RESUMEN
The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or Per2 enhances cancer growth in vitro. These genes also regulate the amount of cell proliferation-related molecules, many of which are therapeutic targets. In animals, tumors grow with clear circadian organization, and Per1 and Per2 exert their tumor suppressor functions in a circadian time-dependent manner. Downregulation of Per1 or Per2 increases tumor growth only at certain specific times of the day. Per1 and Per2 differentially regulate tumor growth rhythm in vivo. These data suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery. The optimal times of day may be shifted in tumors that have mutant Period genes.
Asunto(s)
Ritmo Circadiano/genética , Neoplasias Mamarias Experimentales/metabolismo , Proteínas Circadianas Period/genética , Animales , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Ritmo Circadiano/fisiología , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C3H , Proteínas Circadianas Period/antagonistas & inhibidores , Proteínas Circadianas Period/biosíntesis , FotoperiodoRESUMEN
Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-catenin levels and colon polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased beta-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.
Asunto(s)
Ritmo Circadiano/genética , Neoplasias/genética , Proteínas Circadianas Period/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Ritmo Circadiano/fisiología , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Pólipos del Colon/genética , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ratones , Ratones Mutantes , Mutación , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Circadianas Period/metabolismo , beta Catenina/biosíntesis , beta Catenina/genéticaRESUMEN
Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 p.p.m., equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents but it also treats colitis. Inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also downregulated by American ginseng. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation and subsequent epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC.
Asunto(s)
Colitis/tratamiento farmacológico , Daño del ADN/efectos de los fármacos , Inflamación/tratamiento farmacológico , Panax , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Western Blotting , Linfocitos T CD4-Positivos/efectos de los fármacos , Colitis/inducido químicamente , Ensayo Cometa , Ciclooxigenasa 2/efectos de los fármacos , Sulfato de Dextran/toxicidad , Técnica del Anticuerpo Fluorescente , Células HT29 , Humanos , Inmunohistoquímica , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Fitoterapia/métodos , Estallido Respiratorio/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacosRESUMEN
Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.biloba extract, EGb 761, is an antioxidant that can be used to prevent and treat colitis in mice. Here, we show that EGb 761 suppresses the activation of macrophages and can be used to both prevent and treat mouse colitis. Markers of inflammation (iNOS, Cox-2 and tumor necrosis factor-alpha) and inflammatory stress (p53 and p53-phospho-serine 15) are also downregulated by EGb 761. Furthermore, we show that EGb 761 reduces the numbers of CD4+/CD25-/Foxp3- effector T cells in the colon. Interestingly, EGb 761 drives CD4+ effector T cell apoptosis in vitro and in vivo, providing a mechanistic explanation to the reduction in numbers of this cell type in the colon. This current study is in agreement with previous studies supporting a use of EGb 761 as a complementary and alternative strategy to abate colitis and associated colon cancer.
Asunto(s)
Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Colitis/prevención & control , Fitoterapia , Extractos Vegetales/uso terapéutico , Linfocitos T Reguladores/inmunología , Animales , Apoptosis/fisiología , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Colitis/inmunología , Colitis/metabolismo , Ciclooxigenasa 2/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Factores de Transcripción Forkhead/metabolismo , Ginkgo biloba/metabolismo , Técnicas para Inmunoenzimas , Inflamación , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: Human breast cancer incidence, histopathologic grade, invasiveness, and mortality risk vary significantly throughout each year. In order to better understand this seasonal cancer biology, we investigated the circannual pattern of post-resection breast cancer metastasis, under genetically and environmentally controlled conditions. METHODS: Over a span of 14 consecutive years, we conducted 22 similar experiments to investigate metastatic biology of breast cancer among 1,214 C3HeB/FeJ female mice. All mice were kept in temperature-controlled environment with 12 h light:12 h dark photoperiod, with food and water freely available, from birth until death. At 10-13 weeks of age, each mouse received 20,000 viable syngeneic mammary cancer cells subcutaneously and the tumor bearing leg was resected 10-12 days after tumor inoculation for potential cure. Once 10% of resected mice were found moribund, due to autopsy proven pulmonary metastases, all remaining mice were sacrificed and metastatic lung nodules were counted. RESULTS: The incidence of post-resection pulmonary metastasis was not randomly distributed throughout the year, but peaked prominently in Summer and Winter. Although tumor volume at resection was strongly associated with metastatic potential, a significantly higher probability of pulmonary metastasis was observed if surgery was performed in Summer and Winter, regardless of tumor volume at resection, compared to Spring and Fall. CONCLUSION: These results support the likelihood that human breast cancer seasonality is real and of biological origin. There are implications of this cancer chronobiology for breast cancer prevention, screening, diagnosis, and treatment.
Asunto(s)
Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/cirugía , Estaciones del Año , Animales , Estro , Femenino , Humedad , Ratones , Ratones Endogámicos C3H , Análisis Multivariante , Fitoestrógenos/administración & dosificación , Probabilidad , TemperaturaRESUMEN
The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.