Endocrine Disrupting Chemicals as "structural cues" for the development of drugs for the treatment of Prostate Cancer (Castration Resistant Prostate Cancer) and PCOS

Abstract

<b>Abstract ID 16350</b> <b>Poster Board 238</b> <b>Introduction</b>: Endocrine-disrupting chemicals (EDCs) may influence the development of Prostate Cancer by altering the steroid metabolism. Although their exact mechanism of action in controlling tumor growth is not known, EDCs may inhibit steroidogenic enzymes such as Cytochrome P450 c17 (CYP17A1) or CYP19A1 involved in the production of Androgens or Estrogens. High levels of circulating androgens are linked to Prostate Cancer (PCa) in men and Polycystic Ovary Syndrome (PCOS) in women. Essential Oils (EOs) like lavender oil and tea tree oil are reported to act as potential EDCs and contribute towards sex steroid imbalance in case of prepubertal gynecomastia in boys and premature thelarche in girls due to regular exposure to lavender-based fragrances among the Hispanic population. We screened a range of EO metabolites to determine their effect on CYP17A1 or CYP19A1 activity that might lead to endocrine dysfunction. <b>Methods</b>: The test compounds, found as major components in EOs had been extracted and purified from natural resources. Computational docking was performed to predict the binding of EOs with CYP17A1 using AutoDock Vina. Human adrenal NCI H295R cells were treated with 10 μM of test compounds for 24 hours. Extracts of two medicinal plants (GP and VC) from South Asia were also tested. Enzyme activity was determined using the radiolabelled substrate for CYP17A1 or CYP19A1. Liquid Chromatography high-resolution Mass Spectrometry assays were performed for steroid profiling in adrenal cells. Cell viability assays were done in LNCaP prostate cancer cells, to study the effect of the EOs on tumor development. <b>Results</b>: Docking studies revealed that (+)-Cedrol had the best binding with CYP17A1 and CYP19A1. Though it didn’t inhibit CYP17A1 activity, it caused 30% inhibition of CYP19A1 activity. Dihydro-β-Ionone showed 30% inhibition of both CYP17A1 and CYP19A1 activities. Eucalyptol &amp; (-)-α-pinene showed 20% to 40% inhibition of CYP17A1. Many compounds bind close to the active site of CYP17A1, indicating possible inhibition of CYP17A1 activity. Compounds showed no significant impact on the whole steroid profile, except for Eucalyptol having reduced peak ionization suggesting a possible interaction with CYP17A1. GP and VC extracts showed siginificant inhibition in CYP17A1 activity and LNCaP viability. <b>Discussion</b>: Due to their anti-androgenic activity, these compounds should be studied further as chemical leads for the treatment of hyperandrogenic disorders such as PCa and PCOS. Screening naturally occurring EOs provide structural cues to design better inhibitors for CYP17A1 with lesser side effect and higher efficacy. This becomes essential in the case of Castration-Resistant Prostate Cancer where the tumor develops a mechanism to escape the androgen dependency and starts recognizing androgen-like steroids as its precursors for tumor growth and development. Support/Funding Information: Swiss Government Excellence Scholarship (2019.0385); Swiss Cancer Research (KFS-5557-02-2022) and Swiss National Science Foundation (310030M_204518)