TY - JOUR
T1 - Bicalutamide elicits renal damage by causing mitochondrial dysfunction via ROS damage and upregulation of HIF-1α
AU - Chen, Kuan Chou
AU - Chen, Chang Rong
AU - Chen, Chang Yu
AU - Tzou, Kai Yi
AU - Peng, Chiung Chi
AU - Peng, Robert Y.
N1 - Funding Information:
This research was supported by Taipei Medical University-Shuang Ho Hospital (grant no. 109TMU-SHH-12 and 108TMU-SHH-14) and the Ministry of Science and Technology (MOST 108-2320-B-038-051, MOST 105-2320-B-038-034-MY3, MOST 106-2320-B-038-032), Taiwan. The authors would also like to acknowledge the technical support provided by the Laboratory Animal Center and Core Facility at TMU. We would also like to thank Dr. Tzu-Yu Chen (National Laboratory Animal Center, Taipei, Taiwan) for the pathology examination of the animals and Ms. Jin-Yuan Chung (Taipei Medical University, Taipei, Taiwan) for technical assistance.
Funding Information:
Funding: This research was supported by Taipei Medical University-Shuang Ho Hospital (grant no. 109TMU-SHH-12 and 108TMU-SHH-14) and the Ministry of Science and Technology (MOST108-2320-B-038-051, MOST105-2320-B-038-034-MY3, MOST106-2320-B-038-032), Taiwan.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1α transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1α protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 μM) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1α pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.
AB - Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1α transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1α protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 μM) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1α pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.
KW - Bicalutamide (Bic)
KW - HIF-1α
KW - Mitochondrial dysfunction
KW - Oxygen consumption rate (OCR)
KW - Rat mesangial cell (RMC) line
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U2 - 10.3390/ijms21093400
DO - 10.3390/ijms21093400
M3 - Article
C2 - 32403414
AN - SCOPUS:85084692371
SN - 1661-6596
VL - 21
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 9
M1 - 3400
ER -