Induction of Apoptosis in Human Pancreatic Carcinoma Cells by a Synthetic Bleomycin‐like Ligand

Histidine‐pyridine‐histidine‐3 (HPH‐3) is an oxygen‐activating ligand based on the structure of bleomycin. HPH‐3 induced the death of human pancreatic adenocarcinoma AsPC‐1 cells in 24 h, causing apoptotic morphology and internucleosomal degradation of DNA. HPH‐3‐induced cell death was not inhibited by antioxidants such as reduced glutathione and N‐acetylcysteine, whereas hydrogen peroxide‐induced cell death was inhibited by them, indicating that hydrogen peroxide is not involved in the induction of apoptosis by HPH‐3. Induction of apoptosis by HPH‐3 was inhibited by zinc and copper ions, indicating that chelation with ferrous ion is responsible for induction of apoptosis, as is the case in chelation by bleomycin to cleave DNA. Bleomycin A(2) and its fragment having no DNA‐binding region, glycopeptide‐3, did not induce apoptosis in AsPC‐1 cells. Bleomycin A(2) induced G2/M block in flow‐cytometric analysis, but HPH‐3 did not and instead induced an apoptotic pre‐G1 peak. Thus, HPH‐3 induced apoptosis in human pancreatic carcinoma cells, which is a unique characteristic among bleomycin‐related compounds.