Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

Our plain-English summary of Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis, by A. Raza, B.A. Jacobson, A. Benoit, et al (Investigational New Drugs, 2012).

The study

• Authors: A. Raza, B.A. Jacobson, A. Benoit, M.R. Patel, J. Jay-Dixon, H. Hiasa, D.M. Ferguson, R.A. Kratzke
• Journal: Investigational New Drugs
• Published: 2012;30(4):1443-8
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study tested four acridine-based compounds, called compounds 1 to 4, on four human mesothelioma cell lines grown in culture. The authors describe the compounds as catalytic inhibitors of the enzyme human topoisomerase II. No patients and no asbestos exposure were involved. Cell growth tests lasted 72 hours. Nanomolar doses had no effect. At low micromolar levels, growth fell in a dose-dependent way in all four lines, with EC50 values (concentration giving half the maximum effect) from 6.91 to 32.45 μM. Compound 2 was generally the most effective. In H2373 cells, compound 1 or 4 at 15 μM combined with cisplatin at 1.5 μM gave additive effects. At 30 μM for 48 hours, compounds 1 and 4 caused PARP cleavage, a sign of apoptosis (programmed cell death). Annexin V staining appeared in 17% to 30% of treated cells, compared with less than 3% of untreated cells. The authors concluded that apoptosis was likely the main mechanism of cell death and that the compounds could serve as lead compounds for more potent inhibitors. They noted that the concentrations used may be difficult to achieve in the body.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: in vitro (cell culture) laboratory experiment
• Who was studied: Four human mesothelioma cell lines (H513, H2373, H2461, H2596) obtained from the American Tissue Culture Collection. Non-transformed LP9 mesothelial cells are listed in the methods, but no results for them are reported. No human subjects.
• Exposure: Not asbestos. For the cell growth tests, cells were treated with a panel of acridine-based (9-aminoacridine) compounds 1 to 4 at varying concentrations for 72 hours. Combination tests used compound 1 or 4 at 15 μM with cisplatin at 1.5 μM for 72 hours. Apoptosis tests used compound 1 or 4 at 30 μM for 48 hours.
• Main results:
  • Nanomolar doses produced no response in any cell line.
  • At low micromolar levels there was a dose-dependent effect in all four cell lines, with EC50 values from 6.91 to 32.45 μM.
  • Responses varied between cell lines; compound 2 was generally the most effective.
  • In H2373 cells, compound 1 or 4 combined with cisplatin showed additive effects. The authors report similar results in H513 cells but did not show the data.
  • In treated mesothelioma cells (H2373 and H2461), compounds 1 and 4 at 30 μM caused PARP cleavage within 48 hours, which the authors interpret as apoptosis.
  • Annexin V, a marker of early apoptosis, was seen in 17% to 30% of treated cells versus less than 3% of untreated cells.
• The authors' conclusion: The authors concluded that the compounds induced apoptosis in mesothelioma cells and that this is likely the main mechanism of cell death. They also concluded that the compounds could serve as lead compounds for developing more potent and specific topoisomerase II inhibitors.
• Limitations the authors state:
  • The concentrations used may be difficult to achieve in the body.
  • The suggestion that these compounds may have lower toxicity than topoisomerase II poisons has not yet been rigorously tested.
  • Whether other mechanisms of cell death, such as necrosis or autophagy, are involved was not examined.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Apoptosis, Malignant Mesothelioma, Doxorubicin.

Related studies

• Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II — A.A. Sadiq, M.R. Patel, et al. (2010)
• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells — M. Yamaji, A. Ota, et al. (2017)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)
• Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines — Y. Wang, A.K. Rishi, et al. (2010)
• CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells — S. Jamal, V.T. Cheriyan, et al. (2014)

Browse more research in Investigational New Drugs, or return to medical research.