Energy and endoplasmic reticulum stress induction by gold(III) dithiocarbamate and 2-deoxyglucose synergistically trigger cell death in breast cancer.

The elusiveness of triple-negative breast cancer from targeted therapy has redirected focus towards exploiting the metabolic shortcomings of these highly metastatic subtypes of breast cancer. Cueing from the metabolic heterogeneity of TNBC and the exposition of the dual dependence of some TNBCs on OXPHOS and glycolysis for ATP, we herein report the efficacy of cotreatment of TNBCs with an OXPHOS inhibitor, 2a and 2DG, a potent glycolysis inhibitor. 2a-2DG cotreatment inhibited TNBC cell proliferation with IC50 of ∼5 to 36 times lower than that of 2a alone and over 5000 times lower than IC50 of 2DG alone. 2a-2DG cotreatment suppressed mitochondrial ATP production and significantly induced AMPK activation. Mechanistic studies revealed the distinct yet synergistic contributions of 2a and 2DG to the antiproliferative effect of the cotreatment. While 2a induced apoptotic cell death, 2DG sensitized TNBCs to the antiproliferative effects of 2a via endoplasmic reticulum stress induction. Strikingly, the combination of 2a-2DG ablated SUM159 tumors in an orthotopic xenograft mouse model. This study highlights the synergistic effect of a gold-based complex with 2DG and the potential benefit of multi-metabolic pathways targeting as an effective therapeutic strategy against TNBCs.

A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential.

The cytotoxic and immunogenic-activating properties of a cobalt(III)-cyclam complex bearing the non-steroidal anti-inflammatory drug, flufenamic acid is reported within the context of anti-cancer stem cell (CSC) drug discovery. The cobalt(III)-cyclam complex 1 displays sub-micromolar potency towards breast CSCs grown in monolayers, 24-fold and 31-fold greater than salinomycin (an established anti-breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)-cyclam complex 1 is 69-fold and 50-fold more potent than salinomycin and cisplatin towards three-dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase-2 expression, and prompts caspase-dependent apoptosis. Breast CSCs treated with 1 exhibit damage-associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic-activating effects on breast CSCs.