Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Chemother+Pharmacol 2014 ; 74 (4): 787-98 Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Anticancer Activity of VDR-Coregulator Inhibitor PS121912 #MMPMID25107568
Sidhu PS; Teske K; Feleke B; Yuan NY; Guthrie ML; Fernstrum GB; Vyas ND; Han L; Preston J; Bogart JW; Silvaggi NR; Cook JM; Singh RK; Bikle DD; Arnold LA
Cancer Chemother Pharmacol 2014[Oct]; 74 (4): 787-98 PMID25107568show ga
Purpose: PS121912 has been developed as selective vitamin D receptor (VDR)?coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule. Methods: Antiproliferation and apoptosis was determined using four different cancer cell lines (DU145, Caco2, HL-60, and SKOV3) in the presence of PS121912, 1,25-(OH)2D3, or a combination of 1,25-(OH)2D3 and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by rt-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 include the determination of metabolic stability and CYP3A4 inhibition. Results: PS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)2D3 without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)2D3 were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)2D3 reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factor 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)2D3 that in turn reduced the transcription levels of cyclin A and D thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1 also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)2D3 and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7. Conclusion: Overall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies.
free
free
free
Cancer+Chemother+Pharmacol 2014 ; 74 (4): 787-98
