ZK 156718, a low calcemic, antiproliferative, and prodifferentiating vitamin D analog

The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D(3), plays an important role not only in the establishment and maintenance of calcium metabolism, but also in regulating cell growth and differentiation. Because the clinical usefulness of 1,25-dihydroxyvitamin D(3) is limited by its tendency to cause hypercalcemia, new analogs with a better therapeutic profile have been synthesized, including ZK 156718. We compared the effects of 1,25-dihydroxyvitamin D(3) and ZK 156718 on growth, differentiation, and on p21(Waf1/Cip1) and p27(Kip1) expression in human colon cancer cells (Caco-2). Whereas ZK 156718 at the concentration [10(-8) M] was as potent as 10(-6) M 1,25-dihydroxyvitamin D(3) in inducing differentiation and p21(Waf1/Cip1) expression, it was even more effective in inhibiting cell growth and stimulating p27(Kip1) expression than 1,25-dihydroxyvitamin D(3) itself. In summary, our study presents a new and potent vitamin D analog with a decreased metabolic stability, making it useful for the treatment of a diversity of clinical disorders.