Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein

  • Cell Death Dis. 2022 Dec 12;13(12):1034. doi: 10.1038/s41419-022-05490-5.
Ying Zhang  #  1 ,  Wei Wei  #  2 ,  Changying Li  3 ,  Siyuan Yan  1 ,  Shanshan Wang  1 ,  Shudong Xiao  1 ,  Chenchen He  4 ,  Jing Li  5 ,  Zhi Qi  5 ,  Benyi Li  6 ,  Kuo Yang  7 ,  Changlin Li  8  9
Affiliations
  • 1. Institute of Precision Medicine, Jining Medical University, 272067, Jining, China.
  • 2. Center for Experimental Medicine, School of Public Health, Jining Medical University, 272067, Jining, China.
  • 3. Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China.
  • 4. Department of Radiation Oncology, The First Affiliated Hospital, Xi'An Jiaotong University School of Medicine, 710061, Xi'An, China.
  • 5. Department of Histology and Embryology, School of Medicine, Nankai University, 300071, Tianjin, China.
  • 6. Department of Urology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 7. Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China. [email protected].
  • 8. Institute of Precision Medicine, Jining Medical University, 272067, Jining, China. [email protected].
  • 9. Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 36509750 DOI: 10.1038/s41419-022-05490-5
Abstract

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate Cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate Cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate Cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate Cancer.

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