Calcitriol and some of its analogs have antiproliferative activity, but at the same time, can cause resistance to apoptosis induced by known
cytostatic drugs. In this paper, we examined the effects of treatment with
calcitriol or its side-chain-modified analogs, analog of
Vitamin D2, coded
PRI-1906, with monohomologated and unsaturated side-chain and the analog of
Vitamin D3, coded
PRI-2191, with (24R)
hydroxyl group, and those of known
cytostatics (
genistein,
etoposide,
doxorubicin,
cisplatin, and
taxol) on the apoptosis of HL-60 promyelocytic
leukemia cells. HL-60 cells were incubated in three different sequences: (1) pre-treatment with
calcitriol or its analogs and then treatment with
cytostatics; (2) pre-treatment with
cytostatics and then treatment with
calcitriol; (3) simultaneous treatment with
calcitriol and
cytostatics. Apoptosis was examined either by DNA fragmentation in
agarose gel electrophoresis or by cell-cycle analysis in a FACS Calibur flow cytometer. We showed that pre-treatment with
calcitriol or one of its side-chain-modified analogs
PRI-1906 or
PRI-2191 caused resistance of HL-60 promyelocytic
leukemia cells to
genistein-,
doxorubicin-,
cisplatin-, and
taxol-induced apoptosis. Simultaneous exposure of HL-60 cells to
calcitriol and
drug caused a significant decrease in the apoptotic level of HL-60 cells compared with cells treated with
drug alone. The pre-treatment of HL-60 cells with
drug and then treatment with
calcitriol did not increase the level of apoptosis compared with the
drug effect alone. These results indicate the potential limitations of
calcitriol analogs for treatment of
leukemia.