seocalcitol and Liver-Neoplasms

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Calcitriol; Carcinoma, Hepatocellular; Disease Progression; Female; Humans; Liver Neoplasms; Male; Middle Aged; Receptors, Calcitriol; Treatment Outcome

EB1089 exhibits a high level of antiproliferative activity against various tumors. However, it is not known whether the mechanism of EB1089 induced the growth inhibition in human hepatic-carcinoma. Here we found that EB1089 significantly reduced cell growth in human hepatoma cells (Hep-G2) and blocked Hep-G2 cell-associated tumor formation in nude mice. The growth inhibition was linked to cell cycle G1 phase arrest by the accumulation of p27 and a reduction of Skp2. Knockdown of Skp2 reversed the p27 induction and G1 arrest. Taken together, our data indicate that EB1089 inhibitory activity is associated with alteration of cell cycle checkpoints through Skp2-dependent p27 induction in Hep-G2 cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Calcitriol; Carcinoma, Hepatocellular; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; G1 Phase; Humans; Liver Neoplasms; Mice; Mice, Nude; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; S-Phase Kinase-Associated Proteins; Transfection; Tumor Cells, Cultured

Study regulatory mechanism of EB1089 for hepatocarcinoma cell proliferation.. HHCC were incubated in culture media with 100 nmol/L, 10 nmol/L and 1 nmol/L EB1089 for 2 d, 4 d and 6 d respectively. The anti-proliferative effect were examined by MTT and the plate clone forming test. The apoptosis was detected by Electron Microscope and flow cell device. Westernblot were used to detect p27Kipl and PTEN expression.. EB1089 could inhibit the proliferation of hepatocellular cell line HHCC. EB1089 could induce apoptosis of hepatocarcinoma cells. Western blot showed that EB1089 could elevate the expression level of p27Kipl and PTEN protein.. EB1089's inhibition to hepatocarcinoma is probably realized through inducing apoptosis of hepatocarcinoma cells and elevating the expression level of p27Kipl and PTEN protein.

Topics: Antineoplastic Agents; Apoptosis; Calcitriol; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Humans; Liver Neoplasms; Vitamin D

This study aimed at investigating the effects of vitamin D analogue EB1089 on the proliferation and apoptosis of hepatic carcinoma cells.. Hepatic carcinoma cell strain G(2) (Hep-G(2)) in which prominent vitamin D receptor (VDR) mRNA could be expressed and the cell strain T (HCC-T) negative in VDR gene expression were incubated in culture media with 100 nmol/L, 10 nmol/L and 1 nmol/L EB1089 for 2 d, 4 d and 6 d, respectively. Survival and proliferation of the cells were detected by blue tetrazolium colorimetric test and plate clone-forming test, the VDR mRNA expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and apoptosis of the cells was detected by flow cytometry (FCM) and electron microscopy.. EB1089 could inhibit the proliferation of hepatocellular cell line Hep-G(2) that expressed prominent vitamin D receptor mRNA, the inhibitory rate is 17.5% approximately 72.1%. On the other hand, EB1089 had no anti-proliferative effect on hepatocellular cell line HCC-T in which the gene expression of vitamin D receptors was negative. The electron microscope results showed that EB1089 could induce apoptosis of hepatocarcinoma cells and the percentages of apoptotic cells measured by flow cytometer was 21.4%. Cell cycle progression was blocked at G(1) phase with EB1089.. EB1089 could inhibit proliferation of human Hep-G(2), probably through VDR, and induce apoptosis of the cells.

Topics: Antineoplastic Agents; Apoptosis; Calcitriol; Carcinoma, Hepatocellular; Cell Division; Humans; Liver Neoplasms; Tumor Cells, Cultured

1alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3) has been shown to inhibit the proliferation of various cancer cells including colon, prostate, melanoma, osteosarcoma and breast cancer.. The human hepatoma cell line (HepG2) was cultured with 1,25(OH)2D3 or one of two analogues EB1089 or CB1093 for various durations. Cellular proliferation was measured by uptake of [3H]thymidine, and cell numbers were determined by trypan blue exclusion counting.. 1,25(OH)2D3, EB1089 and CB1093 all inhibited proliferation of HepG2 by up to 90% after 5 days of treatment, compared to the untreated controls. Decreased proliferation was associated with an approximately 50% reduction in cell numbers at concentrations of up to 10(-10) mol/L after 5 days of treatment with 1,25(OH)2D3. Cell proliferation rapidly recovered in cultures treated with lower concentrations of 1,25(OH)2D3 (10(-10) and 10(-11) mol/L) when 1,25(OH)2D3 was removed from the cultures by placing cells in serum containing medium without 1,25(OH)2D3. When HepG2 cells were treated with 10(-8) mol/L 1,25(OH)2D3 for 5 weeks, there was still significant inhibition of proliferation, although at week 5 there was 66% inhibition compared to 93% at the end of week 1.. 1,25(OH)2D3, EB1089 and CB1093 all significantly inhibit the proliferation of HepG2 hepatoblastoma cells, with EB1089 being the most potent at lower concentrations. Inhibition can be maintained for at least 4 weeks, but is reversed after removal of vitamin D3.

Topics: Antineoplastic Agents; Calcitriol; Cell Division; Hepatoblastoma; Humans; Liver Neoplasms; Tumor Cells, Cultured