Design, synthesis, and mechanistic elucidation of lawsone derivatives as novel inducers of ROS-associated mitochondrial apoptosis in breast cancer.

Abstract

Novel monomeric and dimeric lawsone derivatives were designed and investigated for their cytotoxicity. Lawsone derivatives (2-8) were synthesized under solvent-free conditions and tested against MDA-MB-231 and MCF-7 breast cancer cells versus doxorubicin. Mechanistic studies included reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm), cell-cycle distribution, apoptosis, and apoptosis-related genes. Dimeric derivatives 7 and 8 exhibited the highest cytotoxicity, particularly against MDA-MB-231 cells, with half-maximal inhibitory concentration (IC50 values of 0.37 and 1.43 µg/mL, respectively, outperforming doxorubicin (16.3 µg/mL). Both compounds showed high selectivity for MDA-MB-231 cells relative to WI-38 fibroblasts (selectivity index (SI) = 59.5 and 28.2, respectively). Mechanistic investigations demonstrated that compounds 7 and 8 induced significant ROS-related signals, associated with ΔΨm disruption. Concurrently, they induced gap 0/gap 1 (G0/G1) phase cell cycle arrest and promoted apoptosis with minimal necrosis. Compound 7 significantly upregulated Bcl-2-associated X protein (Bax) (6.6-fold) and caspase-9 (8.0-fold) while downregulating B-cell lymphoma 2 (Bcl-2) and poly (ADP-ribose) polymerase 1 (PARP-1), supporting activation of the intrinsic mitochondrial apoptotic pathway. Dimerization substantially enhanced the anticancer potency and selectivity of the lawsone scaffold. Compounds 7 and 8 represent promising lead structures for further optimization and development of potent anticancer agents.

Abstract as supplied by the indexing source. © the authors / publisher.