Investigating the Telomerase Downregulatory Potential of Steroidal Drugs Following Pharmacophore‐Based Rational; Computational and In Vitro Assessments

Abstract

Inhibiting telomerase could lead to telomere shortening, chromosomal instability, and eventually cell death in cancer cells. The use of steroids in cancer treatment is significant; besides, drug repurposing can be a quicker and less expensive method of drug discovery than de novo drug development. Accordingly, diverse 280 steroidal drugs-following a pharmacophore-based rationale-were docked against telomerase receptor and compared to the co-crystallized inhibitor (BIBR1532) as a reference standard. Additionally, a molecular dynamics simulation for 200 ns was performed to confirm the docking results. Moreover, the six steroidal drugs (Betamethasone disproportionate, Beclomethasone disproportionate, Clobetasone butyrate, Desonide, diflucortolone valerate, and Hydrocortisone butyrate) were selected for further in vitro investigation. The antitumor activities of the six steroidal drugs against H1299, HuH7, HCT116, A549, MDA-MB-231, MCF7, PC3, MG63, and A375 cancer cell lines, besides OEC and HSF normal cell lines, were evaluated and compared to doxorubicin (Dox) as a reference positive standard. Especially, Clobetasone butyrate represented the better cytotoxicity against seven cancer cell lines (H1299, HuH7, HCT116, MDA-MB-231, PC3, MG63, and A375) with IC₅₀ values of 12.56, 13.95, 12.00, 17.51, 11.69, 20.64, and 20.21 µg/mL, respectively. The outstanding antitumor six steroidal drugs were further investigated for their telomerase downregulatory potentials. All analogs recorded outstanding downregulatory results against telomerase, especially Clobetasone butyrate, Desonide, Diflucortolone valerate, and Hydrocortisone butyrate, where the protein expression for telomerase was downregulated up to 0.66-, 0.76-, 0.56-, and 0.73-fold change for clobetasone butyrate, desonide, diflucortolone valerate, and hydrocortisone butyrate, respectively, compared to the control.