Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers
Meabh Doherty, Jie Feng, Tongchuan Wang, Cancan Yin, Niall M. Byrne, Sarah Chambers, Rayhanul Islam, Dimitrios A. Lamprou, Jonathan A. Coulter
TL;DR
This paper explores using nanocarriers to target lactate metabolism in cancer cells, improving radiation therapy effectiveness by reducing hypoxia-induced resistance.
Contribution
A novel liposomal formulation of 7ACC2 is proposed to overcome drug limitations and enhance radiosensitization.
Findings
Lactate supports tumor cell survival under hypoxia by fueling mitochondrial respiration.
7ACC2 inhibits lactate influx and sensitizes tumor cells to radiation in 2D and 3D models.
Liposomal 7ACC2 preserves radiosensitizing activity and promotes reoxygenation in tumor models.
Abstract
Lactate, the main product of the Warburg effect, exerts both intrinsic effects on cancer cell metabolism and noncell autonomous effects that promote tumor development, metastasis, and treatment resistance. As such, glycolytic dependence in tumors is frequently associated with poor clinical outcomes. Targeting lactate metabolism has emerged as a promising strategy to enhance the efficacy of conventional therapies. Here, we investigate the therapeutic potential of targeting lactate metabolism via inhibiting MCT1, MCT4, and MPC in PC3 and FaDu tumor cell models. We confirmed lactate as a substrate that fuels mitochondrial respiration and supports cell survival under hypoxic conditions. Inhibition of lactate influx mediated by 7ACC2 reduced oxygen consumption, sensitizing tumor cells to radiation in both 2D-cell cultures and 3D-spheroid models. Encapsulation of 7ACC2 in DPPC liposomes using…
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Taxonomy
TopicsCancer, Hypoxia, and Metabolism · Nanoplatforms for cancer theranostics · ATP Synthase and ATPases Research