RESUMO
Vitamin D is a fat-soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25-dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin-dependent kinase inhibitor 1A (CDKN1A). 1,25-Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, KDM6B. Knockdown of KDM6B attenuates 1,25-dihydroxyvitamin D3-induced senescence and upregulation of INK4A and CDKN1A. KDM6B promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/enzimologia , Glioma/genética , Glioma/patologia , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Regiões Promotoras Genéticas , Transdução de SinaisRESUMO
Studies have shown chemopreventive and/or chemotherapeutic effects of several curcumin-based combinatorial treatments on colorectal cancer cells. However, their in vivo effects remain unclear. This study has demonstrated the therapeutic effect of curcumin and oxaliplatin, alone or in combination, on subcutaneously xenografted LoVo human colorectal cancer cells in immunodeficient (nu/nu) mice in vivo. Combinatorial administration of curcumin and oxaliplatin evidently inhibited the growth of colorectal cancer in nude mice, which was significantly more effective than either agent alone. Curcumin combined with oxaliplatin treatment induced apoptosis, accompanied by ultrastructural changes and cell cycle arrest in S and G2/M phases. Further mechanism analysis indicated that while the number of apoptotic tumor cells and the expression of Bax, caspase-3, and poly (ADP-ribose) polymerase (PARP) increased significantly, the expression of Bcl-2, survivin, HSP70, pro-caspase-3, and pro-PARP were dramatically suppressed in tumor cells after the treatment with combinatorial curcumin and oxaliplatin for 22 days. Taken together, the present study has demonstrated that administration of combined curcumin and oxaliplatin effectively suppressed colorectal carcinoma in vivo through inducing apoptosis and thus may provide an effective treatment for colorectal carcinoma.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Curcumina/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Masculino , Camundongos , Camundongos Nus , Oxaliplatina , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Alcoholic liver disease (ALD) is a serious liver problem in western countries. Our previous study has demonstrated that vitamin C plays a protective role in ALD. The vitamin C homeostasis is tightly regulated by sodium-dependent vitamin C transporters (SVCTs) 1 and 2. But the role of two SVCTs in ALD is less understood. In this study, we examined the expression patterns of two SVCTs in mice after alcohol consumption. Our results suggested that alcohol consumption obviously increased the expression of two SVCTs in liver and SVCT1 in kidney and intestine, which is important for vitamin C absorption. Vitamin C supplement increased the sera vitamin C content and ameliorated the symptom of ALD. Intestinal absorption and renal re-absorption mediated by SVCT1 are key factors to increase the sera vitamin C content after alcohol consumption. We proposed that both reactive oxygen species and low vitamin C concentration regulate the expression of SVCTs, and the protective role of vitamin C is mediated by suppressing the stability of hypoxia-inducible factor-1α. Thus, our study is significant for the understanding of vitamin C homeostasis in ALD and for better use of other antioxidants in ALD therapy.