Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy

Our plain-English summary of Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy, by A. Szulkin, G. Nilsonne, F. Mundt, et al (PloS One, 2013).

The study

• Authors: A. Szulkin, G. Nilsonne, F. Mundt, A.M. Wasik, P. Souri, A. Hjerpe, K. Dobra
• Journal: PloS One
• Published: 2013;8(6):e65903
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit.

Materials And Methods: We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers.

Results: As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect.

Conclusions: The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

In plain English

This laboratory study, done at Karolinska Institutet in Stockholm, tested anti-cancer drugs on six malignant mesothelioma cell lines, not on patients. By cell shape, the authors classed one line as epithelioid, four as biphasic and one as sarcomatoid. They tested two experimental drugs, selenite and bortezomib, and four conventional drugs: carboplatin, pemetrexed, doxorubicin and gemcitabine. Each was given alone and in pairs. Viability was measured after 24 and 48 hours using the cells' metabolic activity. The authors also stained the cells for seven proteins proposed to predict drug response. Most cell lines resisted several drugs. Selenite alone affected four of the six lines. Selenite combined with bortezomib was the most cytotoxic combination. Pemetrexed was the least effective single drug on this metabolic test. Most proposed markers did not predict sensitivity. Unexpectedly, MRP-1 staining predicted carboplatin sensitivity, and xCT staining predicted pemetrexed's effect in a separate cell-cycle analysis. Asbestos exposure was not studied. The authors concluded that the variation between cell lines shows a need for more individualized treatment, and that selenite and bortezomib warrant clinical testing.

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 of drug effects on human mesothelioma cell lines, with cell-cycle analysis and immunocytochemistry for proposed predictive markers
• Who was studied: Six malignant mesothelioma cell lines: STAV-AB (epithelioid); M-14-K, STAV-FCS, ZL-34 and JL-1 (biphasic); DM-3 (sarcomatoid). Jurkat T-cell lymphoma cells were used as controls. The work was done at Karolinska Institutet, Stockholm, Sweden.
• Exposure: No asbestos exposure was studied. The cells were exposed to two experimental drugs (selenite, bortezomib) and four conventional drugs (carboplatin, pemetrexed, doxorubicin, gemcitabine), alone and in combinations, for 24 or 48 hours.
• Main results:
  • Viability was measured with the WST-1 assay, which reflects the metabolic activity of the cell population.
  • Most of the mesothelioma cell lines were resistant to several drugs. Only the STAV-AB and ZL-34 lines were affected by more than three drugs.
  • Selenite alone had strong to moderate effects on four of the six cell lines (M-14-K, ZL-34, STAV-FCS, STAV-AB). The two lines with the highest length/width ratios, JL-1 and DM-3, were not affected.
  • Selenite combined with bortezomib was the most cytotoxic combination tested. After 48 hours it affected all six cell lines in a strong to moderate fashion.
  • Pemetrexed was the least effective single drug on the WST-1 test. In cell-cycle analysis after 48 hours, the number of live cells fell significantly, by 12 to 36%, in STAV-AB, M-14-K and STAV-FCS cells and in the Jurkat control cells. JL-1 and DM-3 cells remained unaffected.
  • None of the hypothesized marker–drug correlations were observed. Unexpectedly, cytoplasmic MRP-1 staining predicted carboplatin sensitivity (p less than 0.001, R2 0.95). Membrane xCT staining predicted pemetrexed effect in the cell-cycle analysis (p = 0.04, R2 0.70).
  • Overall, the drug combinations showed no major synergistic or antagonistic patterns. Doxorubicin was the only drug giving statistically significant synergism.
• The authors' conclusion: The authors concluded that the variability between cell lines shows a need for more individualized treatment based on the sensitivity of individual tumors. They also concluded that selenite and bortezomib performed better than conventional drugs, which they said motivates clinical testing of these agents.
• Limitations the authors state:
  • Drug effects on cell lines may differ from effects on tumors in the body.
  • The authors suspected that pemetrexed increases metabolic activity, which may have concealed its effects on the WST-1 test. They said several methods are needed to study cell viability.

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, Epithelioid, Sarcomatoid, Prognosis, Carboplatin, Pemetrexed (Alimta), Doxorubicin, Gemcitabine.

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• Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma — D.A. Fennell, C. McDowell, et al. (2012)
• BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma — S. Busacca, A.D. Chacko, et al. (2013)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)
• Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions — A. Szulkin, R. Otvös, et al. (2014)

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