Table 1.
Mechanisms of cell cycle arrest induced by calcitriol and/or vitamin D analogues on cancer cell lines.
| Tissue of Origin | Author | Cell Line/s | Treatment (Concentration) | Mechanism of Action | Conclusion |
|---|---|---|---|---|---|
| Breast cancer | S. Jensen et al. [36] | MCF-7 | 1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 increased tumor suppressor pRB expression and decreased expression of CDK 4, 6 and 2 and increased expression of CDKI p21. 1,25(OH)2D3 treatment also decreased C-MYC oncoprotein expression. | G0/G1 cell cycle arrest |
| Chiang et al. [37] | MCF-7 | 1. MART-10 (1 nM, 10 nM and 100 nM) 2. 1,25(OH)2D3 (10 nM, 100 nM and 1000 nM) |
1,25(OH)2D3 and MART-10 induced p21 and p27 CDKI expression and induced G0/G1 cell cycle arrest. | G0/G1 cell cycle arrest | |
| Wu et al. [38] | MCF-7 E MCF-7 L BT20 T47D ZR75 |
EB1089 (0.01 nM, 0.1 nM, 1 nM, 10 nM) | EB1089 induced p21 expression and increased p21-CDK2 complex formation, which caused decreased DNA synthesis in all cell lines except EB1089-resistant MCF-7 L cell line. p27 was increased by EB1089 treatment in BT20 and ZR75 cell lines only. |
Cell-dependent G0/G1 cell cycle arrest | |
| Ovarian cancer | Li et al. [39] | 2008 CAOV3 |
1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 decreased the expression of cyclin E and Skp2, which resulted in decreased CDK2-cyclin E activity and decreased p27 phosphorylation, respectively. The decreased p27 phosphorylation prevents p27 protein degradation, allowing it to accumulate in the cell and induce G1/G0 cell cycle arrest. | G0/G1 cell cycle arrest |
| Li et al. [39] | OVCAR3 | 1,25(OH)2D3 (100 nM) |
VDR stabilized intracellular p27 protein levels by decreasing the activity of the Skp2 proteosome, which is responsible for p27 degradation. | G0/G1 cell cycle arrest | |
| Human head and neck squamous cells | Akutsu et al. [40] | SCC25 | EB1089 (1 nM, 10 nM and 100 nM) | Calcitriol analogue EB1089 upregulated growth repair damage factor GADD45α. | G0/G1 cell cycle arrest |
| Salehi-Tabar et al. [41] | SCC25 | 1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 decreased C-MYC expression and increased C-MYC repressor MAD1 levels. The increased MAD1 prevented C-MYC’s transcriptional regulation of target genes and inhibited cell proliferation. | G0/G1 cell cycle arrest | |
| Thyroid cancer | Liu et al. [42] | PTC-1 NPA WRO |
1. 1,25(OH)2D3 (0.1 nM, 1 nM, 10 nM, 100 nM and 1000 nM) 2. EB1089 (0.1 nM, 1 nM, 10 nM, 100 nM and 1000 nM) |
1,25(OH)2D3 and EB1089 increased p27 expression and decreased Skp2 expression, which allowed p27 to accumulate and induce G0/G1 cell cycle arrest. | G0/G1 cell cycle arrest |
| Promyelocytic leukaemia | Wang et al. [43] | HL60 |
1,25(OH)2D3 (1 nM and 100 nM) | 1,25(OH)2D3 induced p12 and p27 mRNA and protein expression and induced G0/G1 cell cycle arrest. | G0/G1 cell cycle arrest |
| Prostate cancer | Washington et al. [44] | C4-2 | 1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 decreased C-MYC expression and induced G1 cell cycle arrest in a pRB-independent manner. | G0/G1 cell cycle arrest |
| Bao et al. [45] | LNCaP CWR22R PC-3 DU145 |
1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 increased pRB and p27 expression and decreased CDK2 expression, thereby preventing entry into the S phase. | G0/G1 cell cycle arrest | |
| Boyle et al. [46] | LNCaP | 1,25(OH)2D3 (10 nM) | Calcitriol upregulated the mRNA and protein expression of insulin-like growth factor binding protein 3, which resulted in increased expression of p21 and induced a G0/G1 cell cycle arrest. | G0/G1 cell cycle arrest | |
| Flores et al. [47] | LNCaP | 1,25(OH)2D3 (50 nM) | 1,25(OH)2D3 decreased CDK2 activity leading to hypophosphorylation of pRB, which prevented entry into the S phase. | G0/G1 cell cycle arrest | |
| Rohan et al. [48] | LnCaP C4-2 RWPE-1 |
1,25(OH)2D3 (10 nM) | Downregulation of C-MYC mRNA and protein expression induced by 1,25(OH)2D3 treatment. | G0/G1 cell cycle arrest | |
| Colorectal adenoma and carcinoma | Diaz et al. [49] | SW620 PC/JW HT29 |
1. 1,25(OH)2D3 (0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM) 2. EB1089 (0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM) |
Calcitriol and analogue EB1089 increased cells in G1 in a p53- dependent manner. | G0/G1 cell cycle arrest |
| Pancreatic cancer | Li et al. [50] | HPDE6-C7 Panc-1 |
1,25(OH)2D3 (1 nM, 5 nM, 10 nM, 50 nM, 100 nM) | p21 expression was significantly increased in HPDE6-C7 cells but not in metastatic Panc-1 cells. |
G0/G1 cell cycle arrest |
| Petterson et al. [51] | AsPc-1 BxPc-3 T3M-4 |
1. EB1089 (50 nM) 2. CB1093 (50 nM) |
EB1089 and CB1093 induced cell cycle arrest in all cell lines investigated in this study. | G0/G1 cell cycle arrest | |
| Schwartz et al. [52] | BxPC-3 Hs700T Hs766T AsPC-1 |
1. 1,25(OH)2D3 (100 nM) 2. 25(OH)D3 (100 nM or 2µM) |
Increased expression of p21 and p27 proteins in BxPC-3, Hs700T and AsPC-1 cell lines only. | G0/G1 cell cycle arrest | |
| Malignant pleural mesothelioma | Gesmundo et al. [53] | MeT-5A Msto-211H REN |
1,25(OH)2D3 (1 nM, 10 nM, 50 nM and 100 nM) | Reduction in C-MYC expression and cyclin A, cyclin D1 and cyclin D2 which induced a G1/G0 cell cycle arrest. | G0/G1 cell cycle arrest |
| Malignant melanoma | Reichrath et al. [54] | IGR MelJuso MeWo SK-Mel-5 SK-Mel-25 SK-Mel-28 SM2 |
1. 1,25(OH)2D3 (100 nM) 2. 25(OH)D3 (100 nM) 3. EB1089 (100 nM) |
Treatments induced a significant decrease in cell proliferation of MeWo, SK-Mel 28, and SM2 melanoma cell lines. In addition, IGR, MelJuso, SkMel5 and SK-Mel-25 cell lines demonstrated no significant change in cell growth. | Cell cycle not investigated; however, a significant decrease in cell proliferation was observed in a cell-specific manner. |
| Spath et al. [55] | IR6 VAG 1007 |
1,25(OH)2D3 (50 nM) | 1,25(OH)2D3 induced G1/G0 cell cycle arrest in IR6 cell line by p21 and p27 upregulation, and cyclin D downregulation. 1,25(OH)2D3 induced G2/M arrest in VAG cell line by decreased cyclin B1 expression. In 1007 melanoma cell line, 1,25(OH)2D3 increased cells in the proliferative compartments of the cell cycle (S-phase plus G2 phase) by increased cyclin A1, p21 and p27 expression. |
Cell-specific cell arrest responses were observed to 1,25(OH)2D3 treatment. | |
| Liu et al. [56] | U937 | 1,25(OH)2D3 (100 nM) | 1,25(OH)2D3 induced p21 mRNA expression in a p53-independent manner and 1,25(OH)2D3 induced p27 gene and protein expression. | 1,25(OH)2D3 arrested cell proliferation and induced cell surface markers of cell differentiation. |
Abbreviations: 1,25(OH)2D3, calcitriol; 25(OH)2D3, calcidiol; EB1089, Seocalcitol; CB1093, novel 20-epi-vitamin D3 analogue; MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃; pRB, retinoblastoma protein.