Page 222 - Vitamin D and Cancer

9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 209

9.5.5 Vitamin D Analogs as Potential Agent for Skin Cancer
Prevention

Accumulating evidence of the pro differentiating, anti proliferating and photo-
protective effects of 1,25(OH) D from in vitro, in vivo and epidemiologic
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studies have raised a growing interest in the possibility of making vitamin D
a therapeutic agent [21, 107]. Most clinical trials are impeded by the severe
hypercalcemia effect of 1,25(OH) D and the problem of 24-OHase degradation.
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This raises the idea that the development of vitamin D analogs with more spe-
cific actions to minimize current side effects will have a much greater clinical
potential [62, 103].
The hypercalcemic vitamin D analog QW was described earlier in Sect. 9.5.4 in
respect to its photoprotective effects in reducing CPDs [40]. In fact, QW has under-
gone some intense pre-clinical trials and its therapeutic effects was compared to
1,25(OH) D as well as Paricalcitol, another hypercalcemic vitamin D analog. It
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was found that QW was 80–100 times less calciuric than the classical 1,25(OH) D
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[127]. Both QW and Paricalcitol were tested in SCC models and the molecular
mechanism were shown to involve a number of pathways, such as those induced in
growth cycle arrest, DNA synthesis inhibition, as well as apoptosis promotion and
pro survival actions. To elicit their anti-tumor effects, both QW and Paricalcitol
decreased the positive cell cycle regulator cyclin dependant kinase 2 and inhibited
the pro-survival/pro-growth pathway mediators such as phospho-Akt, phospho-
MEK and phospho-ERK. More importantly, apart from its low calcemic properties,
the ability of QW to induce the cell cycle inhibitor p27 and inhibit phospho-ERK
was not seen in 1,25(OH) D . In summary, QW was proved to be a more potent
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compound in SCC inhibition [1] and test results for QW and Paricalcitol to date are
very promising. Testing of other low calcemic vitamin D analogs such as TX527
and TX522 of its photoprotective effects against UV irradiation are also underway.
With a potency of 100 times more than 1,25(OH) D the results demonstrated that
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1,25(OH) D analogs have great promise in chemoprevention therapies for UVB
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induced skin cancer [35].

9.6 Future Perspectives: Current Controversies on Sun
Exposure and Vitamin D Recommendations

Given the detrimental role of UVR in the development of skin cancer, during the last
decades, health campaigns and prevention programs have recommended the use of
sunscreens, protective clothing and the avoidance of sunlight [133]. However, there
is also accumulating evidence from epidemiological, in vitro and in vivo studies on
the benefits of vitamin D. Thus, scientists face the dilemma of how much UVR is
needed to produce an adequate amount of vitamin D to maintain everyday functions,
and more interestingly, anticancer effects (summarized in Table 9.1), while