemia patients. Diethyldithiocarbamate (DTC) is a potent inhibitor of NF-κB show activity of anticancer. In this study, we determined the effect of DTC and TPA in combination on HL-60 cells cultured in vitro and in vivo. In this study, we have shown that DTC and TPA synergistically inhibited the growth of HL-60 cells and strongly induced apoptosis in the cells. Mechanistic studies showed that the combined effects of DTC and TPA were associated with a decrease in Bcl-2. The animal experiment showed that the combination of DTC and TPA more potently inhibited the growth of HL-60 tumors than either agent alone. Our results indicate that the administration of TPA and DTC in combination may be an effective strategy for inhibiting the growth of acute myeloid leukemia cells.


Asunto(s)
Ditiocarba/farmacología , Leucemia Mieloide/patología , Acetato de Tetradecanoilforbol/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Bioorg Chem ; 101: 104022, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32599367

RESUMEN

Gemcitabine (GEM) is a commonly used treatment for advanced pancreatic cancer. However, chemoresistance and toxic side effect limits its clinical success. In an earlier study, our laboratory found that the curcumin analogue, (3E,5E)-3,5-Bis(pyridin-3-methylene)-tetrahydrothiopyran-4-one (FN2) had strong inhibitory effect on human pancreatic cancer cells. In the present study, we investigated the effects of FN2 in combination with GEM on growth inhibition and apoptosis in human pancreatic cancer Panc-1 cells. The results showed that the combination of FN2 and GEM synergistically inhibited the growth of Panc-1 cells. Panc-1 cells survived the GEM treatment became partially resistant to the drug. Treatment with FN2 in combination with GEM strongly inhibited the growth and stimulated apoptosis in the GEM resistant Panc-1 cells. Mechanistic studies showed that inhibition of cell growth and induction of apoptosis in the GEM resistant Panc-1 cells were associated with decreases in activation of NF-κB and Akt. FN2 in combination with GEM also decreased the level of Bcl-2 and increased the level of Bax. Results of the present study indicate that GEM in combination with FN2 may represent an effective strategy for improving the efficacy of GEM and decreasing the resistance of pancreatic cancer to GEM chemotherapy.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/patología , Pironas/farmacología , Antimetabolitos Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Pironas/administración & dosificación , Gemcitabina
9.
RSC Adv ; 10(17): 10254-10262, 2020 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-35498570

RESUMEN

Natural products have shown potential to be combined with current cancer therapies to improve patient outcomes. Nobiletin (NBT) is a citrus polymethoxyflavone and has been shown to exert an anticancer effect in various cancer cells. We investigated the effects and mechanisms of NBT in combination with bicalutamide (BCT), a commonly used anti-androgen drug in prostate cancer therapy, on prostate cancer cells. Our results demonstrate that the combined treatment with NBT and BCT produces an enhanced inhibitory effect on the growth of prostate cancer cells compared to either compound alone. The synergistic action of NBT and BCT was confirmed using isobologram analysis. Moreover, this study has shown that NBT and BCT synergistically inhibited colony formation and migration as well as induced apoptosis. Mechanistic studies demonstrate that NBT and BCT combination reduced key cellular signaling regulators including: p-Erk/Erk, p-STAT3/STAT3 and NF-κB. Overall, these results suggest that NBT combination with BCT may be an effective treatment for prostate cancer.

10.
Invest New Drugs ; 38(3): 855-865, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31388792

RESUMEN

Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Gosipol/análogos & derivados , Neoplasias/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Estudios de Cohortes , Femenino , Gosipol/uso terapéutico , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resultado del Tratamiento
11.
Pathol Oncol Res ; 26(1): 209-216, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29796873

RESUMEN

Atorvastatin is the most prescribed cholesterol-lowering statin, while caffeine enhances chemo-sensitivity and induces apoptosis of tumor cells through its DNA repair-inhibiting effect. The present study investigated the effects and mechanisms of atorvastatin and caffeine in combination on human prostate cancer cells cultured in vitro. Cell growth were determined by the trypan blue exclusion assay. The cell apoptosis and colony formation were determined by morphological assessment. The ability of cell migration and invasion were performed using a scratch wound-healing and Transwell assay. Tumorspheres were formed in suspension under the condition of non-adherence and serum-free medium. Finally, the western blot assay was used to determine the levels of proteins. The combination synergistically suppressed proliferation and induced apoptotic death. Meanwhile, the migration, invasion, and the formation of tumorspheres were significantly inhibited by the combination. We found that atorvastatin and caffeine in combination downregulated phospho-Akt, phospho-Erk1/2, anti-apoptotic Bcl-2 and Survivin protein levels. Results of the present study indicate treatment with the combination of caffeine and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.


Asunto(s)
Apoptosis/efectos de los fármacos , Atorvastatina/farmacología , Cafeína/farmacología , Movimiento Celular/efectos de los fármacos , Neoplasias de la Próstata/patología , Proliferación Celular/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Células PC-3 , Inhibidores de Fosfodiesterasa/farmacología
12.
Cancer Chemother Pharmacol ; 84(4): 899-907, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31463691

RESUMEN

PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Compuestos Heterocíclicos con 3 Anillos , Hidroxicloroquina , Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Autofagia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo
14.
Food Funct ; 9(4): 2398-2408, 2018 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-29595853

RESUMEN

Phenethyl isothiocyanate (PEITC) is a naturally occurring compound found in some cruciferous vegetables. Dibenzoylmethane (DBM) is a minor constituent of licorice. Both compounds have been shown to exert anticancer activities. In the present study, we determined the effects of PEITC and DBM alone or in combination on androgen-independent growth of human prostate cancer cells cultured in vitro and prostate VCaP xenograft tumors in severe combined immunodeficient (SCID) mice. PEITC and DBM in combination had stronger effects on inhibiting the growth and inducing apoptosis than either compound alone in cultured prostate cancer cells. The combination also strongly inhibited cell migration and the formation of tumorspheres in VCaP cells. Mechanistic studies showed that the combined effects of PEITC and DBM on growth inhibition and apoptosis were associated with suppression of nuclear factor-κB (NF-κB), and a decrease in the levels of survivin and phospho-Akt (pAkt). In the in vivo study, SCID mice bearing VCaP tumors were surgically castrated and treated with PEITC and/or DBM. Treatment with PEITC and DBM in combination resulted in a strong inhibition of the progression of androgen-dependent VCaP prostate tumors to androgen independence. Our results indicate that administration of DBM and PEITC in combination may be an effective strategy for inhibiting/delaying the progression of prostate cancer to androgen independence.


Asunto(s)
Andrógenos/metabolismo , Anticarcinógenos/administración & dosificación , Chalconas/administración & dosificación , Isotiocianatos/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimioterapia Combinada , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias de la Próstata/fisiopatología
15.
Biol Pharm Bull ; 40(8): 1247-1254, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28769006

RESUMEN

Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphor-extracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Atorvastatina/uso terapéutico , Metformina/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Atorvastatina/farmacología , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Proteínas Inhibidoras de la Apoptosis/metabolismo , Masculino , Metformina/farmacología , Ratones SCID , FN-kappa B/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Survivin , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Bioorg Med Chem Lett ; 27(11): 2286-2291, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28462831

RESUMEN

Docetaxel is a commonly used chemotherapeutic drug for patients with late stage prostate cancer. However, serious side effect and drug resistance limit its clinical success. Brefeldin A is a 16-membered macrolide antibiotic from mangrove-derived Fungus Aspergillus sp. (9Hu), which exhibited potent cytotoxicity against human cancer cells. In the present study, we determined the effect of brefeldin A on docetaxel-induced growth inhibition and apoptosis in human prostate cancer PC-3 cells. Brefeldin A in combination with docetaxel inhibited the growth of PC-3 cells in monolayer and in three dimensional cultures. The combination also potently stimulated apoptosis in PC-3 cells as determined by propidium iodide staining and morphological assessment. Mechanistic studies showed that growth inhibition and apoptosis in PC-3 cells treated with brefeldin A and docetaxel were associated with decrease in the level of Bcl-2. The present study indicates that combined brefeldin A with docetaxel may represent a novel approach for improving the efficacy of docetaxel, and Bcl-2 may serve as a target for brefeldin A to enhance the effects of docetaxel chemotherapy.


Asunto(s)
Apoptosis/efectos de los fármacos , Brefeldino A/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias de la Próstata/patología , Taxoides/farmacología , Línea Celular Tumoral , Docetaxel , Humanos , Masculino
17.
Int J Med Sci ; 14(4): 356-366, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28553168

RESUMEN

Background: Docetaxel is the first-line treatment for castration-resistant prostate cancer (CRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminishes its efficacy in high-dose monotherapy. YK-4-279 is a small molecule inhibitor of ETV1 that plays an important role in the progression of prostate cancer. The aim of this study was to evaluate the hypothesis that the combination of docetaxel and YK-4-279 will have a synergistic effect on inhibiting growth and accelerating apoptosis in human prostate cancer cells. Methods: Cell growth assessed using CCK-8 and trypan blue exclusion assays. Cell apoptosis was determined by morphological assessment in cells stained with propidium iodide. Standard scratch migration and Matrigel-coated transwell invasion assays were used to assess cell migration and invasion, respectively. Western blotting was used to investigate the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in prostate cancer cells. Results: The combination of low-dose docetaxel and YK-4-279 synergistically inhibited growth and induced apoptosis in human prostate cancer cells. The combination also more efficiently suppressed the migration and invasion of LNCaP and PC-3 cells. The combination of low-dose docetaxel and YK-4-279 caused a stronger decrease in the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in LNCaP cells and of p-Akt, Bcl-2, and p-STAT3 in PC-3 cells compared with either drug alone. Conclusions: These data suggest that the combination of docetaxel and YK-4-279 may be an effective approach for inhibiting the growth and metastasis of prostate cancer. This could permit a decrease in the docetaxel dose necessary for patients with CRPC and thereby lower its systemic toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Indoles/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Docetaxel , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología
18.
Oncol Rep ; 37(2): 953-960, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28075470

RESUMEN

Epidemiologic studies indicate the use of either statins or aspirin have beneficial effects in prostate cancer patients. The present study was undertaken to evaluate the effects and mechanisms of atorvastatin and aspirin alone or in combination in human prostate cancer cells cultured in vitro and grown as xenograft tumors in severe combined immune-deficient (SCID) mice. The growth and apoptosis in prostate cancer cells were determined by the trypan blue exclusion and propidium iodide staining assays. Activation of the nuclear factor κB (NF-κB) was measured by luciferase reporter assay, and the levels of phospho-signal transducer and activator of transcription (Stat)3 and phospho-extracellular signal-regulated kinase (Erk)1/2 were determined by western blot analysis. Mice were injected subcutaneously with PC-3 cells in Matrigel. After 4-6 weeks, mice with PC-3 tumors received i.p. injections of vehicle, atorvastatin (5 mg/kg), aspirin (80 mg/kg), or atorvastatin (5 mg/kg) + aspirin (80 mg/kg) three times a week for 30 days. Our results demonstrated the combination of atorvastatin and aspirin had more potent effects on growth inhibition and apoptosis stimulation in prostate cancer cells than either drug alone. Mechanistic studies indicated the induction of apoptosis in PC-3 cells was associated with strong inhibition of NF-κB and decreases in the levels of phospho-Stat3 and phospho-Erk1/2. Results of the present study demonstrated a strong combined effect of atorvastatin and aspirin on inhibiting the growth of prostate cancer cells in vitro and in vivo. The findings provide a strong rationale for clinical evaluation of the combination of atorvastatin and aspirin in patients with prostate cancer.


Asunto(s)
Apoptosis/efectos de los fármacos , Aspirina/farmacología , Atorvastatina/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias de la Próstata/patología , Animales , Antiinflamatorios no Esteroideos/farmacología , Anticolesterolemiantes/farmacología , Western Blotting , Quimioterapia Combinada , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones SCID , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Cancer Genomics Proteomics ; 13(2): 151-60, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26912805

RESUMEN

AIM: To investigate the effects and mechanisms of docetaxel and atorvastatin administered individually or in combination on prostate cancer cells. MATERIALS AND METHODS: Cell growth and apoptosis were determined by the trypan blue exclusion assay and morphological assessment of cells was performed with propidium iodide. NF-κB activity was determined by luciferase reporter gene assay and the western blot assay was used to determine the levels of Bcl-2, phospho-Akt, VEGF, and phospho-Erk1/2. RESULTS: Results showed that following pre-treatment with cholesterol, resistance of PC-3 prostate cancer cells to docetaxel was increased. The combination of docetaxel with atorvastatin potently inhibited growth and induced apoptosis in PC-3 cells. Mechanistic studies indicated that induction of apoptosis in PC-3 cells was associated with significant decreases in the levels of Bcl-2, VEGF, phosphor-Akt, and phosphor-Erk1/2. CONCLUSION: Treatment with cholesterol decreased the sensitivity of prostate cancer cells to docetaxel. Docetaxel in combination with cholesterol-lowering drugs such as atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Atorvastatina/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Apoptosis , Atorvastatina/administración & dosificación , Línea Celular Tumoral , Colesterol/farmacología , Docetaxel , Sinergismo Farmacológico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , FN-kappa B/genética , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Taxoides/administración & dosificación , Transcripción Genética
20.
Clin Genitourin Cancer ; 14(1): 22-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26476589

RESUMEN

UNLABELLED: In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development. BACKGROUND: We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer. MATERIALS AND METHODS: Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients. RESULTS: A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients. CONCLUSION: The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/secundario , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/administración & dosificación , Neoplasias Óseas/secundario , Gosipol/administración & dosificación , Gosipol/análogos & derivados , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Resultado del Tratamiento
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