Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas

Our plain-English summary of Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas, by M. Sayan, A. Shukla, M.B. MacPherson, et al (American Journal of Respiratory Cell and Molecular Biology, 2014).

The study

• Authors: M. Sayan, A. Shukla, M.B. MacPherson, S.L. Macura, J.M. Hillegass, T.N. Perkins, J.K. Thompson, S.L. Beuschel, J.M. Miller, B.T. Mossman
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2014;51(5):595-603
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.

In plain English

This laboratory study tested two cancer drugs, vandetanib and doxorubicin, on two human malignant mesothelioma cell lines grown in dishes. HMESO is the epithelioid type. H2373 is the sarcomatoid type and is known to resist doxorubicin. No patients or asbestos exposures were studied. Vandetanib alone (5 to 50 µM) significantly reduced HMESO cell numbers. In initial tests it had no significant effect on H2373 cells. Giving vandetanib one hour before doxorubicin reduced cell viability more than doxorubicin alone in both lines (p less than 0.05), which the authors described as synergy. Doxorubicin increased the activation of several cell-survival signals, including ERK5 and CREB. Adding vandetanib lowered most of these signals compared with doxorubicin alone, although in H2373 cells it increased activation of AKT. When gene silencing cut ERK5 or CREB by more than 70% in H2373 cells, cell numbers after doxorubicin or the combination were significantly lower than in control cells. The authors concluded that vandetanib can interrupt survival pathways stimulated by doxorubicin, including ERK5 and CREB. They suggested a three-part treatment approach may be merited in drug-resistant mesothelioma.

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 of cultured human mesothelioma cell lines
• Who was studied: Two human malignant mesothelioma cell lines, studied at the University of Vermont: epithelioid HMESO (doxorubicin-sensitive) and sarcomatoid H2373 (doxorubicin-resistant). No patients were studied.
• Exposure: No asbestos exposure was tested. The cells were treated with vandetanib and doxorubicin, alone and combined. Vandetanib was used at 5 to 50 µM, and at 5 µM in the combination experiments. Doxorubicin was used at 25 µM for HMESO and 100 µM for H2373, and at 1 to 25 µM in the signaling tests. ERK5 or CREB was also reduced by gene silencing in H2373 cells.
• Main results:
  • In HMESO cells, vandetanib alone at 5 to 50 µM significantly decreased total cell numbers at all concentrations compared with untreated controls.
  • In H2373 cells, vandetanib alone had no significant effect on cell viability in the initial dose-response studies.
  • In both cell lines, vandetanib given before doxorubicin decreased cell viability more than doxorubicin alone (p less than 0.05). The authors described this as synergistic.
  • In both cell lines, doxorubicin increased activation (phosphorylation) of ERK1, ERK2, ERK5 and CREB in a dose-dependent way.
  • In HMESO cells at 24 hours, the combination significantly decreased phosphorylation of ERK1, ERK2, ERK5, CREB and AKT compared with doxorubicin alone.
  • Compared with doxorubicin alone, the combination decreased the downstream survival signals, except AKT in H2373 cells.
  • In H2373 cells, the combination increased AKT activation compared with doxorubicin alone.
  • In the silenced H2373 lines, ERK5 or CREB was inhibited by more than 70% compared with scrambled-control clones.
  • In H2373 cells with ERK5 or CREB silenced, cell numbers after doxorubicin or doxorubicin plus vandetanib were significantly lower than in control-silenced cells.
• The authors' conclusion: The authors concluded that vandetanib can interrupt several cell-survival signaling pathways stimulated by doxorubicin, including ERK5 and CREB, which they described as previously unreported. They suggested that a three-part (tri-modal) combination approach may be merited in chemoresistant mesothelioma.
• Limitations the authors state:
  • The authors noted that the EGFR data are hard to interpret because, as another study reported, vandetanib also increases EGFR-activating molecules in tumor tissue.

Topics

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

Medical terms in this study, explained in our Lexicon: Doxorubicin, Mesothelioma, Malignant Mesothelioma, Lung Cancer, Prognosis, Tyrosine Kinase Inhibitor, Clinical Trial, Non-Small Cell Lung Cancer.

Related studies

• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas — A. Shukla, J.M. Miller, et al. (2013)
• Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2 — C.A. Barlow, T.F. Barrett, et al. (2007)
• Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis — A. Shukla, M.W. Bosenberg, et al. (2009)
• The duration of nuclear extracellular signal-regulated kinase 1 and 2 signaling during cell cycle reentry distinguishes proliferation from apoptosis in response to asbestos — Z. Yuan, D.J. Taatjes, et al. (2004)
• An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury — A. Shukla, T.F. Barrett, et al. (2011)
• Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells — S. Buder-Hoffmann, C. Palmer, et al. (2001)

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