Page 221 - Vitamin D and Cancer

208 F.S.G. Cheung and J.K.V. Reichardt

p53 having a dual role of JNK inactivation while in the same time activate cell cycle
arrest related genes to protect cells from apoptosis upon UVB irradiation [99].
If 1,25(OH) D could prevent the apoptosis of UVB irradiated cells, the next concern
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is the danger of allowing cells with increased DNA damage to survive [61]. Gupta et al.

tested whether 1,25(OH) D enhanced cell survival would lead to an accumulation of
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−9
UV induced DNA damage. Cells treated at physiological dose of 1,25(OH) D (10 M)
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24 h prior to irradiation not only showed significant dose dependant increase of cell
survival, but a dose dependant decrease in TD was also observed. Such effects can be
reproduced by treating cells with 1,25(OH) D immediately after irradiation. More
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importantly, there was a corresponding increase in p53 with decreasing TD. As it is
known that UV induced increases in nitric oxide (NO) products [22] can enhance DNA
damage by UVR [151] and inhibit CPD repair [6], the levels of nitrite were also mea-
sured and a significant reduction of nitrite in 1,25(OH) D treated cells was found.
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Therefore these experiments [61] suggest that the reduction of TD or DNA damage by
1,25(OH) D , is due to the increase of p53 along with a decrease of NO products that
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results in increased DNA repair. Taken together, the effect of 1,25(OH) D on UV irra-
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diated cells is to reduce the number of apoptotic cells and enhance cell survival by
improving UVB induced DNA damage repair. The protection of 1,25(OH) D against
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the formation of CPD was also supported by another study [34], however, these effects
were only seen using pharmacological doses and a suppression in p53 was obtained. It
is argued that the suppression of CPD formation by 1,25(OH) D may have prevented
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the need for p53 accumulation for DNA repair. However, such discrepancies may also
be due to the difference in cell culture and irradiation conditions.
The fact that the photoprotective effects of adding 1,25(OH) D immediately
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after irradiation was comparable to those with 24 h 1,25(OH) D pretreatment,
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prompted studies to investigate the mechanism of 1,25(OH) D in producing such
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effects. A series of elegant studies [39, 40, 162] found that the photoprotective
effects of 1,25(OH) D described above can be reproduced by three low- calcemic
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analogs of vitamin D both in vitro and in vivo. It was described in Chapter 2
(Sect. 2.2) that the existence of trans and cis isomers allows 1,25(OH) D to medi-
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ate genomic as well as rapid, non genomic responses. Rapid response signaling is
mediated by the cis conformers. These experiments showed that cis-locked, low
calcemic rapid response agonists, 1,25(OH) lumisterol (JN) and 1,25(OH) –7-
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dehydrocholesterol (JM) added immediately after irradiation, displayed similar
protective effects to that of 1,25(OH) D at physiological doses. A rapid response
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antagonist (HL) completely blocked the photoprotective effects [162] while a
genomic response antagonist (TEI-9647) had no effect [40]. In fact, the protective
effects of the low calcemic rapid response agonist, JN, has been confirmed recently
in vivo [39]. Furthermore, the low calcemic homo hybrid analog (QW) with some
transcriptional capacity, was also able to reduce pyrimidine dimmers as well as
immunosuppression in the same level of effectiveness as 1,25(OH) D when topi-
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cally applied to the epidermis of irradiated hairless Skh:HR1 mice [40]. These
results show QW to be a potential candidate in skin cancer prevention (see
Sect. 9.5.5). Therefore, the data from these studies provide strong evidence for
vitamin D photoprotection via the rapid response pathway.