Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair

Our plain-English summary of Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double-strand break repair, by K. Kryeziu, U. Jungwirth, M.A. Hoda, et al (Molecular Cancer Therapeutics, 2013).

The study

• Authors: K. Kryeziu, U. Jungwirth, M.A. Hoda, F. Ferk, S. Knasmüller, C. Karnthaler-Benbakka, C.R. Kowol, W. Berger, P. Heffeter
• Journal: Molecular Cancer Therapeutics
• Published: 2013;12(6):1073-84
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G2-M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFR-mediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR.

©2013 AACR

In plain English

This laboratory study, done in Vienna, Austria, tested the arsenic-based cancer drug arsenic trioxide together with erlotinib, a drug that blocks a growth-signal receptor called EGFR. The article does not study asbestos exposure. Its link to asbestos topics is that five of the 16 human cancer cell lines tested were mesothelioma lines, and one mouse experiment used P31 mesothelioma cells. In cell cultures the two drugs acted synergistically. Adding erlotinib cut the arsenic trioxide dose needed to halve viable cells by up to 9.4-fold (in the HCT116 colon cancer line), and no antagonism was seen in any line. In A549 lung cancer cells, erlotinib blocked the EGFR activation caused by arsenic trioxide. The combination raised DNA double-strand breaks above either drug alone and lowered the DNA repair proteins Rad50 and Rad51. In mice with P31 mesothelioma cells injected into the abdomen, mean tumor weight was 2.40 g in controls, 0.96 g with arsenic trioxide alone and 0.52 g with the combination. Erlotinib alone was widely ineffective. The authors concluded the combination might be a promising strategy against solid cancer cells.

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 study: cell culture experiments on human cancer cell lines plus xenograft experiments in immunodeficient mice
• Who was studied: 16 human cancer cell lines, including the mesothelioma lines P31, VMC6, VMC12, VMC23 and VMC31 (the VMC lines were established at the Institute of Cancer Research, Vienna), plus lung (A549, A427), liver, colorectal, bone, thyroid and cervical cancer lines. Six- to 8-week-old female SCID mice received A549 cells under the skin (n = 9 per group per the figure legend) or P31 mesothelioma cells injected intraperitoneally.
• Exposure: Arsenic trioxide (ATO) alone and combined with the EGFR inhibitor erlotinib. Other inhibitors tested were gefitinib, lapatinib, LY294002, MK-2206 and U0126. Mice received erlotinib 25 mg/kg by mouth and ATO 5 mg/kg intraperitoneally, 5 times a week for 2 weeks. No asbestos or fiber exposure was studied.
• Main results:
  • In cell lines, ATO plus erlotinib was synergistic compared with ATO alone, with up to a 9.4-fold decrease in IC50 (for HCT116).
  • No antagonistic effects were seen in any tested cell line.
  • In A549 cells, ATO increased EGFR phosphorylation, and erlotinib completely inhibited this ATO-induced phosphorylation.
  • In A549 cells, 72 hours of the highest combination (10 micromoles per liter of each drug) produced up to 90% PI-positive (dead) cells.
  • In A549 cells treated with 10 micromoles per liter ATO plus 5 or 10 micromoles per liter erlotinib, cells arrested in G2–M phase rose from 12% to 22% and 26% at 24 hours, and to 42% and 43% at 48 hours.
  • In A549 cells, the comet assay showed significantly more DNA double-strand breaks after 6 hours of the combination than with either drug alone.
  • In A549 cells, the combination lowered the DNA repair proteins Rad50 and Rad51 and reduced BRCA1 phosphorylation in a concentration-dependent way.
  • In mice with A549 tumors under the skin, neither drug alone had anticancer activity, while the combination significantly reduced tumor growth.
  • In mice with intraperitoneal P31 mesothelioma tumors, ATO alone significantly reduced mean tumor weight from 2.40 g (controls) to 0.96 g, and the combination further reduced it to a mean of 0.52 g. Erlotinib alone was widely ineffective.
  • All treatments were well tolerated in mice, with no signs of toxicity.
• The authors' conclusion: The authors concluded that combining ATO with erlotinib or other EGFR inhibitors might be a promising strategy to make solid cancer cells more susceptible to ATO and to overcome drug resistance.

Topics

Medical terms in this study, explained in our Lexicon: EGFR, Apoptosis, Comet Assay, Lung Cancer, Mesothelioma.

Related studies

• Downregulation of thymidylate synthase and E2F1 by arsenic trioxide in mesothelioma — S.K. Lam, Y.Y. Li, et al. (2015)
• Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells — R. Eguchi, Y. Fujimori, et al. (2011)
• Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation — R.E. Favoni, A. Pattarozzi, et al. (2010)
• DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential? — Z. Msiska, M. Pacurari, et al. (2010)
• Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells — R. Okita, K. Shimizu, et al. (2015)
• Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells — K. Kawaguchi, H. Murakami, et al. (2009)

Browse more research in Molecular Cancer Therapeutics, or return to medical research.