RESUMEN
Acanthopanax trifoliatus (L) Merr (AT) is commonly used as an herbal medicine and edible plant in some areas of China and other Asian countries. AT is thought to have anticancer effects, but potential mechanisms remain unknown. To assess the anticancer properties of AT, we exposed prostate cancer cells to AT extracts and assessed cell proliferation and signaling pathways. An ethanol extract of AT was suspended in water followed by sequential extraction with petroleum ether, ethyl acetate and n-butanol. PC-3 cells were treated with different concentrations of each extract and cell viability was determined by the MTT and trypan blue exclusion assays. The ethyl acetate extract of the ethanol extract had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than any of the other extracts. Mechanistic studies demonstrated that the ethyl acetate extract suppressed the transcriptional activity of NF-kB, increased the level of caspase-3, and decreased the levels of phospho-Erk1/2 and phospho-Akt. This is the first report on the anticancer activity of AT in cultured human prostate cancer cells. The results suggest that AT can provide a plant-based medicine for the treatment or prevention of prostate cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Eleutherococcus , Proteína Quinasa 3 Activada por Mitógenos/efectos de los fármacos , FN-kappa B/efectos de los fármacos , Extractos Vegetales/farmacología , Análisis de Varianza , Apoptosis/genética , Western Blotting , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Humanos , Masculino , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FN-kappa B/metabolismo , Fitoterapia/métodos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Células Tumorales Cultivadas/efectos de los fármacos , TurquíaRESUMEN
In the present study, the effects of δ-tocopherol (δ-T) on growth and apoptosis of human prostate cancer cells were determined and compared with that of α-tocopherol (α-T), a commonly used form of vitamin E. Treatment of human prostate cancer cells with δ-T resulted in strong growth inhibition and apoptosis stimulation, while the effects of α-T were modest. The strong effects of δ-T on the cells were associated with suppression of androgen receptor (AR) activity and decreased level of prostate specific antigen (PSA) that is a downstream target of the AR signaling. In the in vivo study, we found that δ-T had a more potent inhibitory effect on the formation and growth of prostate xenograft tumors than that of α-T. Moreover, δ-T inhibited proliferation and stimulated apoptosis in the tumors. The present study identified δ-T as a better form of vitamin E than α-T for future clinical studies of prostate cancer prevention.
Asunto(s)
Neoplasias de la Próstata/tratamiento farmacológico , Tocoferoles/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Ratones SCID , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/fisiopatología , Receptores Androgénicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The androgen receptor (AR) has a critical role in prostate cancer development and progression. Several curcumin analogues (A10, B10, C10, E10 and F10) with different linker groups were investigated for their effects in human prostate cancer CWR22Rv1 and LNCaP cell lines. The ability of these compounds to inhibit testosterone (TT) or dihydrotestosterone (DHT)induced AR activity was determined by an ARlinked luciferase assay and by TT or DHTinduced expression of prostate specific antigen. Compounds F10 and E10 had stronger inhibitory effects on the growth of cultured CWR22Rv1 and LNCaP cell lines, and they also had enhanced stimulatory effects on apoptosis compared with curcumin and other curcumin analogues (A10, B10, C10) in CWR22Rv1 cells. E10 and F10 were more potent inhibitors of AR activity than curcumin, A10 and B10. The higher activities of E10 and F10 may be correlated with a heteroatom linker. The results indicate that one of the potential mechanisms for the anticancer effect of the curcumin analogues was inhibition of AR pathways in human prostate cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Curcumina/farmacología , Receptores Androgénicos/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Curcumina/análogos & derivados , Dihidrotestosterona/antagonistas & inhibidores , Dihidrotestosterona/metabolismo , Humanos , Masculino , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Transducción de Señal , Testosterona/antagonistas & inhibidores , Testosterona/metabolismoRESUMEN
BACKGROUND/AIM: Lipitor is a cholesterol-lowering drug and Celebrex is a Cyclooxygenase-2 inhibitor. We investigated the effects of Lipitor and Celebrex on human prostate cancer VCaP cells cultured in vitro and grown as orthotopic xenograft tumors in SCID mice. MATERIALS AND METHODS: Apoptosis was measured by morphological assessment and caspase-3 assay. Nuclear factor-kappa B (NF-κB) activation was determined by luciferase reporter assay. B-cell lymphoma-2 (Bcl2) was measured by western blotting and immunohistochemistry. Orthotopic prostate tumors were monitored by the IVIS imaging system. RESULTS: the combination of Lipitor and Celebrex had stronger effects on the growth and apoptosis of VCaP cells than did either drug alone. The combination more potently inhibited activation of NFκB and expression of Bcl2 than either drug alone. The growth of orthotopic VCaP prostate tumors was strongly inhibited by treatment with the drug combination. CONCLUSION: Administration of Lipitor and Celebrex in combination may be an effective strategy for inhibiting the growth of prostate cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ácidos Heptanoicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Pirazoles/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacología , Apoptosis/efectos de los fármacos , Atorvastatina , Celecoxib , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Inhibidores de la Ciclooxigenasa 2/farmacología , Ácidos Heptanoicos/administración & dosificación , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias de la Próstata/patología , Pirazoles/administración & dosificación , Pirroles/administración & dosificación , Sulfonamidas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To compare the effect of TiO2 nanoparticles on antioxidant function and element content of liver and kidney tissues in young and adult rats. METHODS: Forty-eight SD male rats, half in 4-week (youth) old and half in 9-week (adult) old rats, were randomly divided into 8 groups, which were exposed to TiO2 nanoparticles [(75 ± 15) nm, anatase] through intragastric administration at 0, 10, 50 and 200 mg/kg body weight every day for 30 days. The liver and kidney tissues were collected for antioxidant function and element content analysis. RESULTS: 200 mg/kg TiO2 nanoparticles exposure significantly increased the liver total superoxide dismutase (T-SOD) activity and the kidney reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios in young rats, and significantly decreased the liver Mo, Co, Mn and P contents and the kidney Rb and Na contents in young rats. 200 mg/kg TiO2 nanoparticles exposure significantly increased GSH/GSSG ratios and Rb contents and decreased Na contents in the liver of adult rats. No significantly difference was found in antioxidant indexes and elements content in the kidney of adult rats between three experimental groups and control group. CONCLUSION: TiO2 nanoparticles can enhance the antioxidant capacity and decrease the elements content in rat liver and kidney tissues. The liver is the more sensitive target organ and the young animals are more susceptible to TiO2 nanoparticles toxicity by the oral routes.
Asunto(s)
Antioxidantes/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Nanopartículas , Titanio/farmacología , Administración Oral , Animales , Glutatión , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ácidos Heptanoicos/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirroles/administración & dosificación , Quinolonas/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Atorvastatina , Celecoxib , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Ácidos Heptanoicos/uso terapéutico , Humanos , Inyecciones Intraperitoneales , Ratones , Ratones SCID , Neoplasias Experimentales , Neoplasias Pancreáticas/patología , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Quinolonas/uso terapéutico , Sulfonamidas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In the present study, we investigated the effect of a combination of atorvastatin and celecoxib on the formation of interleukin (IL)-6, a cytokine that is increased during the progression of LNCaP tumors from androgen dependence to androgen independence. Culturing LNCaP cells in androgendepleted (AD) medium increased the levels of IL-6 and survivin, and treatment of the cells in AD medium with a combination of atorvastatin and celecoxib strongly inhibited the increase in IL-6 and survivin which is one of the downstream targets of the IL-6 signaling pathway. Addition of recombinant IL-6 partially abrogated the combined effect of atorvastatin and celecoxib on apoptosis in LNCaP cells cultured in AD medium. In SCID mice, we found that the levels of IL-6 and survivin expression were increased when LNCaP tumors became androgen-independent. Treatment of the mice with atorvastatin or celecoxib alone caused decrease in the levels of IL-6 and survivin as LNCaP tumors became androgen-independent, but treatment of the mice with a combination of celecoxib and atorvastatin resulted in a much stronger inhibition in the increase in IL-6 and survivin expression. Our results indicate that decreases in IL-6 and survivin levels by atorvastatin and celecoxib administration are associated with increased apoptosis in LNCaP cells treated with this drug combination. Our in vivo studies indicate that the inhibitory effect of a combination of atorvastatin and celecoxib on the progression of androgen-dependent LNCaP xenograft tumors to androgen independence is associated with inhibition of the increase in IL-6 and survivin that occurs when androgen-dependent LNCaP prostate tumors become androgen-independent.
Asunto(s)
Apoptosis/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Interleucina-6/biosíntesis , Neoplasias de la Próstata/tratamiento farmacológico , Pirazoles/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Atorvastatina , Castración , Celecoxib , Supervivencia Celular , Inhibidores de la Ciclooxigenasa 2/farmacología , Progresión de la Enfermedad , Inhibidores Enzimáticos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Interleucina-6/farmacología , Masculino , Ratones , Ratones SCID , Survivin , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Eleven curcumin-related compounds containing a benzyl piperidone moiety were synthesized and evaluated for their effects on cultured prostate cancer PC-3 cells, pancreas cancer BxPC-3 cells, colon cancer HT-29 cells and lung cancer H1299 cells. Inhibitory effects of these compounds on the growth of PC-3, BxPC-3, HT-29 and H1299 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Compounds benzyl piperidone 2 (P2), P4, P7, 4-bromo-2-fluoro-benzyl piperidone 2 (PFBr2), PFBr3 and PFBr4 (see syntheses and structures in Figs. 1, 2) exhibited potent inhibitory effects on the growth of cultured PC-3, BxPC-3, HT-29 and H1299 cells. The IC50 for these compounds was lower than 2 µM in all four cell lines. PFBr4 was 41-, 36-, 40- and 46-fold more active than curcumin for inhibiting the growth of PC-3, BxPC-3, HT-29 and H1299 cells, respectively. The benzyl piperidone-containing compounds studied also stimulated apoptosis in PC-3 cells. Mechanistic studies indicate that the effects of both curcumin and PFBr4 on PC-3 cells were associated with a decrease in phospho-Akt and phospho-extracellular signal-regulated kinase (Erk)1/2. The present study indicates that P2, P4, P7, PFBr2, PFBr3 and PFBr4 may have useful effects on human cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Curcumina/análogos & derivados , Piperidonas/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Curcumina/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-ActividadRESUMEN
Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3ß,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S)-3α,4ß-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.
Asunto(s)
Carcinogénesis/patología , Crisenos/farmacología , Compuestos Epoxi/farmacología , Neoplasias Cutáneas/inducido químicamente , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/química , Crisenos/química , Crisenos/toxicidad , Cricetinae , Compuestos Epoxi/toxicidad , Humanos , Ratones , Mutagénesis/efectos de los fármacos , Mutágenos/farmacología , Mutágenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Neoplasias Cutáneas/patología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Twelve pyridine analogs of curcumin were studied for their effects on growth and apoptosis in human prostate cancer PC-3 cells. The ability of these compounds to inhibit the transcriptional activity of nuclear factor-kappa B (NF-κB) and the level of phosphorylated extracellular signal-regulated kinases (phospho-ERK1/2) in PC-3 cells was also determined. Treatment of PC-3 cells with the pyridine analogs of curcumin resulted in concentration-dependent growth inhibition and apoptosis stimulation. Only pyridine analogs of curcumin with a tetrahydrothiopyrane-4-one linker (FN compounds) exhibited a strong inhibitory effect on growth and a strong stimulatory effect on apoptosis at low concentrations (≤ 1 µM). Mechanistic studies showed that NF-κB transcriptional activity in PC-3 cells was strongly inhibited by treatment with group FN compounds. Treatment of PC-3 cells with 1 µM FN1 resulted in a decrease of activated ERK1/2. Results from the present study indicate that FN compounds warrant further in vivo studies using suitable animal models of prostate cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Curcumina/análogos & derivados , FN-kappa B/metabolismo , Neoplasias de la Próstata/patología , Piridinas/química , Western Blotting , Curcumina/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Luciferasas/metabolismo , Masculino , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , FN-kappa B/genética , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To explore the effect of titanium dioxide (TiO2) nanoparticles on hemogram in rats with gastric ulcer. METHODS: Physicochemical properties of TiO2 nanoparticles were characterized. Twenty-four clear class SD male rats, aging 8 week-old, were randomly divided into 4 groups, 6 rats for each group. 20% acetic acid were injected into the rats' stomach on the border of gastric body and pyloric antrum, and hereby established the gastric ulcer model. The rats in 4 groups were exposed to TiO2 nanoparticles through intragastric administration at 0, 10, 50 and 200 mg/kg body weight respectively for 30 days. Afterwards, the rats were conducted blood routine test and blood coagulation test for analysis. RESULTS: TiO2 nanoparticles were anatase crystals, closely spherical shape, whose average grain diameter was (75 ± 15) nm. The levels of white blood cell (WBC) count ((8.48 ± 3.28)×109/L), lymphocyte (LYM) ((6.85 ± 2.53)×109/L), monocyte (MOD) ((0.27 ± 0.12)×109/L), granulocyte (GRN) ((1.37 ± 0.86)×109/L), red blood cell (RBC) ((8.20 ± 0.49)×109/L) and hematocrit (HCT) ((45.3 ± 1.4)%) in the 200 mg/kg dose group were significantly higher than those in the control group ((2.63 ± 0.34)×109/L, (2.25 ± 0.26)×109/L, (0.05 ± 0.06)×109/L, (0.33 ± 0.26)× 109/L, (4.87 ± 2.37)×109/L and (27.2 ± 13.3)%, respectively; t values were -3.449, -3.825, -3.554, -3.097, -2.972 and -2.936 respectively, P values all < 0.05). The levels of WBC ((6.88 ± 3.06)×109/L), MOD ((0.20 ± 0.07)×109/L), RBC ((7.79 ± 0.48)×109/L) and HCT ((42.7 ± 2.8)%) in 50 mg/kg dose group were also statistically higher than those in the control group (t values were -2.507, -2.367, -2.605 and -2.511 respectively, all P values < 0.05). There was no statistically difference found in other blood routine index and coagulation index between the three experimental groups and control group. CONCLUSION: The long term intake of TiO2 nanoparticles caused a statistically increase in the amount of WBC and RBC in rats with gastric ulcer; however, there was no obvious changes found in blood platelet and coagulation index.
Asunto(s)
Nanopartículas del Metal/efectos adversos , Úlcera Gástrica/sangre , Titanio/efectos adversos , Animales , Pruebas Hematológicas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
In the present study, the effects of 12-O-tetra-decanoylphorbol-13-acetate (TPA) alone or in combination with gemcitabine on the growth of Panc-1 pancreatic cancer cells cultured in vitro or grown in NCr immunodeficient nude mice were investigated. Combinations of TPA and gemcitabine synergi-stically inhibited the growth and induced apoptosis in Panc-1 cells. The combination of TPA (0.16 nM) and gemcitabine (0.5 µM) induced a marked increase in phosphorylated c-Jun NH2-terminal kinase (JNK) in the Panc-1 cells. In animal experiments, NCr nude mice with established Panc-1 tumors received daily intraperitoneal (i.p.) injections of TPA (50 ng/g body weight/day) or gemcitabine (0.5 µg/g body weight/day) alone or in combination for 26 days. Treatment with daily i.p. injections of low doses of TPA or gemcitabine alone had a modest inhibitory effect on the growth of the tumors. However, the combination of low doses of TPA and gemcitabine more potently inhibited the growth of Panc-1 tumors than either agent used individually. Treatment with TPA or gemcitabine alone or in combination did not affect the body weight of the animals. Clinical trials with TPA alone or in combination with gemcitabine on patients with pancreatic cancer are warranted in order to confirm our results.
Asunto(s)
Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , MAP Quinasa Quinasa 4/antagonistas & inhibidores , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Acetato de Tetradecanoilforbol/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.
Asunto(s)
Andrógenos/metabolismo , Cafeína/administración & dosificación , Progresión de la Enfermedad , Actividad Motora , Neoplasias de la Próstata/patología , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Prueba de Esfuerzo , Interleucina-6/metabolismo , Masculino , Ratones , Ratones SCID , Antígeno Prostático Específico/sangreRESUMEN
Curcumin is a non-nutritive yellow pigment found in the spice turmeric, which is derived from the rhizome of the plant Curcuma longa Linn. Six cyclohexanone analogues of curcumin (A(1)-A(6)) were investigated for their effects on growth and apoptosis in PC-3 human prostate cancer cells. The ability of these compounds to inhibit NF-κB activity in PC-3 cells was also determined. Five out of the six curcumin analogues (A(2)-A(6)) had stronger inhibitory effects compared to curcumin on the growth of cultured PC-3 cells. Compounds A(2)-A(6) also had stronger stimulatory effects on apoptosis in PC-3 cells than curcumin, and these curcumin analogues more potently inhibited NF-κB activity than curcumin. The inhibitory effects of these compounds on NF-κB activity correlated with their effects on growth inhibition and apoptosis stimulation in PC-3 cells. The results of the present study provide a rationale for in vivo studies with A(2)-A(6) using suitable animal models of prostate cancer.
RESUMEN
Sixty-one curcumin-related compounds were synthesized and evaluated for their anticancer activity toward cultured prostate cancer PC-3 cells, pancreas cancer Panc-1 cells and colon cancer HT-29 cells. Inhibitory effects of these compounds on the growth of PC-3, Panc-1 and HT-29 cells were determined by the MTT assay. Compounds E10, F10, FN1 and FN2 exhibited exceptionally potent inhibitory effects on the growth of cultured PC-3, Panc-1 and HT-29 cells. The IC(50) for these compounds was lower than 1 µM in all three cell lines. E10 was 72-, 46- and 117-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. F10 was 69-, 34- and 72-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. FN1 and FN2 had about the same inhibitory effect as E10 and F10 toward Panc-1 cells but were less active than E10 and F10 toward PC-3 and HT-29 cells. The active compounds were potent stimulators of apoptosis. The present study indicates that E10, F10, FN1 and FN2 may have useful anticancer activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Curcumina/síntesis química , Curcumina/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Técnicas de Química Sintética , Curcumina/química , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
We determined the inhibitory effect of dietary atorvastatin, dietary celecoxib and voluntary running wheel exercise (RW) alone or in combination on the formation and growth of androgen-independent LNCaP tumors in castrated SCID mice. Male SCID mice were injected subcutaneously with androgen-dependent prostate cancer LNCaP cells. When the tumors reached a moderate size, the mice were surgically castrated and treated with atorvastatin (0.02% in the diet), celecoxib (0.05% in the diet) or RW alone or in combination for 42 days. RW or celecoxib alone had a moderate inhibitory effect on the androgen-independent growth of LNCaP tumors, but atorvastatin alone had little or no effect on tumor growth. Combinations of atorvastatin and celecoxib had a stronger inhibitory effect on the formation and growth of androgen-independent LNCaP tumors than either drug alone. A combination of RW together with atorvastatin and celecoxib had the most potent inhibitory effect on the progression of LNCaP tumors to androgen independent growth. The serum concentration of atorvastatin after two weeks of oral administration of atorvastatin was 6.1 ng/ml. The serum concentration of celecoxib after treatment with dietary celecoxib for two weeks was 1090 ng/ml. The serum concentration of atorvastatin but not that of celecoxib was substantially reduced when the two drugs were given in combination. The drug concentrations observed in our animal studies are comparable or less than those commonly found in humans treated with atorvastatin or celecoxib. Our results indicate that administration of atorvastatin and celecoxib together with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.
RESUMEN
In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that g-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of g-TmT increased the levels of a-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that g-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of g-TmT for prostate cancer in humans.
RESUMEN
Epidemiology studies suggest that statins and nonsteroidal anti-inflammatory drugs reduce the risk of prostate cancer. In the present study, LNCaP cells were cultured in regular medium containing fetal bovine serum or in medium supplemented with charcoal-stripped fetal bovine serum to mimic androgen deprivation treatment. We found that atorvastatin (Lipitor) or celecoxib (Celebrex) treatment of LNCaP cells cultured in regular or androgen-depleted medium inhibited growth and stimulated apoptosis. A combination of atorvastatin and celecoxib was more effective than either agent alone. In animal studies, severe combined immunodeficient mice were injected s.c. with LNCaP cells in Matrigel. After 4 to 6 weeks, mice with LNCaP tumors (about 0.6 cm wide and 0.6 cm long) were surgically castrated and received daily i.p. injections of vehicle, atorvastatin (10 microg/g body weight/d), celecoxib (10 microg/g/d), or a combination of atorvastatin (5 microg/g/d) and celecoxib (5 microg/g/d) for 42 days. In all groups, the androgen-dependent LNCaP tumors regressed initially in response to castration, but the tumors eventually progressed to androgen independence and started to grow. Treatment of the mice with atorvastatin or celecoxib alone suppressed the regrowth of LNCaP tumors after castration. A combination of low doses of atorvastatin and celecoxib had a more potent effect in inhibiting the growth and progression of LNCaP tumors to androgen independence than a higher dose of either agent alone. Our results indicate that administration of a combination of atorvastatin and celecoxib may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Andrógenos/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Apoptosis/efectos de los fármacos , Atorvastatina , Western Blotting , Celecoxib , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Expresión Génica , Ácidos Heptanoicos/administración & dosificación , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inmunohistoquímica , Masculino , Ratones , Ratones SCID , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Pirazoles/administración & dosificación , Pirroles/administración & dosificación , Sulfonamidas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In the present study, we investigated the effect of voluntary exercise on the formation and growth of the human pancreas Panc-1 and prostate PC-3 tumors in immunodeficient mice. Female severe combined immunodeficient (SCID) mice were injected subcutaneously with human pancreatic cancer Panc-1 cells, and male SCID mice were injected subcutaneously with human prostate cancer PC-3 cells. Voluntary running wheel exercise for 63 days, starting one week before the subcutaneous injection of Panc-1 or PC-3 tumor cells into SCID mice, suppressed the growth of Panc-1 and PC-3 tumors. The exercise regimen increased the food and fluid consumption in the female and male mice. Exercise also decreased the size of the parametrial fat pads in the female mice and the paradidymis fat pads in the male mice, but there was no effect on the body weight. Mechanistic studies showed that voluntary running wheel exercise inhibited proliferation as reflected by a decreased mitosis, and the exercise regimen also stimulated apoptosis as reflected by the increased caspase-3 (active form) expression in the Panc-1 and PC-3 tumors. Voluntary running wheel exercise decreased the ratio of the percent mitotic cells/apoptotic cells in Panc-1 and PC-3 tumors by 38 and 32%, respectively. The present study demonstrated an inhibitory effect of voluntary exercise on the growth of pancreas and prostate tumors in a SCID mouse xenograft model.
Asunto(s)
Actividad Motora , Neoplasias Pancreáticas/patología , Neoplasias de la Próstata/patología , Animales , Caspasa 3/metabolismo , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Ratones SCID , Índice Mitótico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination with an NF-kappaB inhibitor, (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), on the growth and apoptosis of human prostate cancer PC-3 cells cultured in vitro or grown in immunodeficient mice were studied. Treatment of cultured PC-3 cells with TPA (0.2-10 ng/ml) for 96 h resulted in growth inhibition and apoptosis in a concentration-dependent manner. BAY inhibited NF-kappaB activity in PC-3 cells as determined by a luciferase reporter assay and enhanced TPA-induced growth inhibition and apoptosis in cultured PC-3 cells. In animal studies, NCr immunodeficient mice were injected subcutaneously with PC-3 cells in Matrigel. Mice with well-established tumors received daily i.p. injections with TPA (100 ng/g body weight/day), BAY (4 microg/g/day), or a combination of TPA (100 ng/g/day) and BAY (4 microg/g/day) for 36 days. Tumor growth occurred in all of the vehicle-treated control mice. The percent of animals with some tumor regression after 36 days of treatment was 0% for the control group, 40% for the TPA group, 50% for the BAY group and 100% for the TPA + BAY group. Mechanistic studies indicated that treatment of the mice with TPA or TPA + BAY decreased proliferation and increased apoptosis in the tumors. Results from our studies indicate that inhibition of NF-kappaB activity is associated with enhanced TPA-induced growth inhibition and apoptosis in PC-3 cells. Inhibition of NF-kappaB activity by suitable pharmacological inhibitors may be an effective strategy for improving the therapeutic efficacy of TPA in prostate cancer.