Undescribed diterpenes from Euphorbia mauritanica L. as modulators of the breast cancer resistance: Mechanistic and in silico studies

Abstract

As part of efforts to identify natural modulators of multi-drug-resistant breast cancer, Euphorbia mauritanica L. chloroform extract yielded four undescribed oxygenated diterpenes, including three nor-ent-abietanes, euphomauritanol C-E (1–3), and one polyacylated jatrophane, euphomauritanolide A (4), along with two knowns, helioscopinolide A (5) and enukokurin (6). The chemical structures and configurations of compounds were established by combination of HRMS, FTIR, and NMR spectroscopic tools along with experimental and calculated TDDFT-ECD. The cytotoxicity evaluation of isolated compounds against the MCF-7^ADR revealed 4 and 2 are the most potent with IC₅₀ values of 3.2 ± 0.58 and 4.67 ± 0.29 μM, respectively. Co-administration of compounds 4 and 2 with DOX improved its cytotoxic effect, with a combination index value of 0.41 for 4, indicating a synergistic effect. Mechanistically, 4 modulated DOX anticancer properties via potentiating DOX-induced Go/G1 cell cycle arrest rather than G2M arrest of DOX alone and shifting the cell death of DOX to be mainly apoptotic cell death. Furthermore, 4 alone and combined with DOX showed promising anti-migratory effects against MCF-7^ADR. In conclusion, 4 showed promising co-chemotherapeutic effects to the DOX against MCF-7^ADR, indicating that this compound possesses potential as an auspicious lead chemical to target breast cancer cells resistant to doxorubicin.