calcitriol and Carcinoma--Squamous-Cell

1,25(OH)2D regulates a number of cellular events which contribute to its ability to stimulate differentiation of the keratinocyte. 1,25(OH)2D raises the intracellular calcium (Cai) level in part by increasing the expression of the calcium receptor (CaR). This sensitizes the cell to extracellular calcium, triggering the signaling pathway coupled to the CaR, which results in a rise in Cai. 1,25(OH)2D induces the family of phospholipases C (PLC). These enzymes mediate the hydrolysis of phosphatidyl inositol bisphosphate (PIP2) to form inositol tris phosphate (IP3) and diacylglycerol (DG), which stimulate calcium release from intracellular stores and activate protein kinases C (PKC), respectively. The CaR and other G protein coupled receptors signal through PLC-beta, whereas tyrosine kinase growth factor receptors such as the EGF receptor signal through PLC-gamma. Calcium and PKC regulate the expression of genes in part by controlling the levels and activity of AP-1 transcription factors. 1,25(OH)2D also directly induces structural genes such as involucrin, a substrate for transglutaminase, which crosslinks it to other substrates to form the cornified envelope. 1,25(OH)2D regulates gene expression by activating the vitamin D receptor (VDR), a transcription factor, which, in combination with the retinoid X receptor (RXR) or retinoid A receptor (RAR), binds to its vitamin D response elements (VDRE) in the promoters of genes whose expression it regulates. The VDR also binds to one of two coactivator complexes, Mediator/DRIP (VDR interacting proteins) or p160/SRC (steroid hormone receptor complex), complexes which link the VDR to the RNA polymerase complex. We have recently discovered that the binding of VDR to these complexes is sequential. Binding to Mediator/DRIP occurs in the undifferentiated keratinocyte, but as the cell differentiates, DRIP(205) (the key protein of the DRIP complex binding to the VDR) levels fall, and p160/SRC binding takes over. We hypothesize that this sequential replacement of Mediator/DRIP by p160/SRC is critical for differentiation. Squamous cell carcinomas (SCC) fail to respond to the prodifferentiating actions of 1,25(OH)2D. These cells have normal levels of VDR and normal binding of VDR to VDREs. However, they fail to down-regulate DRIP(205) such that the p160/SRC complex fails to bind to VDR. This lack of sequential binding of these coactivator complexes to the VDR, we believe, maintains the cell in a state of continued proliferati

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Humans; Mediator Complex; Nuclear Proteins; Trans-Activators; Transcription Factors; Vitamin D

Mineral metabolism is dysregulated within days of acute renal injury in critically ill patients. On univariate analysis, high levels of calcitriol were associated with adverse clinical outcome in AKI. This association was not apparent after adjusting for age and APACHE II. Large controlled studies are needed to confirm these results, and determine if higher 1,25(OH). Los genotipos C/C y C/T en Colombia son tan variables como en otros grupos sanos en otras poblaciones. Los sujetos de nuestra población podrían tener riesgo para el desarrollo de enfermedades asociadas al polimorfismo del genMTHFR y con genotipos de riesgo de presentar toxicidad y efectos adversos del MTX, lo cual sugiere la necesidad de evaluar alternativas terapéuticas con estudios farmacogenéticos.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adult; Advanced Oxidation Protein Products; Aged; Aged, 80 and over; Analgesics, Opioid; Animals; Antibodies, Monoclonal; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Automation; Benzaldehydes; Bromates; Calcifediol; Calcitriol; Carcinoma, Squamous Cell; Catalase; Chromatography, Liquid; Coloring Agents; Cross-Over Studies; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytokines; Diabetic Foot; Diabetic Neuropathies; Diagnostic Self Evaluation; Diosmin; DNA Damage; Double-Blind Method; Drug Combinations; Electrodes; Endothelin-1; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Exercise; Female; Follow-Up Studies; Gene Expression Regulation; Glutathione; Hesperidin; Humans; Illicit Drugs; Indians, North American; Injections, Intravenous; Interferometry; Interleukin-1beta; Interleukin-6; Interviews as Topic; Ions; Jejunum; Kidney; Leukocyte Count; Lipid Peroxidation; Lithium; Liver; Luminescent Measurements; Male; Mice; Middle Aged; Monocytes; Nanostructures; Oklahoma; Organ Specificity; Oxidative Stress; Oxycodone; Photochemistry; Predictive Value of Tests; Pregnane X Receptor; Preoperative Period; Prescription Drugs; Receptors, Steroid; Reference Values; Reproducibility of Results; Retinoid X Receptor alpha; Retrospective Studies; RNA, Messenger; Rumen; Sheep, Domestic; Shoes; Solar Energy; Superoxide Dismutase; Survival Rate; Tandem Mass Spectrometry; Titanium; Treatment Outcome; Tumor Necrosis Factor-alpha; Varicose Veins; Vitamin D; Water Pollutants, Chemical; Weight-Bearing; Young Adult

An active form of vitamin D

Topics: Carcinoma, Squamous Cell; Genomics; Humans; Protein Disulfide-Isomerases; Receptors, Calcitriol; TRPV Cation Channels; Vitamin D

The inverse association between vitamin D and cancer risk is well-established, but the relationship with oral cancer is less well-understood. To further the understanding of these relationships, this study sought to evaluate any growth-inhibiting effects of vitamin D on well-characterized oral cancers.. This study utilized 1,25-dihydroxy Vitamin D3 to evaluate any changes in growth using CAL27, SCC15, and SCC25 oral cancer cell lines at physiological and supraphysiological concentrations.. These assays revealed that the growth of all three cancer cell lines was significantly reduced by vitamin D administration, with maximal inhibition in SCC15 of -6.8% at 50 nmol, -19.7% in CAL27, and -43.6% in SCC25 at 100 nmol (p < .05). In addition, the observed decreases in growth were associated with significant decreases in viability (ranging from -18% in SCC15, -23% in CAL27, and -47% in SCC25 cells), as well as activation of two key apoptotic pathways (caspase and bcl:bax).. The results of this study demonstrate the growth-inhibitory effects of vitamin D administration in specific oral cancer cell lines, which will enhance the understanding of oral oncologists and oral health researchers in developing standards for generalizing the health-protective effects of diet and dietary supplements as treatment options for patients with oral cancer.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Squamous Cell; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dietary Supplements; Humans; Mouth Neoplasms; Vitamin D; Vitamins

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC50 value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G0/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a strong induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment.

Topics: Alkynes; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Disease Models, Animal; Drug Screening Assays, Antitumor; Enzyme Activation; Inhibitor of Apoptosis Proteins; Mice; Transcription, Genetic; Vitamin D; X-Linked Inhibitor of Apoptosis Protein

The anticarcinogenic potential of vitamin D 25(OH)D has been attributed to the inhibition of proliferation of cells from different carcinomas. Reduced serum levels of 25(OH)D are associated with an increased incidence of various types of cancer. The influence of serum 25(OH)D on the incidence and outcome of patients with vulvar cancer is unknown.. The serum 25(OH)D levels in 24 patients with vulvar cancer and 24 age-matched cancer-free patients was investigated. The blood samples were collected between October 2009 and September 2010 and time of blood collection of each patient and control was matched to avoid seasonal variations between the pairs.. The median 25(OH)D serum levels in the under 50 year old group of patients were significantly lower in the vulvar cancer group than the controls. The younger cancer group also had an age-related trend of lower median serum level than the older population. In the control population the trend was vice versa, yet this finding was not statistically significant.. Serum 25(OH)D has a possible role in the pathogenesis and progression of vulvar cancer, but further investigations of the association of vitamin D and vulvar cancer as well as regarding its influence on patient survival and quality of life are warranted in the future.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Carcinoma in Situ; Carcinoma, Squamous Cell; Case-Control Studies; Female; Humans; Incidence; Middle Aged; Risk Factors; Seasons; Survival Rate; Vitamin D; Vulvar Neoplasms

Incorporation of zinc-binding groups into the side-chain of 1alpha,25-dihydroxyvitamin D(3) (1,25D) fully bifunctional hybrid molecules which act both as vitamin D receptor agonists and histone deacetylase inhibitors. These bifunctional hybrids display in vitro antiproliferative activity against the AT84 squamous carcinoma cell line while lacking the in vivo hypercalcemic effects of 1,25D.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase Inhibitors; Humans; Receptors, Calcitriol; Vitamin D; Zinc

1alpha,25-Dihydroxyvitamin D3 (1,25D3) exhibits antitumor activity in a variety of cancers including squamous cell carcinoma (SCC). Intrinsic resistance of SCC cells to cisplatin was observed and led to the investigation into whether 1,25D3 sensitizes SCC cells to cisplatin. Pretreatment with 1,25D3 followed by cisplatin enhanced growth inhibition in SCC cells compared with 1,25D3 alone as assessed by cytotoxicity and in vitro clonogenic assays. In addition, 1,25D3 sensitized SCC cells to cisplatin-mediated apoptosis. Treatment of tumor-bearing C3H mice with 1,25D3 before cisplatin reduced clonogenic survival using in vivo excision clonogenic assay. These results were not observed in a 1,25D3-resistant SCC variant, indicating the critical role of 1,25D3 in sensitizing SCC cells to cisplatin. Further, a marked decrease in fractional tumor volume was observed when SCC tumor-bearing mice were treated with 1,25D3 before cisplatin compared with either agent administered alone. Cisplatin has been shown to modulate p73 protein level in certain cancer cells. Our data showed that p73 level was not affected by cisplatin but increased by 1,25D3 in SCC cells. Knocking down p73 by small interfering RNA protected SCC cells against 1,25D3 and cisplatin-mediated clonogenic cell kill and apoptosis. Increasing p73 protein level by knocking down UFD2a, which mediates p73 degradation, promoted 1,25D3 and cisplatin-mediated clonogenic cell kill. These results suggest that 1,25D3 potentiates cisplatin antitumor activity in vitro and in vivo in a SCC model system possibly through p73 induction and apoptosis. The combination treatment may provide a more effective therapeutic regimen in cancer treatment.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Disease Models, Animal; DNA-Binding Proteins; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Mice; Nuclear Proteins; Tumor Protein p73; Tumor Suppressor Proteins; Vitamin D