Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol

Abstract

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5–20 μM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10–50 μM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Graphical Abstract

Keywords:

• Enzalutamide
• Lupeol
• LNCaP
• 22Rv1
• PNT2
• genotoxicity
• hepatotoxicity
• renal toxicity
• amelioration

Acknowledgements

The authors are grateful to the Department of Zoology, AMU, Aligarh for providing the necessary facilities. MAK (09/112(0599)/2018-EMR-I); DS (524/(UGC NET JUNE 2019)); HF & SKM expresses their gratitude to the CSIR, UGC, UGC-MANF, and DST, India for fellowships, respectively. HRS is thankful to the UGC [Grant no. F0.30–377/2017(BSR)] and DST-SERB (Grant no. EMR/20l7/001758), New Delhi, for providing financial help.

Author contributions

H.R. Siddique: Conception and Study supervision; M.A. Khan, D. Singh, H.R. Siddique: Genotoxicity, Cytotoxicity and Histopathology study; M.A. Khan, D. Singh, H. Fatma, S.K. Maurya, H.R. Siddique: Oxidative parameters; M.A. Khan, D. Singh, F. Arjmand, H.R. Siddique: DNA interaction studies; M.A. Khan, D. Singh, H. Fatma, S.K. Maurya, F. Arjmand, H.R. Siddique: Data Acquisition; M.A. Khan, D. Singh, H. Fatma, S.K. Maurya, F. Arjmand, K. Akhtar, H.R. Siddique: Data Analysis and interpretation; MA Khan, D. Singh, H.R. Siddique: Writing of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the University Grants Commission (UGC) under Grant [F0.30–377/2017(BSR)] and Department of Science and Technology-Science and Engineering Research Board (DST-SERB) under Grant [EMR/20l7/001758].