Engineering synergistic liposomes against ovarian cancer via concurrent targeting of myeloid cell leukemia-1(MCL-1) and glutamate-cystine antiporter (SLC7A11)

Ovarian cancers (OC) often resist current standard chemotherapy because of the cancer heterogeneity and over-expression of an anti-apoptotic protein, myeloid cell leukemia-1 (MCL-1). The heterogeneous OC shows impaired redox homeostasis and relies heavily on glutathione peroxidase 4 to eliminate toxic lipid peroxides. Therefore, integrated apoptosis and ferroptosis therapy is promising for OC management. The current work reports a liposomal nanosystem for apoptotic and ferroptotic OC therapy. Simvastatin (Sim) and vorinostat (Saha) were selected as the pleiotropic model drugs. The successive release of Saha and Sim from liposomes enabled the sequential amplification of MCL-1 by Saha, and then MCL-1 inhibition by Sim. Such a strategy could potently induce apoptosis in a human OC cell line (SKOV3), as indicated by increased intracellular cytochrome c concentration, caspase 3/9 activity, and the extent of apoptosis. Besides, Saha played multiple roles in cell death. It could induce cell cycle arrest at the G 2 /M phase and apoptosis. Saha also inhibited the glutamate-cystine transporter (SLC7A11) and provoked ferroptosis, which was corroborated by the depletion of glutathione, reduced nicotinamide adenine dinucleotide phosphate, and boost of lipid peroxides and malondialdehyde in SKOV3 cells. The current work integrated the “sequential amplification and inhibition of MCL-1 target” concept with combinational apoptosis and ferroptosis OC therapy, which might offer a new approach for managing resistant OC and other malignant diseases.