Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants
Open Access
- 21 July 2020
- Vol. 12 (7), 1991
- https://doi.org/10.3390/cancers12071991
Abstract
Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.Keywords
Funding Information
- National Cancer Institute (R01CA105304)
This publication has 57 references indexed in Scilit:
- An androgen receptor N-terminal domain antagonist for treating prostate cancerJCI Insight, 2013
- Androgen Receptor Variants Occur Frequently in Castration Resistant Prostate Cancer MetastasesPLOS ONE, 2011
- Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variantJCI Insight, 2010
- Residual γH2AX foci as an indication of lethal DNA lesionsBMC Cancer, 2010
- Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot studyBMC Cancer, 2010
- DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancerEndocrine-Related Cancer, 2009
- Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate CancerCancer Research, 2008
- Use of the Rad51 promoter for targeted anti-cancer therapyProceedings of the National Academy of Sciences of the United States of America, 2008
- γH2AX and cancerNature Reviews Cancer, 2008
- Biomarkers for DNA DSB inhibitors and radiotherapy clinical trialsCancer and Metastasis Reviews, 2008