Upregulation of NADPH oxidases (NOXs) in cancer cells leads to chronic increase in intracellular reactive oxygen species (ROS) and adaptation to a high ROS level for cell survival and, thereby, low sensitivity to radiotherapy. To overcome resistance to radiotherapy, we have developed a bioactive and CD44 targeted hyaluronic acid nanoparticle encapsulated with an NOX inhibitor, GKT831 (HANP/GKT831). We found that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 alone in cancer cells. Systemic delivery of HANP/GKT831 led to the targeted accumulation in breast cancer patient derived xenograft (PDX) tumors in nude mice. Importantly, the combination of systemic delivery of HANP/GKT831 with a low dose of local radiotherapy significantly enhanced tumor growth inhibition in breast cancer PDX models. Our results showed that HANP/GKT831 primed tumor cells to radiation-induced DNA damage and cell death by downregulation of DNA repair function and oncogenic signal pathways.
Keyphrases
- reactive oxygen species
- hyaluronic acid
- radiation induced
- dna damage
- dna repair
- cancer therapy
- cell death
- cell proliferation
- radiation therapy
- low dose
- early stage
- locally advanced
- oxidative stress
- drug delivery
- dna damage response
- signaling pathway
- squamous cell carcinoma
- type diabetes
- high dose
- transcription factor
- adipose tissue
- poor prognosis
- cell cycle arrest
- metabolic syndrome