Combination of onconase and dihydroartemisinin synergistically suppresses growth and angiogenesis of non-small-cell lung carcinoma and malignant mesothelioma

Our plain-English summary of Combination of onconase and dihydroartemisinin synergistically suppresses growth and angiogenesis of non-small-cell lung carcinoma and malignant mesothelioma, by R. Shen, J. Li, D. Ye, et al (Acta Biochimica et Biophysica Sinica, 2016).

The study

• Authors: R. Shen, J. Li, D. Ye, Q. Wang, J. Fei
• Journal: Acta Biochimica et Biophysica Sinica
• Published: 2016;48(10):894-901
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Onconase (Onc) is a cytotoxic ribonuclease derived from leopard frog oocytes or early embryos, and has been applied to the treatment of malignant mesothelioma in clinics. Onc also exhibits effective growth suppression of human non-small-cell lung cancer (NSCLC). Artemisinin (Art) and its derivatives are novel antimalarial drugs that exhibit antitumor and antivirus activities. In this study, we investigated the antitumor effects of combinations of Onc and an Art derivative, dihydroartemisinin (DHA), both in vitro and in vivo Isobologram analyses showed synergistic effects on the proliferation of NSCLC cells under the treatment with Onc and DHA. In vivo experiments also showed that the antitumor effect of Onc was markedly enhanced by DHA in mouse xenograft models. No obvious adverse effect was observed after the treatment. The density of microvasculature in the tumor tissues treated with Onc/DHA combination was lower than those treated with Onc or DHA alone. The above results are consistent with the results of the matrigel plug test for angiogenesis suppression using the Onc/DHA combination. These results imply that the anti-angiogenesis effects may make important contributions to the in vivo antitumor effects of the Onc/DHA combination treatment. The Onc/DHA combination therapy may have the potential to become a novel regimen for NSCLC and mesothelioma.

© The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: [email protected].

In plain English

This laboratory and mouse study tested whether combining onconase, a protein from leopard frog eggs, with dihydroartemisinin (DHA), an antimalarial drug, slowed the growth of human non-small-cell lung cancer and malignant mesothelioma. It did not study asbestos exposure. In cultures of four lung cancer cell lines and one mesothelioma line (MSTO-211H), the combination worked better than expected from either drug alone (synergy) in every line. In nude mice carrying human tumors, five per group, DHA significantly increased onconase's effect on tumor growth in both a lung cancer (A549) and a mesothelioma (MSTO-211H) model. Body weight changed only slightly; no obvious adverse effects were seen. The combination reduced VEGF staining in mesothelioma tumors, lowered blood-vessel density in implanted gel plugs compared with saline (P = 0.018), and reduced vessel-like tube formation by cultured blood-vessel lining cells. Compared with either drug alone, it did not significantly increase apoptosis (a form of cell death). Synergy depended on giving DHA one day after onconase. The authors concluded the combination may have potential as a new regimen for lung cancer and mesothelioma, and said its mechanism needs further exploration.

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 (cell culture) and animal experiment: drug-combination tests on cancer cell lines, and human tumors grown in nude mice (xenograft models)
• Who was studied: Human cell lines: four non-small-cell lung cancer lines (NCI-H661, SK-MES-1, SPC-A-1, A549) and one human mesothelioma line (MSTO-211H), plus human umbilical vascular endothelium cells. Animals: male BALB/c nude mice, five per group in the tumor experiments, and 20 mice in four groups for the Matrigel plug test. Work done in Shanghai, China.
• Exposure: No asbestos exposure was studied. The treatments were onconase (Onc) and dihydroartemisinin (DHA), alone or combined, with DHA given one day after Onc. In mice with A549 tumors the doses were Onc 3 mg/kg intravenously and DHA 10 mg/kg intraperitoneally. In mice with MSTO-211H tumors the doses were Onc 1.5 mg/kg and DHA 20 mg/kg. Both regimens were given twice a week for 3 weeks.
• Main results:
  • In cell culture, the combination showed synergistic effects in all four lung cancer cell lines and the mesothelioma cell line.
  • In SK-MES-1 lung squamous cell carcinoma cells, IC50 values for both drugs dropped from 1200 to 10 µM with the combination. The lowest value the article calls 'CI' was 0.019 in these cells and 0.285 in Spc-A-1 cells.
  • In mice with A549 lung cancer tumors, DHA significantly increased the antitumor effect compared with Onc alone.
  • In mice with MSTO-211H mesothelioma tumors, DHA also significantly increased the antitumor effect compared with Onc alone.
  • Blood biochemistry showed no significant differences between treated and control mice. The data were not shown.
  • In MSTO-211H mesothelioma tumors, VEGF expression was significantly reduced in combination-treated mice compared with mice given either drug alone and with control mice.
  • In the Matrigel plug test, microvessel density in the combination group was lower than in the saline group (P = 0.018). The single-drug groups did not differ significantly from saline.
  • The combination reduced endothelial cell tube formation compared with the other groups.
  • The combination did not significantly increase apoptosis compared with single treatments, either in tumors (TUNEL assay) or in cultured cells (Annexin V assay).
  • The drug interaction depended on timing. It was antagonistic when DHA was given 1 day before Onc, additive when both were given together, and synergistic only when DHA was given 1 day later.
• The authors' conclusion: The authors concluded that the Onc/DHA combination may have the potential to become a novel regimen for non-small-cell lung cancer and mesothelioma.
• Limitations the authors state:
  • The authors state that the mechanism behind the synergistic antitumor activity is not known and needs further exploration.

Topics

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

Medical terms in this study, explained in our Lexicon: Angiogenesis, Carcinoma, Malignant Mesothelioma, Lung Cancer, Synergistic Effect, Mesothelioma.

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