RESUMEN
The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptosis , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Humanos , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Neoplasias Hepáticas/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Vitamina E/análogos & derivados , Vitamina E/farmacología , Vitamina E/uso terapéuticoRESUMEN
Many cancer patients receive their classical therapies together with vitamin supplements. However, the effectiveness of these strategies is on debate. Here we aimed to evaluate how vitamin E supplementation affects the anticancer effects of interferon (IFN-α) using an early-model of liver cancer development (initiation-promotion, IP). Male Wistar rats subjected to this model were divided as follows: untreated (IP), IP treated with recombinant IFN-α-2b (6.5 × 105 U/kg), IP treated with vitamin E (50 mg/kg), and IP treated with combination of vitamin E and IFN-α-2b. After treatments rats were fasted and euthanized and plasma and livers were collected. Combined administration of vitamin E and IFN-α-2b induced body weight drop, increased liver apoptosis, and low levels of hepatic lipids. Interestingly, vitamin E and IFN-α-2b combination also induced an increase in altered hepatic foci number, but not in size. It seems that vitamin E acts on its antioxidant capability in order to block the oxidative stress induced by IFN-α-2b, blocking in turn its beneficial effects on preneoplastic livers, leading to harmful final effects. In conclusion, this study shows that vitamin E supplementation in IFN-α-2b-treated rats exerts unwanted effects; and highlights that in spite of being natural, nutritional supplements may not always exert beneficial outcomes when used as complementary therapy for the treatment of cancer.
Asunto(s)
Anticarcinógenos/farmacología , Interferón alfa-2/farmacología , Neoplasias Hepáticas/prevención & control , Vitamina E/farmacología , Vitaminas/farmacología , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Interacciones Farmacológicas , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Ratas WistarRESUMEN
OBJECTIVE: Vitamin K2, which is present in dairy products and has been recommended as a micronutrient supplement in humans, contains anticancer properties. Interferon (IFN)-α-2b administered during development of hepatic preneoplasia decreased both number and volume percentage of altered hepatic foci (AHF) by increasing apoptosis in the foci. The aim of this study was to evaluate the effects of IFN-α-2b treatment supplemented with vitamin K2 in the early stages of liver cancer development in rats. METHODS: Adult male Wistar rats were subjected to a two-phase model of hepatocarcinogenesis (initiated-promoted [IP] group). Animals were divided into four groups: untreated (IP), IP treated with IFN-α-2b (6.5â¯×â¯105 U/kg), IP treated with vitamin K2 (10 mg/kg), and IP treated with both compounds. RESULTS: The study results demonstrated that vitamin K2 blocked IFN-α-2b-induced reduction in size and volume of the altered hepatic foci and inhibited IFN-α-2b-induced apoptosis. Its inhibition of IFN-α-2b-induced apoptosis was mediated by increased levels of total hepatic Bcl-2 in rat preneoplastic livers. CONCLUSION: These findings demonstrate that supportive vitamin supplements or therapies are not always safe because they could put the life of patients treated with IFN-α-2b at risk.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinogénesis/efectos de los fármacos , Suplementos Dietéticos , Interferón alfa-2/administración & dosificación , Vitamina K 2/administración & dosificación , Vitaminas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Hígado/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Lesiones Precancerosas/tratamiento farmacológico , Ratas , Ratas WistarRESUMEN
BACKGROUND: One established model to induce hepatic preneoplasia (HP) (DEN 150) uses diethylnitrosamine (DEN) as initiator agent and 2-acetylaminofluorene (2-AAF) as a promoter drug. In addition, both chemicals cause liver cholestasis and fibrosis. AIM: We compared DEN 150 model with another adapted by us, DEN 200 to simplify the first one and to evaluate the effectiveness of both treatments to induce HP in rats. MATERIAL AND METHODS: Male Wistar rats were divided in 3 groups: controls; DEN 150 (rats received 2 doses of DEN, 150 mg/kg body weight, 2 weeks apart, and then 2-AAF, 20 mg/kg body weight, 4 doses per week during 3 weeks); and DEN 200 (rats received a single dose of DEN 200 mg/kg body weight, and 2 weeks apart 2-AAF, 20 mg/kg body weight, 2 doses per week during 3 weeks). Four hepatic enzymes, prothrombin time percentage, the number of bile ductules, total collagen amount, the number of altered hepatic foci (AHF) per liver and the percentage of liver occupied by foci were analyzed. Results. There were no differences in the number of AHF per liver between treated groups. Rats from DEN 200 group showed a significant diminution in the volume of liver occupied by foci. DEN 200 group had no fibrosis and better hemostatic conditions than DEN 150 group. Both groups developed cholestasis. CONCLUSION: In conclusion, both protocols are good alternatives to induce HP in rats and the new protocol proposed is an effective and a simple methodology to provide subclinic states of liver cancer.