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

Abstract

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.

Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine–pyridine–histidine system

“…7,8) Herein we prepared a series of HPH compounds possessing various imidazole substituents, namely HPH-1Trt, HPH-2Bzl, HPH-1Bzl, HPH-2Me, and HPH-1Me, and examined the influence of the imidazole substitution. HPH-1Trt and HPH-2Trt were highly active against AsPC-1, U87, and U251 cells while the other HPH compounds were virtually inactive.…”

“…7,8) HPH-2Trt-induced cell death was not inhibited by antioxidants such as reduced glutathione and N-acetylcysteine. 7) Induction of apoptosis by HPH-2Trt was inhibited by zinc and copper ions. 8) Thus, the imidazole substitution seemed to exert a profound effect on the biological function of HPH.…”

“…7) It was remarkable since AsPC-1 cells are apoptotic resistant; Bleomycin A 2 , adriamycin, and vinblastine did not induce apoptosis in AsPC-1 cells even at high concentrations. 7,8) HPH-2Trt-induced cell death was not inhibited by antioxidants such as reduced glutathione and N-acetylcysteine. 7) Induction of apoptosis by HPH-2Trt was inhibited by zinc and copper ions.…”

Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery

“…In addition, diketopiperazines are also known to exhibit potential antitumor activity. More recent approaches attempts to develop the therapeutics that target the drug resistance developed due to mutation in cancer stem cells 173,174 . Lucietto et al 175 reported in vitro anticancer potential of histidine‐containing cyclic diketopiperazines.…”

l-Histidyl-glycyl-glycyl-l-histidine. Amino-acid structuring of the bleomycin-type pentadentate metal-binding environment capable of efficient double-strand cleavage of plasmid DNA

“…2A) [5], and Me 2 N-HPH-2Trt that induces apoptosis in apoptosis resistant human pancreatic carcinoma cells ( Fig. 2A) [6]. The X-ray crystal analysis of the copper complex of HPH-Pep revealed a distorted square pyramidal structure in which the pyridine nitrogen, the two amide nitrogens, and one imidazole nitrogen make a basal plane and the other imidazole occupies the apical position ( Fig.…”