Abstract
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.
Highlights
Bicalutamide (Bic) is a non-steroidal antiandrogen which provides blockade at tumor sites to facilitate treatment of prostate cancer (PCa) [1]
Lactate Dehydrogenase (LDH) and Kidney Injury Molecule (KIM)-1 Are Affected by Bic in rat mesangial cell (RMC) Cells
LDH activity was shown to be elevated in chronic renal failure and was correlated with the blood urea nitrogen (BUN) level [41]
Summary
Bicalutamide (Bic) is a non-steroidal antiandrogen which provides blockade at tumor sites to facilitate treatment of prostate cancer (PCa) [1]. Bic possesses excellent affinities to androgen receptors [2], through which Bic induces apoptosis of androgen-dependent benign PWR-1E prostatic cells. In androgen-independent PC-3 cells, Bic induces apoptosis by mechanisms partially inhibited by pan-caspase inhibition [3]. A report from the US Food and Drug Administration demonstrated that up to 37.5% of patients who have taken Bic therapy for 1–6 months may experience kidney failure, with an incidence rate of 94.17% for males aged over 60 years [13]. The literature revealed that Bic and leuprorelin induced tubulointerstitial nephritis, interstitial pneumonitis and liver dysfunction [6]. We recognized a Bic-increased renal-damaging effect in vitro and in vivo (Figure S1) [14]
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have