Asbestos induces doxorubicin resistance in MM98 mesothelioma cells via HIF-1alpha

Our plain-English summary of Asbestos induces doxorubicin resistance in MM98 mesothelioma cells via HIF-1alpha, by C. Riganti, S. Doublier, E. Aldieri, et al (The European Respiratory Journal, 2008).

The study

• Authors: C. Riganti, S. Doublier, E. Aldieri, S. Orecchia, P.G. Betta, E. Gazzano, D. Ghigo, A. Bosia
• Journal: The European Respiratory Journal
• Published: 2008;32(2):443-51
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibre deposition in the lung may cause hypoxia and iron chelation at the fibre surface. Hypoxia-inducible factor (HIF)-1alpha, which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. The present study aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1alpha and an increased expression of Pgp. After 24-h incubation with crocidolite asbestos or with the iron chelator dexrazoxane, or under hypoxia, HMM cells were tested for HIF-1alpha activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect. Crocidolite, dexrazoxane and hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity. These effects were prevented by the co-incubation with the cell-permeating iron salt ferric nitrilotriacetate, which caused an increase of intracellular iron bioavailability, measured as increased activity of the iron regulatory protein-1. Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in human malignant mesothelioma cells by increasing hypoxia-inducible factor-1alpha activity, through an iron-sensitive mechanism.

In plain English

This was a laboratory study of cells grown in dishes, not of patients. The authors used one cell line, MM98, established from the pleural effusion of a male patient with malignant mesothelioma. For 24 hours the cells were grown with the cancer drug doxorubicin plus crocidolite asbestos fibres, the iron-binding drug dexrazoxane, or low oxygen (3% instead of 20%), with or without the iron compound ferric nitrilotriacetate (FeNTA). Crocidolite, dexrazoxane and low oxygen each lowered the amount of doxorubicin inside the cells and reduced drug-induced cell death. They also raised P-glycoprotein, a pump that pushes drugs out of cells, and nuclear HIF-1alpha, a protein that switches on the P-glycoprotein gene. Adding FeNTA reversed these effects. A HIF-1alpha blocker, YC-1, prevented the rise in P-glycoprotein and abolished the effects on doxorubicin. A pump blocker, verapamil, increased doxorubicin accumulation and toxicity under every condition. Crocidolite raised a marker of low iron inside the cells. The authors concluded that crocidolite likely activates HIF-1alpha by reducing the iron available in the cell. They noted that their results came from an in vitro model.

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 laboratory experiment on a single human malignant mesothelioma cell line
• Who was studied: MM98 cells, a human malignant mesothelioma cell line established from the pleural effusion of one male patient with histologically confirmed malignant mesothelioma (Turin and Alessandria, Italy)
• Exposure: 24-hour incubation, in medium containing doxorubicin, with UICC crocidolite asbestos fibres, compared with the iron chelator dexrazoxane, hypoxia (3% oxygen), and the iron salt ferric nitrilotriacetate (FeNTA)
• Main results:
  • In MM98 cells, crocidolite significantly lowered intracellular doxorubicin accumulation and increased P-glycoprotein (Pgp) expression compared with control; dexrazoxane and hypoxia had the same effects
  • Dexrazoxane, crocidolite and hypoxia significantly reduced the number of MM98 cells undergoing doxorubicin-induced cell death (cells positive for annexin V and propidium iodide)
  • FeNTA completely reversed the effects of crocidolite, dexrazoxane and hypoxia, increasing drug content in the cells and decreasing Pgp
  • Crocidolite increased IRP-1 binding activity, which the authors used as a sign of lower intracellular iron, compared with control; hypoxia did not change IRP-1 activity
  • Crocidolite, dexrazoxane and hypoxia markedly increased HIF-1alpha in nuclear extracts; FeNTA repressed this
  • The HIF-1alpha inhibitor YC-1 prevented Pgp induction under all conditions and abolished the effects of crocidolite, dexrazoxane and hypoxia on doxorubicin accumulation and toxicity
  • The Pgp inhibitor verapamil lowered Pgp activity and increased doxorubicin accumulation and toxicity under each experimental condition
  • After 24 h of hypoxia, HIF-1alpha and Pgp returned to baseline after 6 h back in normal oxygen
  • Crocidolite alone, without doxorubicin, made 15% of cells positive for annexin V and propidium iodide (data not shown)
• The authors' conclusion: The authors concluded that crocidolite exposure of MM98 cells induces HIF-1alpha activation, accompanied by more Pgp and greater doxorubicin resistance. They concluded that crocidolite likely does this by decreasing iron availability in the cell, and that increased intracellular iron may decrease the resistance.
• Limitations the authors state:
  • The results were obtained in an in vitro (cell culture) model
  • The authors could not exclude that part of the crocidolite effect is mediated by oxidative stress

Topics

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

Medical terms in this study, explained in our Lexicon: Doxorubicin, Mesothelioma, Asbestos Exposure, Deposition, Hypoxia, Glycoprotein, Crocidolite.

Related studies

• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)
• Long-term exposure of mesothelial cells to SV40 and asbestos leads to malignant transformation and chemotherapy resistance — A.L. Cleaver, K. Bhamidipaty, et al. (2014)
• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• Resistance to platinum-based chemotherapy in lung cancer cell lines — J. Chen, N. Emara, et al. (2010)
• Activation of Nrf2 pathways correlates with resistance of NSCLC cell lines to CBP501 in vitro — N. Mine, S. Yamamoto, et al. (2014)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)

Browse more research in The European Respiratory Journal, or return to medical research.