calcitriol and Liver-Neoplasms

The combined antitumor effects of 1,25‑dihydroxy vitamin D3 [1,25(OH)2D3] and the Notch inhibitor N‑[N‑-(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT, a synthetic γ secretase inhibitor) in liver cancer cells remain to be fully elucidated. In the present study, HepG2 cells were divided into six groups and different treatments were applied: Control, 10‑10 M 1,25(OH)2D3, 10‑8 M 1,25(OH)2D3, 10‑6 M 1,25(OH)2D3, 1 µM DAPT, 5 µM DAPT, 10 µM DAPT, and 10‑6 M 1,25(OH)2D3 + 10 µM DAPT. The proliferation, cell cycle, apoptosis, migration and invasion of the cells were then examined. The expression levels of Notch and its ligand Jagged were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. The results revealed that 1,25(OH)2D3 inhibited cell proliferation, migration and invasion; arrested cell cycle at the G1 phase, and promoted apoptosis in a concentration‑dependent manner between 10‑10 and 10‑6 M. DAPT inhibited cell proliferation, migration and invasion, arrested cell cycle at the G1 phase, and promoted apoptosis in a concentration‑dependent manner between 1 and 10 µM. Additionally, 1,25(OH)2D3 and/or DAPT reduced the expression of Notch1, Notch2, Jagged1 and Jagged2. The co‑application of 10 µM DAPT further increased the anticancer effect of 10‑6 M 1,25(OH)2D3. Collectively, these results indicated that the treatment of HepG2 cells with 1,25(OH)2D3 inactivated Notch signaling, prevented proliferation, migration and invasion, and promoted apoptosis. The combined application of 1,25(OH)2D3 with DAPT may be a useful treatment for preventing the onset or progression of liver cancer.

Topics: Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Movement; Cell Proliferation; Diamines; Drug Combinations; Humans; Liver Neoplasms; Neoplasm Invasiveness; Receptors, Notch; Thiazoles; Tumor Cells, Cultured; Vitamin D

Hepatic progenitor cells (HPCs) might be the origin of hepatocellular carcinoma. 1α,25-Dihydroxyvitamin D3 (1,25(OH)

Topics: Acyltransferases; Adaptor Proteins, Signal Transducing; Aflatoxin B1; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Dedifferentiation; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Liver Neoplasms; Mice; Mice, Inbred ICR; Phosphatidylinositol 3-Kinases; Phosphoproteins; Poisons; Proto-Oncogene Proteins c-akt; Stem Cells; Transcription Factors; Tumor Cells, Cultured; Vitamin D; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

Hepatocellular carcinoma (HCC) is the most diagnosed liver cancer without effective treatments available for advanced HCC. Vitamin D is getting popular due to its anti-cancer characteristics. However, the clinical application of 1α,25(OH)2D, the active form of vitamin, is hampered by its hypercalcemia side effect. 1α,25(OH)2D is converted from 25(OH)D, the index of serum vitamin D status, by CYP27B1, which is originally found in kidneys but recently detected in non-renal tissues. 25(OH)D has been shown to repress some cancers expressing CYP27B1 due to the local conversion of 25(OH)D to 1α,25(OH)2D, which works in a intra-, auto-, or paracrine manner and thus minimizes the risk of hypercalcemia. In this study, we found CYP27B1 expression in human hepatocyte, HCC, and HepG2 cells. As we treated HepG2 cells with 25(OH)D, the 1α,25(OH)2D target gene CYP24A1 expression was increased and was further upregulated as CYP27B1 transfection or downregulated as CYP27B1 knockdown. Other 1α,25(OH)2D target genes in HepG2 cells, p21 and p27 were also stimulated by 25(OH)D after CYP27B1 transfection. Further, 25(OH)D could inhibit HepG2 cells growth, which was potentiated by CYP27B1 transfection. Collectively, we showed for the first time that HCC expressed CYP27B1 and was able to covert 25(OH)D to 1α,25(OH)2D in vitro, thus responsive to 25(OH)D treatment. Our data justifies the application of 25(OH)D and CYP27B1 gene transfection therapy in further HCC treatment studies.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Carcinoma, Hepatocellular; Cell Proliferation; Hep G2 Cells; Humans; Liver Neoplasms; Vitamin D

The discovery that the active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)(2)D] can modulate cellular proliferation and differentiation of cancer cells has led to its potential application as a chemotherapeutic agent to treat a variety of cancers. However, the use of 1α,25(OH)(2)D is limited due to its lethal side effect of hypercalcemia upon systemic administration. To overcome this drawback, numerous analogs have been synthesized. In this report, we examined the anti-proliferative activity of a new analog, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10), in HepG2 liver cancer cells, and studied the potential mechanisms mediating this action. We found that MART-10 exhibited approximately 100-fold greater activity than 1α,25(OH)(2)D(3) in inhibiting HepG2 cell proliferation as determined by cell number counting method. MART-10 was also approximately 100-fold more potent than 1α,25(OH)(2)D(3) in the upregulation of p21 and p27, that in turn arrested HepG2 cells at the G(0)/G(1) phase to a greater extent. Given that no active caspase 3 was detected and treatment with 1α,25(OH)(2)D(3) or MART-10 did not further increase the fractions of apoptotic and necrosis cells over the controls, the growth-inhibitory effect of 1α,25(OH)(2)D(3) and MART-10 on HepG2 cells may not involve apoptosis. Overall, our findings suggest that MART-10 is a good candidate as a novel therapeutic regimen against liver cancer. Further pre-clinical studies using animal models and the subsequent human clinical trials are warranted.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Vitamin D