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.