92. Calcitriol and its analog down-regulates αvβ3 integrin expression and suppresses the tumorigenesis of lewis lung carcinoma (LLC) cell line

Abstract

Aim Calcitriol (CAL) [1,25-(OH)203], active hormonal form of vitamin D3, reveals antitumor activity both in vitro and in vivo. CAL may activate the β3-integrin subunit gene and promote the plasma membrane appearance of αvβ3 on osteociast precursors and on HL-60 leukemia cells. In this study we evaluated the effect of calcitriol and its new analogue (PRI-2191), synthesized in order to avoid hypercalcemic effect of calcitriol, on αvβ3 integrin-dependent mouse lung cancer invasiveness. Material and Methods The influence of CAL or PRI-2191 on the proliferation, adhesion properties and celi cycle of mouse LLC cells were tested by FACS analysis, adhesion and antiproliferative assays. Monoclonal antibodies and flow cytometry were applied for evaluation of integrins expression. Antitumor activity in vivo was examined in the model of subcutaneously growing tumors in C57BI/6 mice. Results We have shown, that LLC cells express a high level of αvβ3 (but not of αllbβ3) integrin and this expression was signiticantly reduced by the in vitro treatment with CAL or PRI-2191. Both compounds inhibited (in about 60%) LLC cells proliferation after 72 h of in vitro treatment. Moreover, both agents augmented adhesion of LLC cells to collagen (ligand tor allb integrin subunit) and diminished adhesion to fibrinogen (ligand for β3 integrin subunits). Further, in vitro incubation of LLC cells with both agents retarded the growth of subcutaneous tumors in mice. n all experiments, biological activity of PRI-2191 was higher than this of CAL, what is in accordance with our previous experiments, showing higher antiproliterative, lower calcemic activities and lower lethal toxicity of new analog as compared to parental drug. Conclusions Our data demonstrate that new analog of calcitriol, PRI-2191, is a good candidate for an antitumor drug, especially in the treatment of cancers in which the invasive potential is, atleast in part, dependent on expression of β3 integrins.