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

¹ Dept of Genetics, Biology and Biochemistry, ² Research Center for Experimental Medicine (CeRMS), ⁴ Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, University of Turin, Turin, and ³ Pathology Unit, Dept of Oncology, Azienda Sanitaria Ospedaliera, Alessandria, Italy.

CORRESPONDENCE: D. Ghigo, Dipartimento di Genetica, Biologia e Biochimica (Sezione di Biochimica), Via Santena, 5/bis, 10126 Torino, Italy. Fax: 39 0116705845. E-mail: dario.ghigo{at}unito.it

Keywords: Asbestos, doxorubicin resistance, hypoxia-inducible factor-1, iron, mesothelioma, P-glycoprotein

Received: July 17, 2007
Accepted March 18, 2008

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)-1, 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-1 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-1 activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect.

Crocidolite, dexrazoxane and hypoxia caused HIF-1 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-1 activity, through an iron-sensitive mechanism.