Page 245 - Vitamin D and Cancer

232 C.M. Barnett and T.M. Beer

10.6.1.1 Steroids

In preclinical models, the steroid, dexamethasone, enhances the antineoplastic
activity of vitamin D [101, 102]. It has been shown to increase vitamin D
induced cell cycle arrest and apoptosis and increase vitamin D-mediated sup-
pression of phospho-Erk 1/2, phospho-Akt levels and tumor derived endothelial
cell growth [101–104]. Dexamethasone has also been shown to directly increase
VDR protein levels and ligand binding in the squamous cell carcinoma model
SCC [102].

10.6.1.2 Cytotoxic Chemotherapy

Combining of VDR ligands with several classes of chemotherapy drugs has
shown to result in additive and supra-additive activity in several preclinical
models of cancer. Specifically, docetaxel [105], paclitaxel, [106] platinum com-
pounds [107], and mitoxantrone [108] have been rendered more active by com-
binations with vitamin D in preclinical in vitro models of prostate cancer.
Confirmation in in vivo models has been reported for paclitaxel and mitoxan-
trone [106, 108]. Studies in models of other neoplasms yield similar observa-
tions [109–112], but further study is required to fully clarify the mechanisms of
these interactions.

10.6.1.3 Retinoid Receptor Ligands

As previously mentioned, after ligand binding, VDR forms heterodimers with the
retinoid X receptor (RXR), thus interactions between these two receptor systems
would be expected [113, 114]. Both apoptosis [114] and angiogenesis inhibition is
synergistically enhanced when VDR and RXR ligands are co-administered in pre-
clinical models [114]. Several overlapping mechanisms of anticancer activity,
including modulation of IGFBP-3 expression, [115] inhibition of telomerase
reverse transcriptase in prostate cancer cells [116] as well as induction of cell cycle
checkpoint proteins like p21 may explain these observations.

10.6.1.4 Tamoxifen

A study in Sprague-Dawley rats reports that there was a significant increase in the
inhibition of N-nitroso-N-methylurea (NMU) induced mammary carcinogenesis
when VDR ligands are co-administered with tamoxifen [117]. Enhanced apoptosis
was seen in MCF-7 cells in vitro and in vitro when this combination was evaluated
[118, 119]. It maybe that MCF-7 cells are inversely sensitive to vitamin D and
antiestrogens [120]. While these findings originate from breast cancer models, they
may have relevance to prostate cancer biology as well.