EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells

Our plain-English summary of EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells, by H.I. Onen, A. Yilmaz, E. Alp, et al (Human & Experimental Toxicology, 2015).

The study

• Authors: H.I. Onen, A. Yilmaz, E. Alp, A. Celik, S.M. Demiroz, E. Konac, I.C. Kurul, E.S. Menevse
• Journal: Human & Experimental Toxicology
• Published: 2015;34(2):117-26
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The most widespread neoplasm of the pleura is malignant pleural mesothelioma (MPM) with low prevalence rate. The mechanistic target of rapamycin signaling pathway, inhibited by RAD001, was shown to be deregulated in MPM development and considered a novel target for the MPM therapy. The EF24, a curcumin analog, also affects several signaling pathways and kills cancer cells as a single agent or in combination with classical drugs. We aimed to evaluate possible effects of RAD001, EF24, cisplatin, and oxaliplatin treatments on both malignant pleural mesothelioma (MSTO-211H) and nonmalignant mesothelial (Met-5A) cell lines. The effects of the agents on MSTO-211H and Met-5A cells were evaluated in terms of cell viability, cytotoxicity, DNA synthesis rate, quantitation of apoptotic DNA fragmentation, and cleaved caspase 3 levels. Moreover, quantitative messenger RNA (mRNA) analysis of apoptotic (CASP9) and antiapoptotic (BCL2L1 and BCL2) genes were also performed. We found that both EF24 and RAD001 alone treatments decreased only MSTO-211H cell viability, but cisplatin and oxaliplatin affected both cell lines. Pretreatment with EF24 or RAD001 followed by cisplatin increased the effects of cisplatin alone application. EF24 and RAD001 pretreatment decreased DNA fragmentation rate when compared with cisplatin alone treatment in Met-5A cells. Sequential treatments resulted in a significant increase of CASP9 mRNA expression in MSTO-211H cells but not in Met-5A cells. Our preliminary results suggest that pretreatment with EF24 or RAD001 may reduce cytotoxic effect of cisplatin on nonmalignant mesothelial cells and increase cell death response of MPM cells. Further analyses using animal models are needed to confirm these findings in vivo.

© The Author(s) 2015.

In plain English

This was a laboratory study on human cells, not a study of people or of asbestos exposure. The authors tested EF24 (a curcumin-like compound) and RAD001 (everolimus), alone and as a 24-hour pretreatment before the chemotherapy drugs cisplatin or oxaliplatin. They used one malignant pleural mesothelioma cell line (MSTO-211H) and one nonmalignant mesothelial cell line (Met-5A). EF24 and RAD001 alone reduced the viability of the mesothelioma cells but not the nonmalignant cells. Cisplatin and oxaliplatin alone slightly reduced viability in both lines. Pretreatment followed by cisplatin reduced the growth of both lines more than single treatments did. In the viability test, neither drug made the cells more sensitive to oxaliplatin. However, in mesothelioma cells, EF24 before oxaliplatin raised the cell-death marker cleaved caspase 3 compared with oxaliplatin alone. In the nonmalignant cells, pretreatment lowered a marker of cell death (DNA fragmentation) compared with chemotherapy alone. In the mesothelioma cells, pretreatment raised the mRNA expression of the cell-death gene CASP9. For example, RAD001 before oxaliplatin raised it 4.7-fold compared with oxaliplatin alone. The authors called their results preliminary and said animal studies are needed.

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 two human cell lines, comparing drugs given alone and in sequence
• Who was studied: Two commercially purchased human cell lines: MSTO-211H (biphasic malignant pleural mesothelioma) and Met-5A (described elsewhere in the article as nonmalignant mesothelial cells). No human subjects.
• Exposure: Drug treatments, not asbestos. EF24 or RAD001 (everolimus) was given for 24 h, followed by cisplatin (CDDP) or oxaliplatin (1-OHP) for a further 24 h. Each drug was also tested alone. No asbestos fibers were studied.
• Main results:
  • EF24 alone inhibited growth of MSTO-211H mesothelioma cells only at concentrations above 2 (units as printed: mM). This decrease was not seen in Met-5A cells.
  • RAD001 alone decreased the viability of MSTO-211H cells.
  • Cisplatin alone and oxaliplatin alone each slightly reduced viability in both cell lines.
  • In the cell-viability test, EF24 or RAD001 pretreatment followed by cisplatin reduced growth of both cell lines more than single-agent treatment. In the same test, neither drug sensitized either cell line to oxaliplatin.
  • In MSTO-211H cells, EF24 followed by oxaliplatin raised cleaved (active) caspase 3 levels compared with oxaliplatin alone (p less than 0.05).
  • In the cytotoxicity (LDH) assay, RAD001 pretreatment lowered the cytotoxicity of cisplatin in Met-5A cells (p less than 0.05) but raised it in MSTO-211H cells.
  • In Met-5A cells, EF24 pretreatment reduced DNA fragmentation compared with cisplatin alone (p less than 0.05).
  • In Met-5A cells, RAD001 pretreatment reduced DNA fragmentation compared with cisplatin or oxaliplatin alone (p less than 0.05).
  • In MSTO-211H cells, EF24 pretreatment raised DNA synthesis compared with cisplatin alone.
  • In MSTO-211H cells, EF24 pretreatment raised CASP9 expression about twofold compared with cisplatin alone.
  • In MSTO-211H cells, RAD001 plus cisplatin raised CASP9 expression 2.22-fold compared with cisplatin alone (p less than 0.001).
  • In MSTO-211H cells, RAD001 followed by oxaliplatin raised CASP9 mRNA expression 4.7-fold compared with oxaliplatin alone (p less than 0.001).
• The authors' conclusion: The authors concluded that their preliminary results showed that EF24 or RAD001 pretreatment enhanced the effects of platinum-based drugs, reduced the cytotoxic effect of these drugs on nonmalignant mesothelial cells, and increased the cell death response of mesothelioma cells. They said animal studies are needed.
• Limitations the authors state:
  • Laboratory cell studies cannot reproduce conditions in the body and may not reflect the tumor environment, so animal studies are needed.
  • The reason for the apparent protective effect on nonmalignant cells is unknown and needs further study.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Pleura, Cisplatin, MeT-5A Cells, Mesothelial Cells.

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