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  3. Artepillin C overcomes apalutamide resistance through blocking androgen signaling in prostate cancer cells

Artepillin C overcomes apalutamide resistance through blocking androgen signaling in prostate cancer cells

  • Arch Biochem Biophys. 2023 Jan 12;109519. doi: 10.1016/j.abb.2023.109519.
Atsumi Ota 1,  Mina Kawai 1,  Yudai Kudo 1,  Jin Segawa 1,  Manami Hoshi 1,  Shinya Kawano 1,  Yuta Yoshino 1,  Kenji Ichihara 2,  Masaki Shiota 3,  Naohiro Fujimoto 4,  Toshiyuki Matsunaga 5,  Satoshi Endo 6,  Akira Ikari 1
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Gifu, Japan.
  • 2 Nagaragawa Research Center, API Co., Ltd., Gifu, 502-0071, Japan.
  • 3 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • 4 Department of Urology, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
  • 5 Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu, 502-8585, Japan.
  • 6 Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, 501-1196, Gifu, Japan. Electronic address: [email protected].
PMID: 36642262 DOI: 10.1016/j.abb.2023.109519
Abstract

Prostate Cancer has a relatively good prognosis, but most cases develop resistance to hormone therapy, leading to castration-resistant prostate Cancer (CRPC). Androgen Receptor (AR) antagonists and a Cytochrome P450 17A1 inhibitor have been used to treat CRPC, but Cancer cells readily develop resistance to these drugs. In this study, to improve the therapy of CRPC, we searched for natural compounds which block androgen signaling. Among cinnamic acid derivatives contained in Brazilian green propolis, artepillin C (ArtC) suppressed expressions of androgen-induced prostate-specific antigen and transmembrane protease serine 2 in a dose-dependent manner. Reporter assays revealed that ArtC displayed AR antagonist activity, albeit weaker than an AR antagonist flutamide. In general, aberrant activation of the androgen signaling is involved in the resistance of prostate Cancer cells to hormone therapy. Recently, apalutamide, a novel AR antagonist, has been in clinical use, but its drug-resistant cases have been already reported. To search for compounds which overcome the resistance to apalutamide, we established apalutamide-resistant prostate Cancer 22Rv1 cells (22Rv1/APA). The 22Rv1/APA cells showed higher AR expression and androgen sensitivity than parental 22Rv1 cells. ArtC inhibited androgen-induced proliferation of 22Rv1/APA cells by suppressing the enhanced androgen signaling through blocking the nuclear translocation of AR. In addition, ArtC potently sensitized the resistant cells to apalutamide by inducing apoptotic cell death due to mitochondrial dysfunction. These results suggest that the intake of Brazilian green propolis containing ArtC improves prostate Cancer therapy.

Keywords

Androgen receptor; Apalutamide resistance; Artepillin C; Brazilian green propolis; Prostate cancer cells.

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