Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

Our plain-English summary of Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma, by I.C. Salaroglio, I. Campia, J. Kopecka, et al (Oncotarget, 2015).

The study

• Authors: I.C. Salaroglio, I. Campia, J. Kopecka, E. Gazzano, S. Orecchia, D. Ghigo, C. Riganti
• Journal: Oncotarget
• Published: 2015;6(2):1128-42
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.

In plain English

This was a laboratory study of cells. It was not a study of patients' treatment. The authors compared tumor cells from ten people with human malignant mesothelioma, held at a tissue bank in Alessandria, Italy, with non-cancerous mesothelial cells from three patients with pleural fluid due to heart failure. The patients' asbestos exposure was recorded as professional for four, environmental for one, unlikely for one and not determined for four. The study did not test asbestos itself. All ten tumor samples needed significantly higher concentrations of seven chemotherapy drugs to cut cell survival by half than the non-cancerous cells did. Adding zoledronic acid at 1 μmol/L lowered the amounts of doxorubicin, vinblastine and etoposide needed, but not of cisplatin, gemcitabine or pemetrexed. The tumor cells made more kynurenine, an immune-suppressing substance. Compared with non-cancerous cells, they supported less immune T-cell growth and expanded regulatory T-cells. Zoledronic acid counteracted these effects. The authors concluded that zoledronic acid may be a promising added drug for future mesothelioma 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) study comparing primary human malignant mesothelioma cells with non-transformed mesothelial cells, with and without zoledronic acid
• Who was studied: Tumor cell samples from 10 human malignant mesothelioma patients (5 epithelioid, 2 biphasic, 3 sarcomatous; 1 SV40-positive), from the Biologic Bank of Malignant Mesothelioma, S.S. Antonio e Biagio Hospital, Alessandria, Italy. Comparison cells were non-transformed mesothelial cells from 3 patients with transudative pleural fluid due to congestive heart failure and no history of malignant disease.
• Exposure: The cells were treated with 1 μmol/L zoledronic acid for 48 h, alone and combined with chemotherapy drugs (doxorubicin, vinblastine, etoposide, cisplatin, gemcitabine, pemetrexed, mitoxantrone). Patient asbestos exposure was only recorded in a table: professional (4), environmental (1), unlikely (1), not determined (4). No fiber types were named.
• Main results:
  • In all ten mesothelioma samples, the drug concentration needed to halve cell viability (IC50) and the resistance factor were significantly higher than in the non-cancerous mesothelial cells, for each drug tested. For example, the doxorubicin IC50 was 4.3 µmol/L in non-cancerous cells versus 22.88 to 59.38 µmol/L in the tumor samples (p less than 0.01).
  • In mesothelioma cells, zoledronic acid lowered the IC50 of drugs pumped out by P-glycoprotein (doxorubicin, vinblastine, etoposide).
  • Zoledronic acid did not change the IC50 of cisplatin, gemcitabine or pemetrexed in mesothelioma cells.
  • Zoledronic acid alone had a mean IC50 of 96.3 μmol/L (SD 8.7) in the mesothelioma samples, about 100 times the 1 μmol/L concentration used in the experiments.
  • Mesothelioma cells made more kynurenine and had higher IDO mRNA and protein than non-cancerous mesothelial cells; zoledronic acid reduced all of these.
  • Non-cancerous mesothelial cells stimulated T-lymphocyte proliferation more than mesothelioma cells did. Zoledronic acid-treated mesothelioma cells significantly increased T-cell proliferation.
  • Mesothelioma cells expanded the number of regulatory T-cells (Tregs), and zoledronic acid counteracted this.
  • In two mesothelioma samples, silencing STAT3 (but not STAT1) lowered IDO mRNA and activity.
  • No significant differences in the measured parameters were seen by tumor histotype.
• The authors' conclusion: The authors concluded that zoledronic acid is an effective chemo-immunosensitizing agent in mesothelioma cells and may represent a promising adjuvant drug for future treatment protocols.
• Limitations the authors state:
  • The authors noted that animal studies were still in progress to test whether kynurenine is actually responsible for the regulatory T-cell expansion and the immunosuppression in living organisms.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Hypoxia, Glycoprotein.

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• Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma — J.D. Veltman, M.E. Lambers, et al. (2010)
• Effect of IL-18 on expansion of gammadelta T cells stimulated by zoledronate and IL-2 — W. Li, S. Kubo, et al. (2010)
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