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Published on: March 6, 2018
Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that
Carmen A Banuelos1, Yusuke Ito1, Jon K Obst1
1Department of Genome Sciences, British Columbia Cancer, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
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.
Insights
Ralaniten, a novel therapy, enhances prostate cancer cell sensitivity to radiotherapy by blocking androgen receptor (AR) activity and DNA repair. This combination shows promise for treating resistant prostate cancers.
Area of Science:
- Oncology
- Radiotherapy
- Molecular Biology
Background:
- Androgen deprivation therapy (ADT) improves radiotherapy response in prostate cancer but can increase resistance via androgen receptor variants (AR-Vs).
- AR-Vs regulate DNA damage repair, contributing to treatment resistance.
- Existing therapies like enzalutamide may not overcome AR-V-mediated resistance.
Purpose of the Study:
- To investigate if ralaniten, by blocking both full-length AR and AR-Vs, enhances prostate cancer cell sensitivity to radiotherapy.
- To evaluate combination therapies of ralaniten with ionizing radiation.
Main Methods:
- Combination therapies using ralaniten and ionizing radiation were tested on human prostate cancer cells.
- Assays included proliferation, colony formation, cell cycle, DNA damage (γH2AX), and Western blot analyses.
- Effects of ralaniten, EPI-7170, and enzalutamide were compared.
Main Results:
- Ralaniten and EPI-7170 decreased DNA repair gene expression; enzalutamide did not.
- Ralaniten combined with radiation increased DNA damage (γH2AX) and decreased proliferation.
- Ralaniten compounds showed additive effects on proliferation in enzalutamide-resistant cells.
Conclusions:
- Ralaniten and EPI-7170 sensitize prostate cancer cells expressing AR and AR-Vs to radiotherapy.
- Unlike enzalutamide, ralaniten provides added benefit when combined with radiotherapy, offering a potential strategy against treatment resistance.
