Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol
Mohammad A Khan1, Deepti Singh1, Homa Fatma1
1Department of Zoology, Aligarh Muslim University, Aligarh, India.
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.
Insights
Lupeol may reduce Enzalutamide toxicity in prostate cancer treatment. This study shows Lupeol protects normal cells from Enzalutamide
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Androgen deprivation therapy is standard for prostate cancer.
- Enzalutamide, an androgen receptor inhibitor, treats castration-resistant prostate cancer.
- Lupeol, a natural triterpene, exhibits antioxidant and antiproliferative properties.
Purpose of the Study:
- To assess Enzalutamide-induced toxicity.
- To investigate Lupeol's potential to mitigate Enzalutamide's adverse effects.
- To explore Lupeol's selective anticancer activity.
Main Methods:
- In vitro and in vivo experiments were conducted.
- Cytotoxicity assays were performed on normal and cancer cell lines.
- Genotoxicity, oxidative stress, and organ damage markers were evaluated.
Main Results:
- Enzalutamide induced cytotoxicity in both normal and cancer cells.
- Lupeol demonstrated selective cytotoxicity against cancer cells.
- Lupeol attenuated Enzalutamide-induced cytotoxicity, genotoxicity, oxidative damage, and reversed hepatic/renal toxicity.
Conclusions:
- Lupeol exhibits selective anticancer activity and protects normal cells.
- Lupeol can ameliorate Enzalutamide-induced toxicity.
- Lupeol shows potential as an adjuvant therapy to enhance Enzalutamide efficacy and reduce side effects.
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