tretinoin and maxacalcitol

Vitamin A and D(3) have a very strong differentiation induction effect.. We examined the anti tumor effect on head and neck squamous cell carcinoma (HNSCC) by treatment with several vitamins having strong differentiation induction effects in vitro.. We used KB cell that an oral floor squamous cell carcinoma, vitamins as all-trans retinoic acid (ATRA), 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), 1alpha,25(OH)(2)D(3) (calcitriol) and 22-oxa-1,25-(OH)(2)D(3) (OCT). We determined receptors of vitamin A and D(3) using RT-PCR. Furthermore, we investigated the proliferation of tumor cells in concentration dependency using [3H]TdR uptake method, apoptosis and apoptosis related factors using TUNEL method and real-time PCR, cell cycle changes using flow cytometry, changing of the sensitivity of using MTT method, cytokine production and the angiogenesis factor using ELISA, by treatment with these vitamins.. The deficit of RAR-beta was found in the KB cell. Each vitamin suppressed the cell proliferation, induced apoptosis, and cell cycle arrest, upregulated sensitivity of the chemotherapeutics drugs and downregulated several angiogenesis factors and an apoptotic factor; survivin.. These results support the idea that vitamin A, D(3) and their derivatives are useful for preventing and/or treating patients with HNSCC.

Topics: Angiogenesis Inducing Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Calcitriol; Carcinoma, Squamous Cell; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cisplatin; Cytokines; Flow Cytometry; Fluorouracil; Head and Neck Neoplasms; Humans; In Situ Nick-End Labeling; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tretinoin; Vitamin A; Vitamin D

Our previous studies demonstrated retinoic acid (RA) inhibition of activation protein-1 (AP-1) formation in TNF-alpha-treated osteoblastic MC3T3-E1 cells via c-fos suppression. In the present study, we observed that 1alpha25(OH)2D3 was able to interfere at the transcriptional level with RA inhibition of TNF-alpha-induced c-fos gene expression in cells when the cells were incubated with the vitamin for 24 hr before the RA treatment. 22-Oxa-1,25(OH)2D3 (OCT), an analog derivative of 1alpha25(OH)2D3, having high affinity for the vitamin D3 receptor (VDR), also interfered with the RA-induced inhibition of c-fos gene expression in the TNF-alpha-treated cells. In contrast, this was not the case for 24,25(OH)2D3. Moreover, we observed that the interfering effect was clearly blocked by pretreatment with VDR antisense oligonucleotide. 1alpha25(OH)2D3 interfered with RA inhibition of the TPA-response element binding activity of AP-1 in the cytokine-treated cells. Furthermore, 1alpha25(OH)2D3 actually blocked the AP-1-mediated gene expression of monocyte chemoattractant JE/MCP-1 induced in the cytokine-treated cells. The present study suggests a regulatory interference by 1alpha25(OH)2D3 for RA inhibition of TNF-alpha-induced AP-1 activity in osteoblasts.

Topics: 3T3 Cells; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Blotting, Northern; Calcitriol; Chemokine CCL2; DNA, Antisense; Drug Interactions; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation; Genes, fos; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Osteoblasts; Receptors, Calcitriol; Transcription Factor AP-1; Transcription, Genetic; Tretinoin; Tumor Necrosis Factor-alpha; Vitamin D; Vitamin D Response Element

Pulmonary metastasis is a major cause of death and a major obstacle to the successful treatment of canine osteosarcoma. However, the residual capacity of the neoplasia for differentiation and its susceptibility to undergo apoptosis may be used to suppress its growth and metastatic properties. The highly metastasizing POS (HMPOS) canine osteosarcoma cell line which preferentially metastasize to the lungs was used to test the possible efficacy of 22-oxa-calcitriol (OCT) and all- trans retinoic acid (ATRA) to inhibit growth and pulmonary metastasis of the subcutaneously grown osteosarcoma in nude mice. Treatments in vitro, morphologically elongated and increased alkaline phosphatase activity and staining of cells. Tumour growth in vivo was inhibited significantly and the combination treatment of OCT and ATRA (OCT + ATRA) exerted a synergistic and stronger suppression at concentration of 1.0 microg kg(-1)body weight when given subcutaneously three times a week for 5 weeks. The subcutaneous tumours of the control mice consisted of osteoblast-like cells and isolated chondroblast-like cells, but formed several areas of osteoid and increased amount of collagen tissue in all treated mice. Pinpoint macrometastatic nodules developed only in all control mice. Micrometastatic nodule developed only in two of six mice treated with ATRA. However, nodule size and number, and lung wet weight were all reduced significantly. Metastasis were not seen in the mice treated with OCT or OCT + ATRA. This study demonstrated that inhibition of growth and pulmonary metastasis was induced by subcutaneous treatment with these drugs and suggest that both its differentiating and apoptotic inducing activities may be responsible for the antitumour effects. These drugs may be useful in the clinic as an adjunct for the treatment of canine osteosarcoma.

Topics: Alkaline Phosphatase; Animals; Antineoplastic Agents; Biomarkers; Bone Neoplasms; Calcitriol; Cell Division; Dog Diseases; Dogs; Female; Lung Neoplasms; Mice; Mice, Nude; Osteosarcoma; Transplantation, Heterologous; Tretinoin; Tumor Cells, Cultured

The effects of 22-oxacalcitriol (OCT), calcitriol and all-trans retinoic acid (ATRA) on the induction of functional differentiation and growth inhibition of the canine osteosarcoma cell line POS were investigated in vitro via bone differentiation markers and proliferation assays, respectively. The intracellular alkaline phosphatase (ALP) activity and the gamma-carboxyglutamic acid osteocalcin (GLA-OC) and procollagen type I C peptide (PIP) production were used as markers of differentiation. Treatment with 10(-8) M concentrations of all drugs for 72 h significantly inhibited growth (P < 0.0001) and increased ALP activity and GLA-OC and PIP production in POS. OCT, calcitriol and ATRA significantly increased the: ALP activity from 1.58 +/- 0.14 mumol/min/mg protein (mean +/- SD; control) to 2.50 +/- 0.09 (P < 0.0001), 2.30 +/- 0.14 (P < 0.0001) and 2.00 +/- 0.14 (P = 0.0008), respectively; GLA-OC production from 0.71 +/- 0.01 ng/ml (control) to 2.87 +/- 0.01 (P < 0.0001), 2.87 +/- 0.11 (P < 0.0001) and 1.36 +/- 0.06 (P < 0.0001), respectively; and PIP production from 433.91 +/- 23.29 ng/ml (control) to 536.54 +/- 15.46 (P = 0.0002), 497.06 +/- 1.99 (P = 0.0028) and 481.66 +/- 0.01 (P = 0.0104), respectively. This study demonstrated that treatment with these drugs induced a phenotypic maturation of POS cells into cells that exhibit the properties of functionally mature bone cells with parallel growth inhibition. The effects of these drugs on functional differentiation may be useful to complement the progression of a normal osteogenic differentiation process in the sarcoma.

Topics: Alkaline Phosphatase; Animals; Antineoplastic Agents; Bone Neoplasms; Calcitriol; Dog Diseases; Dogs; Osteocalcin; Osteosarcoma; Peptide Fragments; Procollagen; Tretinoin; Tumor Cells, Cultured

A promyelocytic leukemia cell line, HL-60, was induced to differentiate into monocyte-macrophage lineage cells by treatment with active vitamin D3 and phorbol esters, and into granulocyte lineage ones by retinoic acid and dimethylsulfoxide. The changes in intracellular concentration of free calcium ions ([Ca2+]i) were measured and analyzed by calcium-imaging analysis with Fura 2-AM. A significant and transient increase in [Ca2+]i was observed in active vitamin D3 and phorbol ester systems; however, no change was detected with retinoic acid and dimethylsulfoxide. This increase was due to the influx of calcium ions from outside of the cells, and L-type calcium channels were shown to mainly contribute to this influx. Protein kinase C was also shown to be involved in the increase in [Ca2+]i.

Topics: Calcitriol; Calcium; Cell Differentiation; Dimethyl Sulfoxide; Fura-2; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Macrophages; Monocytes; Protein Kinase C; Spectrophotometry, Ultraviolet; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured