Abstract
To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop “treatable”, pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 μg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential “treatable”, pre-neoplastic, biomarkers of risk for colorectal neoplasms.
Highlights
Colorectal cancer remains the second leading cause of cancer death in the United States, and mortality has only modestly declined in recent years despite advances in screening, treatment, and prevention [1]
In a previous pilot, randomized, controlled trial in sporadic colorectal adenoma patients (n = 92), we found that supplemental calcium (2,000 mg/day) and vitamin D3 (800 IU/day [20 μg/day]) over six months increased the expression of p21 [11] and bax [12] in the normal-appearing colorectal mucosa, and in a full-scale trial (n = 193) calcium supplementation statistically significantly shifted downward the colorectal crypt proliferation zone [13]
The mean serum 25(OH)D increased from baseline to 1-year follow-up by 9.17 ± SD 9.68 ng/mL (22.97 ± SD 24.20 mmol/L or 0.0000917 ± SD 0.0000968 kg/m3) among participants assigned to the vitamin D treatment groups, and decreased by 1.69 ± SD 9.45 ng/mL (4.22 ± SD 23.62 mmol/L or 0.0000169 ± SD 0.0000945 kg/m3) among those who received vitamin D placebo
Summary
Colorectal cancer remains the second leading cause of cancer death in the United States, and mortality has only modestly declined in recent years despite advances in screening, treatment, and prevention [1]. Proposed mechanisms of calcium against colorectal cancer include binding to bile acids and fatty acids to protect colonocytes from their toxic and mutagenic effects [6]; direct regulation of the cell cycle via binding with the calcium-sensing receptor, resulting in suppression of proliferation and promotion of differentiation and apoptosis [4, 7, 8]; inhibition of oxidative DNA damage [4]; and modification of colorectal cancer-related cell signaling pathways [4]. Proposed mechanisms of vitamin D against colorectal cancer include modulation of more than 200 genes involved in, among others, bile acid metabolism, cell cycle regulation, cell adhesion, and growth factor signaling [7]
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