Targeting heme for the identification of cytotoxic agents.
Certain tumor types have an increased capacity for heme synthesis, which serves as the basis for photodynamic therapy. Heme also serves as the target for the anti-malaria drug artemisinin, which has also been used as an anti-cancer drug. We developed a high-throughput screening assay to identify heme interacting (HI) compounds, which included imidazole, pyridine, carbonitrile, isocyanide, and quinoline core structures that are known to interact with heme or hemin. The cytotoxicity of several of the compounds towards human leukemia cell lines could be modulated by increasing or decreasing heme synthesis. Spectral analysis indicated that distinct molecular interactions occurred with heme, suggesting that HI compounds appear to target heme with exquisite specificity. These studies suggest that heme may serve as a novel therapeutic target for cancer drug discovery.
Geisinger Clinic, Danville, PA 17822, USA.
Shiming
S
Zhang
Hui
H
Chen
Jessica
J
Webster
Glenn S
GS
Gerhard
D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D003486:Cyanides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D006418:Heme / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D003486:Cyanides; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D011804:Quinolines; D006418:Heme; C031327:artemisinin