In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. LB-039-LB-039
Abstract:
Cisplatin-based combination chemotherapy is the standard approach to therapy of advanced bladder cancer. While there is a substantial initial response rate and occasional complete response, long term control is not common. There is a need to develop new therapeutic approaches to bladder cancer. 1,25 dihydroxyvitamin D3 (1,25D3), the active metabolite of vitamin D, enhances the anti-tumor effects of cisplatin in preclinical bladder cancer models. We evaluated the mechanism of 1,25D3 potentiation of cisplatin cytotoxicity through in vitro studies in bladder cancer cell lines. Our studies suggest that enhanced cytotoxicity is mediated through modulation of p73. The ratio of the pro-apoptotic TAp73 isoform to the anti-apoptotic ΔNp73 isoform is important in determining cellular response to cisplatin. Our studies demonstrate that pretreatment with 1,25D3 (0.5 uM) for 24 hrs followed by cisplatin (0.75 ug/ml) for 48 hrs increases the ratio of TA/ΔNp73 mRNA transcripts 2-fold in the T24 bladder cancer cell line, and increases TAp73's transcriptional target, BAX approximately 3-fold compared to cisplatin alone. Protein levels of p73 and BAX, are also increased with 1,25D3 pretreatment followed by cisplatin in T24 cells as determined by western blot. Using a TransAm p53 binding assay after p53 immunodepletion, cisplatin treatment was found to decrease TAp73 functional ability to bind DNA by approximately half, although this has not yet been determined to be statistically significant. 1,25D3 pretreatment followed by cisplatin prevents the decrease in TAp73 DNA binding found after cisplatin alone. These data suggest an increase in TAp73 pro-apoptotic functional abilities resulting from 1,25D3 pretreatment followed by cisplatin in T24 cells. These findings suggest that 1,25D3 may have potential to be used in combination with cisplatin to increase the apoptotic response. Further studies are being performed to determine the requirement of TAp73 in 1,25D3 potentiation of cisplatin cytotoxicity by using T24 cells transfected with TAp73 shRNA in assays previously used to determine synergism, ie. MTT, clonogenic, and apoptosis assays. Supported by NCI grants CA067267 and CA016056. Citation Format: Brittany L. Bunch, Anna Woloszynska-Read, Donald L. Trump, Candace S. Johnson. 1,25 dihydroxyvitamin D3 and cisplatin combination modulate p73 in bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-039. doi:10.1158/1538-7445.AM2015-LB-039
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-LB-039
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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