Investigations into Aziridinomitosene DNA-Protein Crosslinking in Human Cancer Cells
Aziridinomitosenes (AZMs) are organic molecules with high structural similarity to mitomycin C (MC), a natural anti-tumor/antibiotic that has been used for treatment of several types of cancers. The formation of DNA-DNA interstrand crosslinks (ICL) are the main source of MC-induced cytotoxicity. Investigations within our laboratory have shown that AZMs are capable of forming ICLs with similar or increased frequency than MC in Jurkat and other cancer cell lines. In addition to ICLs, circumstantial evidence suggested that AZMs are capable of forming DNA-protein crosslinks (DPCs). Here, we attempt to verify the formation of DPCs in AZM-treated Jurkat cells. To do this, we conducted a K-SDS assay to test for DPC’s, which utilizes the complexing of protein with sodium dodecyl sulfate to separate DNA bound protein by AZM-induced crosslinks. Our studies demonstrate that our synthetic AZMs produce DNA/protein adducts in a concentration-dependent manner, and in greater abundance than does MC. These results solidify the preliminary studies, and provide the first substantial evidence that AZMs are able to covalently link protein to DNA.
Kulm, Hannah; Carfi, Ryan; Cornell, Ken; and Warner, Don, "Investigations into Aziridinomitosene DNA-Protein Crosslinking in Human Cancer Cells" (2015). College of Arts and Sciences Presentations. Paper 18.