Phosphonate Analogues of 1α, 25 Dihydroxyvitamin D 3 are Promising Candidates for Antitumoural Therapies
2014
The active metabolite of vitamin D, 1α, 25 dihydroxyvitamin D 3 (calcitriol) is classically
known to regulate calcium and phosphate homeostasis and bone mineralization. In addition, calcitriol
has also been documented to act as a potent anticancer agent in multiple cell culture and animal models
of cancer. However, major side effects, such as hypercalcemia, hinder broad-spectrum therapeutic uses of calcitriol in
cancer chemotherapy. Synthesis of calcitriol analogues with the same or increased antiproliferative and pro-differentiating
activities, and with reduced undesired effects on calcium and bone metabolism, is getting significant attention towards rational
therapeutics to treat cancer. In this regard, phosphonate analogues have been shown to display a certain degree of
dissociation between the vitamin D activity in vitro and undesired hypercalcemia in vivo. However, few phosphonates
have been described in the literature and fewer of them tested for antitumoral effects. Our group has synthesized a novel
vitamin D analogue (EM1) bearing an alkynylphosphonate moiety that combines the low calcemic properties of phosphonates
with the decreased metabolic inactivation due to the presence of a triple bond between C-23 and C-24. Biological
assays demonstrated that this analogue has potent antiproliferative effects in a wide panel of tumour cell lines, even in
those resistant to calcitriol treatment. Importantly, EM1 does not show toxic effects in animals, even administered at high
doses and for extended periods of time. In the current review we discuss the effects and the potential application in cancer
of vitamin D and its derivatives, with an emphasis on phosphonate analogues.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
10
Citations
NaN
KQI