Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

Our plain-English summary of Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy, by B. Fischer, C. Frei, U. Moura, et al (Lung Cancer, 2012).

The study

• Authors: B. Fischer, C. Frei, U. Moura, R. Stahel, E. Felley-Bosco
• Journal: Lung Cancer
• Published: 2012;78(1):23-9
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a relatively chemoresistant malignancy. Diverse biological targets are under investigation to develop new therapeutic options. One of these targets, namely the phosphoinositide-3-kinase (PI3K) pathway, has been shown to be a regulator of the side population (SP) phenotype in different cancers. The SP phenotype is due to drug efflux abilities providing drug-resistant properties. The presence of a SP fraction in MPM was recently observed in our laboratory. The aim of this study was to investigate the role of the PI3K pathway in the regulation of the SP phenotype in MPM. Treatment of overnight serum-starved cells with IGF increased phosphorylation of downstream target AKT, S6 and 4EBP1 and SP fraction in ZL55, ZL34 and SDM103T2 MPM cell lines. The PI3K/mTOR inhibitor NVP-BEZ235 and PI3K inhibitor wortmannin reduced the phosphorylation of downstream target AKT, S6 and 4EBP1 and decreased the SP fraction. Chemotherapy resistance mediated by drug efflux was tested by treating the cells with mitoxantrone. NVP-BEZ235 increased mitoxantrone cytotoxicity and this effect was mimicked by fumitremorgin C, a specific ABCG2 inhibitor, although not to the same extent, indicating that ABCG2-mediated drug efflux participates to chemoresistance. The involvement of ABCG2 in drug efflux was confirmed by determination of ABCG2-mediated decrease of intracellular mitoxantrone accumulation and silencing experiments. NVP-BEZ235-mediated decrease in drug efflux was associated with a significant decrease of ABCG2 present at the cell surface in ZL55 and SDM103T2 cells. In conclusion, the PI3K pathway is playing an important role in regulating the SP phenotype in MPM cells and inhibition of this activity may contribute to a more efficient cancer treatment.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory study used cancer cells grown in dishes, not patients, and did not examine asbestos. Researchers at University Hospital Zurich used three malignant pleural mesothelioma cell cultures (ZL34, ZL55 and SDM103T2). They tested whether blocking a signaling pathway called PI3K reduces the cells' ability to pump chemotherapy drugs out through a transporter protein, ABCG2. Compared with cells starved of serum overnight, the growth factor IGF raised the share of drug-pumping 'side population' cells seven- to nine-fold. Pre-treatment with the inhibitors NVP-BEZ235 or wortmannin cut that share by 68 to 99%. NVP-BEZ235 made mitoxantrone more effective at limiting cell growth in all three cultures and reduced mitoxantrone pumping by 15 to 26%. Blocking ABCG2 directly, with fumitremorgin C or by silencing the gene, also reduced pumping. NVP-BEZ235 lowered surface ABCG2 in SDM103T2 and ZL55; ZL34 showed no statistically significant change. NVP-BEZ235 also increased the effect of pemetrexed. The authors concluded that the PI3K pathway plays an important role in regulating this trait in mesothelioma cells, and that blocking it may contribute to more efficient cancer treatment.

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: Laboratory (in vitro) experiment on cultured mesothelioma cells; the authors call it a proof of principle study
• Who was studied: Three malignant pleural mesothelioma cell cultures: cell lines ZL34 and ZL55, established in the authors' laboratory (University Hospital Zurich), and primary culture SDM103T2, established from a xenograft. No human subjects.
• Exposure: No asbestos exposure was studied. Cells were treated with the growth factor IGF, the PI3K/mTOR inhibitor NVP-BEZ235 (500 nM) or the PI3K inhibitor wortmannin (500 nM), the chemotherapy drugs mitoxantrone and pemetrexed, the ABCG2 inhibitor fumitremorgin C (FTC), and ABCG2-targeted siRNA.
• Main results:
  • In all three cultures, adding IGF increased the side population fraction seven- to nine-fold compared with overnight serum-starved cells.
  • Pre-treatment with 500 nM NVP-BEZ235 or 500 nM wortmannin decreased the side population by 68 to 99% in all three cultures, and NVP-BEZ235 was more efficient than wortmannin.
  • NVP-BEZ235 pre-treatment increased the effect of mitoxantrone in all three cell lines. The effect was synergistic in ZL55 cells (p less than 0.01).
  • FTC decreased mitoxantrone efflux by 38% in ZL34 and ZL55 cells. In SDM103T2 cells the reduction was 27%, which was significant but smaller.
  • Silencing ABCG2 in ZL34 cells decreased mitoxantrone efflux by 48%.
  • In ZL34 and ZL55 cells, adding FTC increased the cytotoxicity of mitoxantrone (1 ng/ml) by 15 to 20%.
  • NVP-BEZ235 decreased mitoxantrone efflux by 15 to 26% in the three cell lines.
  • NVP-BEZ235 significantly decreased ABCG2 at the cell surface in SDM103T2 and ZL55 cells. In ZL34 cells no statistically significant change was observed. Total ABCG2 levels were not affected.
  • Combining NVP-BEZ235 with pemetrexed significantly increased the effect of pemetrexed. This result was reported in a supplementary figure.
• The authors' conclusion: The authors concluded that the PI3K pathway plays an important role in regulating the side population phenotype in mesothelioma cells, and that inhibiting it may contribute to more efficient cancer treatment.
• Limitations the authors state:
  • In ZL34 cells, NVP-BEZ235 and FTC both increased mitoxantrone cytotoxicity, yet no significant change in surface ABCG2 was seen. The authors offered two possible explanations: surface ABCG2 may be too low to detect differences, or NVP-BEZ235 may inhibit the transporter directly.
  • The authors stated that further studies are needed to settle whether NVP-BEZ235 directly inhibits ABCG2.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy.

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