Page 30 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 17

population of apoptotic cells, raised Bax (a pro-apoptotic protein), and also reduced
expression of a multidrug resistance-associated protein [124]. In an animal model
for squamous cell carcinoma a combination of only 10 nM 1,25-(OH) D together
2 3
with cisplatin resulted in greater caspase-3 activation than either substance given
alone. It was suggested that increased cytotoxicity resulting from a 1,25-(OH) D /
2 3
cisplatin treatment could be due to raised 1,25-(OH) D -induced apoptotic signal-
2 3
ing through the MEKK-1 pathway [118]. Also the anti-EGFR drug cetuximab
applied together with 1,25-(OH) D seems to provide increased cell cycle arrest and
2 3
apoptosis in prostate cancer cell cultures [125].
Another valid approach to cancer therapy with 1,25-(OH) D would be the use
2 3
of vitamin D analogs to block CYP24A1 activity directly. A 24-phenylsulfone
analog of vitamin D raised CYP24A1 mRNA expression in colon, prostate, and
mammary cancer cells, but inhibited its activity very rapidly in a dose-dependent
manner. This analog apparently binds to the VDR to stimulate transactivation, but
also directly interacts with and inhibits CYP24A1 protein [126].
These few examples suggest that there are various options for the use of vitamin
D for patient therapy. Most approaches are concerned with reducing activity of the
catabolic hydroxylase CYP24A1. This is based on the hypothesis that reduced
degradation of the active metabolite in combination therapy will allow the use of
much lower concentrations of 1,25-(OH) D
2 3.

1.5 Conclusion

It is well-recognized that sporadic malignancies have a multifactorial etiology.
While there is strong evidence that serum 25-(OH)D levels are inversely related to
3
tumor incidence, there are other factors equally important that will determine the
optimal concentration of 1,25-(OH) D synthesized from the precursor in extrarenal
2
3
tissues. A person’s genetic background with respect to VDR, CYP27B1 and
CYP24A1 expression caused by specific splicing mechanisms and polymorphisms
will determine production in kidney as well as in extrarenal cells. Growth factors
and sex hormones regulate expression of vitamin D hydroxylases and of the VDR
in several tissues known to be affected by sporadic cancers. Hyperproliferative cells
early during tumor progression may express CYP27B1 strongly as a defense
against progression, resulting in enhanced apoptosis and reduced mitosis. High
concentrations of 1,25-(OH) D in such tissues will invariably result in raised
3
2
expression of the catabolic hydroxylase and this necessitates the use of potent
CYP24A1 inhibitors to maintain tissue levels of the active metabolite. This high-
lights the need for reliable methods to measure tissue concentrations of 1,25-(OH) D .
2
3
However, functional analysis of vitamin D metabolism in cancer is complicated by
the heterogeneous composition of tumors, not only with respect to cell types but
also to biological grade of cells. In at least 50% of G3 undifferentiated colon
tumors, expression of CYP24A1 mRNA is extremely high whereas that of
CYP27B1 is very low. This is probably because of epigenetic mechanisms and