2. Academic Validation
  3. Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress

Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress

  • Cancer Lett. 2024 Apr 1:586:216666. doi: 10.1016/j.canlet.2024.216666.
Ram Sharma 1,  Yung-Hsiao Chiang 2,  Hsien-Chung Chen 3,  Hong-Yi Lin 4,  Wen-Bin Yang 5,  Kunal Nepali 6,  Mei-Jung Lai 7,  Kai-Yun Chen 5,  Jing-Ping Liou 8,  Tsung-I Hsu 9
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan; Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
  • 3 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan; Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
  • 4 Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 6 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 7 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan. Electronic address: jpl@tmu.edu.tw.
  • 9 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan. Electronic address: dabiemhsu@tmu.edu.tw.
PMID: 38311053 DOI: 10.1016/j.canlet.2024.216666
Abstract

Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced Apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.

Keywords

CYP17A1; Glioblastoma; HDAC6; Temozolomide resistance.

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