Dual inhibition of oxidative phosphorylation and glycolysis using a hyaluronic acid nanoparticle NOX inhibitor enhanced response to radiotherapy in colorectal cancer

Metabolic reprogramming characterized by mitochondrial dysfunction and increased glycolysis is associated with aggressive tumor biology and poor therapeutic response. The interplays among NADPH oxidase (NOX)-mediated reactive oxygen species, regulation of glycolysis and oxidative phosphorylation (OXPHOS) in cancer cells suggest an opportunity to develop a new cancer therapy. We found that treatment with a hyaluronic acid nanoparticle encapsulated with GKT831 (HANP/GKT831), a NOX1/4 inhibitor, markedly inhibited the proliferation and invasion of cancer cells. Treated tumor cells had reduced levels of mitochondrial ROS, glycolysis, and OXPHOS. The combination of HANP/GKT831 with radiation reduced colony formation and invasion of tumor cells. The combination therapy markedly inhibited the levels of molecules in glycolysis, OXPHOS, and DNA repairing pathways in tumor cells. Systemic administrations of HANP/GKT831 combined with radiotherapy significantly inhibited tumor growth by 84.7 % in a mouse colorectal tumor model. Tumors treated with HANP/GKT831 and radiation had increased DNA damage and apoptotic cell death. Furthermore, the combined therapy increased intratumoral infiltration of activated cytotoxic T cells and M(1) macrophages but reduced the levels of immunosuppressive fibroblasts and M(2) macrophages. Our results support HANP/GKT831 as a cancer nanotherapeutic agent that induces redox and bioenergy stresses in cancer cells for enhanced therapeutic response to radiotherapy.