Figure 8. Caption to summary illustration.
Astemizole synergizes calcitriol antiproliferative activity by downregulating CYP24A1, upregulating VDR and blocking Eag1 activity. Cell proliferation is stimulated by ion permeation through Eag1 channels (1). Eag1 gene expression and activity are blocked by calcitriol and astemizole, respectively (2 and 3). Astemizole downregulates CYP24A1 mRNA expression (4), allowing calcitriol to evade catabolism. Astemizole upregulates VDR expression (5) favoring calcitriol biological effects. Upon activation by calcitriol, the VDR forms heterodimers with the RXR and binds to vitamin D response elements (VDRE) on DNA resulting in expression or transrepression of specific gene products (6). VDR = vitamin D receptor; RXR = retinoid X receptor; 9cRA = 9-cis retinoic acid. CYP24A1 = cytochrome involved in calcitriol inactivation. Green rhomboid = calcitriol. Red triangle = astemizole. Dashed lines depict mechanistic events not yet fully clarified.