Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors.
Hannah E BridgewaterElizabeth M BolithoIsolda Romero-CanelónPeter J SadlerJames P C CoverdalePublished in: Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry (2023)
Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural D-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.
Keyphrases
- low dose
- highly efficient
- oxidative stress
- breast cancer cells
- combination therapy
- small molecule
- cancer therapy
- induced apoptosis
- clinical trial
- high dose
- metal organic framework
- ionic liquid
- transition metal
- ischemia reperfusion injury
- stem cells
- emergency department
- cell cycle arrest
- drug delivery
- papillary thyroid
- randomized controlled trial
- risk assessment
- mesenchymal stem cells
- squamous cell
- endoplasmic reticulum stress
- protein protein
- open label
- gold nanoparticles
- heat stress
- human health
- replacement therapy
- electronic health record
- capillary electrophoresis