title: Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis.
abstract: Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the anti-proliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC(50) values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.
authors.affiliation: Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Raza
authors.forename: Blake A
authors.initials: BA
authors.lastname: Jacobson
authors.forename: Adam
authors.initials: A
authors.lastname: Benoit
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.forename: Joe
authors.initials: J
authors.lastname: Jay-Dixon
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiasa
authors.forename: David M
authors.initials: DM
authors.lastname: Ferguson
authors.forename: Robert Arthur
authors.initials: RA
authors.lastname: Kratzke
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D002945:Cisplatin