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

¹ Dept of Genetics, Biology and Biochemistry, University of Torino; and Research Center on Experimental Medicine (CeRMS), Via Santena 5/bis, 10126 Torino, Italy
² Pathology Unit, Department of Oncology, Azienda Sanitaria Ospedaliera, Via Venezia 16, I-15100 Alessandria, Italy
³ Dept of Genetics, Biology and Biochemistry, University of Torino; and Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, Università di Torino, Italy.

^* To whom correspondence should be addressed. E-mail: dario.ghigo{at}unito.it.

	Abstract

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibers deposition in the lung may cause hypoxia and iron chelation at the fibers surface. Hypoxia-inducible factor-1 (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. This study has been 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 a 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 coincubation with the cell-permeating iron salt ferric nitrilotriacetate (FeNTA), which caused an increase of intracellular iron bioavailability, checked as increased activity of the iron regulatory protein-1 (IRP-1). Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in HMM cells by increasing HIF-1 activity, through an iron-sensitive mechanism.

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