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Tumor Biology |
Cancer Research Campaign Colorectal Tumour Biology Research Group, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom [G. D. D., C. P.]; University Department of Surgery, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom [M. G. T.]; Biological Research and Development, LEO Pharmaceutical Products, DK-2750 Ballerup, Denmark [L. B.]; and Department of Oral and Dental Science, University of Bristol Dental School, Bristol BS1 2LY, United Kingdom [A. H.]
Vitamin D3 is believed to reduce the risk of colon
cancer, and serum levels inversely correlate with colorectal cancer
incidence. The active metabolite, 1
,25-dihydroxyvitamin
D3, has previously been shown to inhibit growth and promote
differentiation of colon cancer cells. The vitamin D analogue, EB1089,
is currently under clinical trial in a variety of cancers because of
its growth-inhibitory effects in vitro and reduced
hypercalcemic effects in vivo. The mechanism of growth
inhibition by EB1089, however, remained to be determined. In this study
we examined the effects of 1,25-dihydroxyvitamin D3 and
EB1089 on five colorectal tumor cell lines (two adenoma and three
carcinoma) to determine the mechanism of growth inhibition and to
ascertain whether premalignant adenoma cells were responsive to these
agents. 1,25-Dihydroxyvitamin D3 and EB1089 induced
p53-independent apoptosis in adenoma and carcinoma cell lines in a
dose-dependent manner between 10-10 and 10-6
M. EB1089, as well as inducing apoptosis, increased the
proportion of cells in the G1 phase, particularly in
the adenoma cell lines. In two of the three carcinoma cell lines (SW620
and PC/JW), levels of apoptosis induced by EB1089 were similar or
greater than those induced by 1,25-dihydroxyvitamin D3.
Although the carcinoma cell line HT29 was relatively resistant to
apoptosis induced by EB1089 compared with 1,25-dihydroxyvitamin
D3, EB1089 markedly inhibited cell yields. These
observations offer promise for the clinical use of EB1089. To determine
whether the induction of apoptosis by 1,25-dihydroxyvitamin
D3 and EB1089 was potentially via a differentiation
pathway, alkaline phosphatase activity was measured as a marker of
differentiation. Induction of alkaline phosphatase was observed in the
floating apoptotic cells as well as in the adherent population. A link
between the induction of differentiation and apoptosis by
1,25-dihydroxyvitamin D3 and EB1089 is suggested by the
occurrence of apoptosis subsequent to the induction of differentiation.
To investigate the molecular pathway to apoptosis induction, members of
the Bcl-2 family of proteins were examined (Bcl-2, Bcl-x, Bax, and
Bak). Decreased Bcl-2 was observed in some cell lines, particularly in
response to EB1089, but was not essential for apoptosis. Levels of the
proapoptotic protein Bak, however, were consistently increased in all
of the five cell lines in association with apoptosis induced by either
agent. The results implicate Bak protein in the induction of apoptosis
by 1,25-dihydroxyvitamin D3 or its analogue EB1089. The
ability of EB1089 to induce apoptosis in colorectal carcinoma cells
suggests that this or other vitamin D analogues may prove clinically
effective for the treatment of colorectal cancer. Furthermore, the fact
that it induces cell cycle arrest and apoptosis in the premalignant
adenoma cells may suggest an application in colorectal cancer
chemoprevention.
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P. A. Hershberger, T. F. McGuire, W.-D. Yu, E. G. Zuhowski, J. H. M. Schellens, M. J. Egorin, D. L. Trump, and C. S. Johnson Cisplatin Potentiates 1,25-Dihydroxyvitamin D3-induced Apoptosis in Association with Increased Mitogen-activated Protein Kinase Kinase Kinase 1 (MEKK-1) Expression Mol. Cancer Ther., August 1, 2002; 1(10): 821 - 829. [Abstract] [Full Text] [PDF]
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U. Peters, K. A. McGlynn, N. Chatterjee, E. Gunter, M. Garcia-Closas, N. Rothman, and R. Sinha Vitamin D, Calcium, and Vitamin D Receptor Polymorphism in Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1267 - 1274. [Abstract] [Full Text] [PDF]
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K. A. Moffatt, W. U. Johannes, T. E. Hedlund, and G. J. Miller Growth Inhibitory Effects of 1{alpha}, 25-Dihydroxyvitamin D3 Are Mediated by Increased Levels of p21 in the Prostatic Carcinoma Cell Line ALVA-31 Cancer Res., October 1, 2001; 61(19): 7122 - 7129. [Abstract] [Full Text] [PDF]
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J. Prudencio, N. Akutsu, N. Benlimame, T. Wang, Y. Bastien, R. Lin, M. J. Black, M. A. Alaoui-Jamali, and J. H. White Action of Low Calcemic 1{{alpha}},25-Dihydroxyvitamin D3 Analogue EB1089 in Head and Neck Squamous Cell Carcinoma J Natl Cancer Inst, May 16, 2001; 93(10): 745 - 753. [Abstract] [Full Text] [PDF]
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U. Maurer, F. Jehan, C. Englert, G. Hubinger, E. Weidmann, H. F. DeLuca, and L. Bergmann The Wilms' Tumor Gene Product (WT1) Modulates the Response to 1,25-Dihydroxyvitamin D3 by Induction of the Vitamin D Receptor J. Biol. Chem., February 2, 2001; 276(6): 3727 - 3732. [Abstract] [Full Text] [PDF]
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T. F. McGuire, D. L. Trump, and C. S. Johnson Vitamin D3-induced Apoptosis of Murine Squamous Cell Carcinoma Cells. SELECTIVE INDUCTION OF CASPASE-DEPENDENT MEK CLEAVAGE AND UP-REGULATION OF MEKK-1 J. Biol. Chem., July 6, 2001; 276(28): 26365 - 26373. [Abstract] [Full Text] [PDF]
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