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

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)-1a, 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-1a 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-1a activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect.Crocidolite, dexrazoxane and hypoxia caused HIF-1a 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-1a activity, through an iron-sensitive mechanism.

A Phase I Trial of Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies

“…Tests for PIK3CA and K-RAS mutations were performed using a similar method. Exons 9 (codons 532-554) and 20 (codons 1011-1062) for examined PIK3CA mutations, and codons 12, 13 and 61 were examined for KRAS mutations 7 . PTEN loss was assessed using immunohistochemistry 12 (monoclonal mouse anti-human PTEN, clone 6H2.1, Dako®, Denmark) 12 .…”

“…Recently, up regulation of the transcription factor hypoxia-inducible factor alpha (HIF-1α), with subsequent increases in the production of proteins that promote angiogenesis, anaerobic metabolism and other cellular survival pathways, has been demonstrated as an important mechanism of anthracycline resistance 5-7 .…”

Sorafenib inhibits ERK1/2 and MCL-1L phosphorylation levels resulting in caspase-independent cell death in malignant pleural mesothelioma

“…Improved, but modest, response rates have been achieved with combination therapy of cisplatin with gemcitabine, vinorelbine, ironotecan, raltitrexed or vinflunine. The resilient, aggressive nature of this malignancy is attributed to TRAIL resistance resulting from elevated baseline levels of known pro-survival effectors including FLIP L ,5 HIF-1α,6 BCL-X L ,7,8 IAP-1,9,10 survivin,10,11 XIAP,10 MCL-1 L , p21,12 PECAM-1,13 HSP70 and the stem cell factor (SCF)/c-Kit/Slug pathway 14. In addition to these resistance patterns, MPM human cell lines have also been demonstrated to have high levels of c-src15 and AKT pathway activity.…”

The Impact of Extracellular Low pH on the Anti-Tumor Efficacy Against Mesothelioma

“…The expression of p-glycoprotein was up-regulated at low pH conditions in EMT6 cells and prostate cancer cells (Thews et al, 2006 ). This upregulation of p-glycoprotein is partially dependent on HIF-1 (Riganti et al, 2008) and extracellular low pH has been reported to induce HIF-1 (Mekhall et al, 2004). So, this mechanism might contribute to the pHdependent loss of cytotoxicity as shown in Fig.1, in addition to the possibility derived from its weakly basic conformation (Raghunand et al, 1999).…”