Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II

Our plain-English summary of Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II, by A.A. Sadiq, M.R. Patel, B.A. Jacobson, et al (Investigational New Drugs, 2010).

The study

• Authors: A.A. Sadiq, M.R. Patel, B.A. Jacobson, M. Escobedo, K. Ellis, L.M. Oppegard, H. Hiasa, R.A. Kratzke
• Journal: Investigational New Drugs
• Published: 2010;28(1):20-5
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Simocyclinone D-8 (SD8), a semi-synthetic compound derived from yeast, has been shown to decrease the proliferation of MCF-7 breast cancer cells. It has been shown to be a potent bacterial DNA gyrase inhibitor, a homologue of human topoisomerase II (hTopoII). We tested SD8 activity alone and in combination with cisplatin against malignant mesothelioma (MM) and non-small cell cancer (NSCLC) cell lines.

Methods: Inhibition of hTopoII supercoiling function by SD8 and a known hTopoII poison, etoposide, were done by in vitro assay using purified hTopoII and kinetoplast DNA as the substrate. The DNA products were analyzed by agarose gel electrophoresis after treatment with increasing concentrations of each drug. Mesothelioma cell lines (H2373, H2461 and H2596) and NSCLC cell lines (H2030, H460, and H2009) grown in RPMI with 10% calf serum were used. Non-malignant mesothelial cells, LP9, were grown in 1:1 ratio of MCDB:199E medium supplemented with 15% calf serum, 0.4 microg/mL hydrocortisone, and 15 ng/mL epidermal grown factor. Cell proliferation assays were performed in 96-well plates using the CCK-8 kit (Dojindo inc.). Cells were treated for 72 h with various SD8 concentrations and controls containing equal volume of the vehicle, DMSO. Treated cells were assayed for the induction of apoptosis with poly ADP-ribose polymerase-1 (PARP) cleavage assay.

Results: Biochemical assays revealed that the IC(50) for hTopoII inhibition was 100 microM for SD8 and 400 microM for etoposide. SD8 inhibited hTopoII function without inducing DNA cleavage events. SD8 inhibited the growth of NSCLC and Mesothelioma cells with IC(50) ranging from 75-125 microM. Furthermore, SD8 was not toxic to non-transformed primary mesothelial cell line, LP9 at the IC(50) doses. SD8 induced apoptosis in all cell lines tested.

Conclusions: SD8 inhibits hTopoII in vitro without inducing DNA strands breaks and has significant activity against NSCLC and MM cell lines. While doses required for SD8 anticancer activity are unlikely to be achieved in vivo, chemical modifications to SD8 to increase its potency could lead to improved therapies for these diseases.

In plain English

This laboratory study tested simocyclinone D8 (SD8), a compound produced by the bacterium Streptomyces antibioticus, on human cells grown in dishes. It did not involve patients, animals or asbestos exposure. In enzyme experiments, SD8 blocked human topoisomerase II, an enzyme cells need to handle DNA, at a half-maximal concentration (IC50) of about 80 µM. Unlike the drug etoposide, it did not make the enzyme cut DNA. Over 72 hours, SD8 slowed the growth of two non-small cell lung cancer cell lines, with an IC50 of about 75 µM for H2009 and about 130–140 µM for H2030. It also slowed two malignant mesothelioma cell lines: about 125 µM for H2461 and 100 µM for H2596. Non-cancerous mesothelial cells (LP9) had an IC50 of about 150 µM. SD8 triggered a marker of programmed cell death in the cancer cell lines tested. The authors concluded that SD8 could be a starting compound for less toxic anticancer drugs. They noted that the doses needed may be hard to reach in the body and that the compound needs chemical changes to make it stronger before animal or clinical testing.

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: Laboratory (in vitro) study: enzyme assays and experiments on cultured human cancer and non-cancerous cell lines
• Who was studied: Two non-small cell lung cancer cell lines (H2009, H2030) and two malignant mesothelioma cell lines (H2596, H2461) from the American Tissue Culture Collection, plus a non-transformed mesothelial cell line (LP9) from the National Institute of Aging; purified human topoisomerase II for the enzyme assays
• Exposure: The experimental compound simocyclinone D8 (SD8) at a range of concentrations (up to 200 µM in the growth assays) for 72 hours; etoposide was used as a comparison in the enzyme assays. No asbestos or fiber exposure was studied.
• Main results:
  • In the enzyme (decatenation) assay, SD8 inhibited human topoisomerase II in a dose-dependent manner with an IC50 of approximately 80 µM.
  • Unlike etoposide, SD8 did not stimulate DNA cleavage by topoisomerase II. The authors interpreted this as SD8 acting as a catalytic inhibitor rather than a poison of the enzyme.
  • Lung cancer cell line H2009: growth IC50 approximately 75 µM.
  • Lung cancer cell line H2030: growth IC50 approximately 130–140 µM.
  • Mesothelioma cell lines: growth IC50 approximately 125 µM for H2461 and 100 µM for H2596.
  • Non-transformed mesothelial cells (LP9): growth IC50 approximately 150 µM, higher than for the cancer cell lines tested.
  • SD8 caused PARP cleavage, a marker of apoptosis, in the cancer cell lines. In H2030 cells it was seen only after 48 hours.
• The authors' conclusion: The authors concluded that SD8 is a true catalytic inhibitor of topoisomerase II that does not induce DNA strand breaks, and that it could serve as a lead agent for developing new anticancer drugs with lower toxicity.
• Limitations the authors state:
  • The concentrations at which SD8 inhibited cell growth may be difficult to achieve in the body.
  • SD8 needs chemical modification to improve its potency and cytotoxicity before it can be tested in animals or clinical trials.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Malignant Mesothelioma, Mesothelioma, Mesothelial Cells, Apoptosis.

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