RESUMEN
The aim of the present study was to determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and diethyldithiocarbamate (DDTC) alone or in combination on human pancreatic cancer cells cultured in vitro and grown as xenograft tumors in nude mice. Pancreatic cancer cells were treated with either DDTC or TPA alone, or in combination and the number of viable cells was then determined by trypan blue ecxlusion assay and the number of apoptotic cells was determined by morphological assessment by staining the cells with propidium idiode and examining them under a fluorescence microscope. Treatment with DDTC or TPA alone inhibited the growth and promoted the apoptosis of pancreatic cancer cells in a concentration-dependent manner. These effects were more prominent following treatment with TPA in combination with DDTC than following treatment with either agent alone in PANC-1 cells in monolayer cultures and in 3 dimensional (3D) cultures. The potent effects of the combination treatment on PANC-1 cells were associated with the inhibition of nuclear factor-κB (NF-κB) activation and the decreased expression of Bcl-2 induced by DDTC, as shown by NF-κB-dependent reporter gene expression assay and western blot analysis. Furthermore, treatment of nude mice with DDTC + TPA strongly inhibited the growth of PANC-1 xenograft tumors. The results of the present study indicate that the administration of TPA and DDTC in combination may be an effective strategy for inhibiting the growth of pancreatic cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Ditiocarba/farmacología , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Acetato de Tetradecanoilforbol/farmacología , Animales , Línea Celular Tumoral , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
αTomatine is a glycoalkaloid that occurs naturally in tomatoes (Lycopersicon esculentum). In the present study, the effects of αtomatine on human myeloid leukemia HL60 cells were investigated. Treatment of HL60 cells with αtomatine resulted in growth inhibition and apoptosis in a concentrationdependent manner. Tomatidine, the aglycone of tomatine had little effect on the growth and apoptosis of HL60 cells. Growth inhibition and apoptosis induced by αtomatine in HL60 cells was partially abrogated by addition of cholesterol indicating that interactions between αtomatine and cell membraneassociated cholesterol may be important in mediating the effect of αtomatine. Activation of nuclear factorκB by the phorbol ester, 12Otetradecanoylphorbol13acetate failed to prevent apoptosis in HL60 cells treated with αtomatine. In animal experiments, it was found that treatment of mice with αtomatine inhibited the growth of HL60 xenografts in vivo. Results from the present study indicated that αtomatine may have useful antileukemia activities.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Tomatina/análogos & derivados , Animales , Peso Corporal/efectos de los fármacos , Colesterol/farmacología , Femenino , Células HL-60 , Humanos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratones , Ratones SCID , FN-kappa B/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Tomatina/química , Tomatina/farmacología , Tomatina/uso terapéutico , Trasplante HeterólogoRESUMEN
Indanones are very useful molecules as starting building blocks for the synthesis of biologically active compounds. A series of novel curcumin-related compounds containing indan-2-one were synthesized and screened for anticancer activities. The structures were confirmed by spectral data (IR, NMR, and Mass). Inhibitory effects of these compounds on the growth of prostate cancer PC-3 cells, pancreatic cancer BxPC-3 cells, colon cancer HT-29 cells, lung cancer H1299 cells and non-tumorigenic human prostate epithelial RWPE-1 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 for compound IND-4 was lower than 1 µM in the four cancer cell lines. The present study indicates that IND-4 may have useful effects on human cancer cells.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Curcumina/análogos & derivados , Curcumina/química , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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
Four curcumin analogues ((2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (2E,5E)-2,5-bis(thiophen-3-methylene) cyclopentanone (BS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydropyran-4-one (ES) and (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4-one (FS) as shown in Fig. 1) with different linker groups were investigated for their effects in human prostate cancer CWR-22Rv1 and PC-3 cells. Compounds FS and ES had stronger inhibitory effects than curcumin, AS and BS on the growth of cultured CWR-22Rv1 and PC-3 cells, as well as on the androgen receptor (AR) and nuclear factor kappa B (NF-κB) activity. The strong activities of ES and FS may be correlated with a heteroatom linker. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously (s.c.) with PC-3 cells in Matrigel. After 4 to 6 weeks, mice with PC-3 tumors (about 0.6 cm wide and 0.6 cm long) received daily intraperitoneal (i.p.) injections of vehicle, ES and FS (10 µg/g body weight) for 31 d. FS had a potent effect in inhibiting the growth and progression of PC-3 tumors. Our results indicate that FS may be useful for inhibiting human prostate tumors growth.
Asunto(s)
Apoptosis/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Curcumina/química , Curcumina/uso terapéutico , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Masculino , Ratones SCID , Estructura Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Testosterona/farmacología , 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.