github link
Accession IconGSE137952

A vasodilator Oxyfedrine Inhibits Aldehyde Metabolism and thereby Sensitizes Cancer Cells to Glutathione Depleting Agents

Organism Icon Homo sapiens
Sample Icon 12 Downloadable Samples
Technology Badge Icon Affymetrix Clariom S Human array (clariomshuman)

Submitter Supplied Information

Description
The major antioxidant glutathione (GSH) protects cancer cells from oxidative damage leading to ferroptosis, an iron-dependent cell death. Therapy-resistant cancer cells often manifest high expression of the cystine-glutamate antiporter subunit xCT which enhances cystine uptake leading to GSH synthesis and thereby survive oxidative damage and ferroptosis. The use of GSH-depleting agents including xCT inhibitors might thus be expected to enhance the efficacy of cancer therapy. On the other hand, the efficacy of xCT-targeted therapy depends on the cellular metabolism affecting antioxidant system in cancer cells and metabolic reprograming might reduce the efficacy of cancer therapy using xCT inhibitors. Recently, to overcome the resistance to xCT-targeted therapy, we performed a library screening and identified an oral anesthetics dyclonine (DYC) as a sensitizing drug for xCT inhibitor sulfasalazine (SSZ). However, DYC is a local anesthetic and might not suitable for the systemic administration combined with SSZ in a clinical setting. In this study, we identified a vasodilator oxyfedrine (OXY) which is clinically used in systemic administration also acts as a sensitizing drug to GSH-depleting agents in multiple type of cancer cells. OXY and DYC share the motif required for the covalent inhibition of aldehyde dehydrogenases (ALDHs), and combined treatment with OXY and SSZ induced the accumulation of cytotoxic aldehyde 4-hydroxynonenal (4-HNE) and induce cell death in SSZ-resistant cancer cells. Furthermore, we found that OXY sensitizes cancer cells to radiation therapy which decreases intracellular GSH content. Our findings establish a rationale for repurposing of OXY as a sensitizing drug for xCT-targeted cancer therapy.
PubMed ID
Total Samples
12
Submitter’s Institution

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Specimen part
Processing Information
Additional Metadata
No rows found
Loading...