Page 276 - Vitamin D and Cancer

11 Vitamin D and Hematologic Malignancies 263

from chemotherapeutic agents. A variety of agents, including ATRA, arsenic
trioxide(As O ), Non-steroidal anti-inflammatory drugs (NSAIDs), carnosic acid,
2 3
MAPK inhibitor, cisplatin, taxol, paclitacel, doxorubicin, a HIV-protease inhibitor
as well as a demethylating agent have been combined with vitamin D compounds
in a variety of cancers including leukemia.
Our group and others have shown that the combination of a vitamin D compound
and either all-trans-retinoic acid (ATRA) or 9-cis-retinoic acid (9-cis-RA) can
potentiate the terminal monocytic differentiation of HL-60, NB4 and U937 cells
[110–113]. These combinations included ATRA (10 M) and either 1,25(OH) –
–9
2
–10
–9
16-ene-23-yne D , 1,25(OH) –23-yne D (10 to 10 M), or 9-cis-RA and
3 2 3
KH1060 (a 20-epi-vitamin D analog) [47, 114–117]. These cells often differentiate
3
atypically, having a neutrophilic morphology, but acquiring other properties typi-
cal of monocytes (e.g., CD14 expression); ability to bind to bacterial LPS, and
express lineage specific enzymes like nonspecific acid esterase [112, 113]. The
combination enhanced the decrease expression of c-myc. Interestingly, U937
cells exposed to a moderate thermal stress responded with increased differentia-
tion after the addition of 1,25(OH) D and ATRA suggesting that induction of
2 3
heat-shock protein may be sequestering a protein that may favors proliferation or
differentiation [118].
19-nor-1,25-dihydroxyvitamin D (paricalcitol) and As O are both approved
2 2 3
Food and Drug Administration drugs. Their combination resulted in a strong anti-
proliferative effect on HL-60, NB4 and PML-RARa over-expressing U937 cells
[119]. As O decreased the levels of both the repressive PML-RARa fusion protein
2 3
and the vitamin D metabolizing protein, which had been increased by paricalcitol.
This combination may be effective for ATRA-resistant APL patients, as well as
those with other types of AML.
NSAIDs enhance the differentiation of HL-60 cells in response to 1,25(OH) D
2 3
and its analogs [120, 121]. This effect may occur because of a block of NF-kB
activation. Bhatia et al. showed that the combination of 1,25(OH) D and TPA with
2 3
M-CSF resulted in a synergistic response in NB4 cells, causing a complete differ-
entiation to fully functional adherent macrophages with a rapid arrest of cell growth
in the first 24 h [122].
Vitamin D compounds have also been combined successfully with naturally
occurring plant products. One of these is carnosic acid, a plant-derived polyphenol
antioxidant which can potentiate the pro-differentiative effects of 1,25(OH) D
2 3
[123–125]. Differentiation was correlated with antioxidant activity, and was associ-
ated with activation of the Raf-ERK pathway and increased binding of the AP-l
transcription factor to the promoter of VDR. A p38 MAPK inhibitor (SB202190)
enhanced the ability of 1,25(OH) D to induce differentiation of HL-60 cells [126].
2 3
In addition, the combination of the three agents (SB202190, carnosic acid and
1,25(OH) D ) further potentiated the antileukemic activity against HL-60 cells and
2 3
primary AML blasts [127]. This augmented potency was associated with increased
activation of the JNK-MAP kinase pathway.
Combining vitamin D compounds with traditional chemotherapy agents such as
cisplatin, etoposide and doxorubicin reduces the concentration of chemotherapy