Steroidal epoxides as anticancer agents in lung, prostate and breast cancers: The case of 1,2-epoxysteroids

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Cancer remains a major global health threat, with lung, prostate, and triple-negative breast cancers being particularly deadly.
• Steroidal compounds are a diverse therapeutic class with proven efficacy against various cancers.
• The 1,2-epoxide functional group is frequently linked to anticancer properties.

Purpose of the Study:

• To evaluate the anticancer potential of novel 1,2-epoxysteroid derivatives against key cancer cell lines.
• To assess the selectivity of these compounds by testing them against a normal human lung cell line.
• To investigate the mechanisms of action, including cell death pathways and genotoxicity.

Main Methods:

• Synthesis of three known 1,2-epoxysteroid derivatives (EP1, EP2, EP3) and one novel oxysteride.
• In vitro cytotoxicity assays using H1299 (lung), PC3 (prostate), and HCC1806 (triple-negative breast) cancer cell lines, and MRC-5 (normal lung) cells.
• Apoptosis/necrosis assays, reactive oxygen species (ROS) production measurements, and DNA double-strand break assessments.
• In silico analysis of Absorption, Distribution, Metabolism, and Excretion (ADME) and toxicity parameters.

Main Results:

• EP2 demonstrated the highest potency across all tested cancer cell lines, with IC50 values ranging from 1.95 to 3.67 µM.
• EP3 also exhibited significant activity, with IC50 values between 12.65 and 15.10 µM.
• Both EP2 and EP3 induced dose-dependent cell death via apoptosis and necrosis, increased ROS production, and caused DNA double-strand breaks.
• EP2 and EP3 showed reduced toxicity against normal MRC-5 cells, suggesting potential selectivity.
• In silico ADME/toxicity profiles were favorable, and no compounds induced hemoglobin release.

Conclusions:

• The 1,2-epoxysteroid derivatives EP2 and EP3, particularly EP2, show significant promise as novel therapeutic agents for lung, prostate, and triple-negative breast cancers.
• Their efficacy is mediated through apoptosis, necrosis, ROS generation, and DNA damage induction.
• The observed selectivity towards cancer cells over normal cells, coupled with favorable in silico profiles, warrants further investigation and development.