Resistance to therapy-mediated apoptosis in inflammatory breast cancer (IBC), an aggressive and distinct subtype of breast cancer was recently attributed to increased antioxidant expression (superoxide dismutase [SOD]; reduced glutathione) and decreased accumulation of reactive oxygen species (ROS) resulting in redox adaptation and increased cell survival. Mn porphyrins (MnPs) are amongst the most potent synthetic mimics of the antioxidant, superoxide dismutase (SOD). In the present study, we demonstrate the unique ability of two Mn porphyrin (MnP)-based SOD mimics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+) to act as pro-oxidants when combined with ascorbate (vitamin C) and enhance ROS-mediated cell death. We identified that the ethyl species, MnTE-2-PyP5+, was less stable than its butoxyethyl analog, MnTnBuOE-2-PyP5+, resulting in greater potency in inducing cytotoxicity via radical-driven oxidative degradation in cellular models of IBC isolated from patient tumors and an isogenic derivative with acquired resistance to therapeutic apoptosis. The combination of MnP and ascorbate induced accumulation of mitochondrial superoxide and H2O2-derived radicals in both therapy-sensitive and therapy-resistant cell lines. High intracellular ROS resulted in decreases in both pro-survival signaling (pNF-κB, pERK1/2) and expression of X-linked inhibitor of apoptosis protein (XIAP), the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and Annexin V staining, administration of a pan-caspase inhibitor (QVD-OPh) did not reverse the observed cytotoxicity. Nuclear translocation of apoptosis inducing factor (AIF) was observed, suggesting a caspase-independent cell death following mitochondrial outer membrane permeabilization after treatment with this combination. In conclusion, this study provides the molecular basis of a novel MnP-based anti-cancer strategy and suggests the feasibility of using MnPs to sensitize cancer cells to many chemotherapies and radiotherapy that are dependent on potent induction of the oxidative stress response.
Citation Format: Myron Evans, Artak Tovmasyan, Ines Batinic-Haberle, Gayathri Devi. Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5552. doi:10.1158/1538-7445.AM2013-5552
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.