Investigation of potent anticarcinogenic activity of 1, 3-diarylpyrazole acrylamide derivatives in vitro

Our plain-English summary of Investigation of potent anticarcinogenic activity of 1, 3-diarylpyrazole acrylamide derivatives in vitro, by A. Demiroglu-Zergeroglu, N. Ayvali, G. Turhal, et al (The Journal of Pharmacy and Pharmacology, 2018).

The study

• Authors: A. Demiroglu-Zergeroglu, N. Ayvali, G. Turhal, H. Ceylan, S. Nacak Baytas
• Journal: The Journal of Pharmacy and Pharmacology
• Published: 2018;70(12):1619-1629
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Pyrazole derivatives are pharmacologically powerful agents pointing at new horizons in the development of anticancer therapies. In this study, anticarcinogenic potential of a series of pyrazole-acrylamide derivatives has been investigated in mesothelial, malignant mesothelioma and lung cancer cell lines.

Methods: The effect of compounds on the viability of cells and the distribution of cell cycle were examined through MTS assay and PI staining, respectively. Apoptosis was evaluated via caspase-3 enzymatic assay and AO/EB staining. Proteins involved in proliferation, survival and apoptosis were analysed by immunoblotting.

Key Findings: Twelve compounds of 21 (4a-4v) reduced the viability of cells but, only the subset of five (4f, 4i, 4j, 4k and 4v) induced the caspase-3 activity. Among five, only one compound (4k) significantly suppressed phosphorylation and expression of ERK1/2 and AKT proteins in 24 h. Exposing cancer cells to successive concentrations of 4k gave rise to dose- and time-dependent G2/M phase arrest and apoptosis.

Conclusions: 4k has revealed its potent antiproliferative activity by decreasing viability and inhibiting proliferation and survival signals of cancer cells. Moreover, 4k has exposed cytostatic and apoptotic effect especially, on cancer cells. Therefore, it may be necessary to examine the biological actions of 4k in vivo as well.

© 2018 Royal Pharmaceutical Society.

In plain English

This laboratory study used cultured cells, not people or animals, and did not test asbestos. The authors screened 21 previously made compounds (pyrazole-acrylamide derivatives 4a to 4v) on non-cancerous mesothelial cells (MeT-5A) and malignant mesothelioma cells (SPC212). They later also tested compound 4k on non-small-cell lung cancer cells (A549). At 50 micromolar for 24 hours, several compounds reduced mesothelioma cell viability. The results named nine as more toxic to these cells than the same dose of the chemotherapy drug cisplatin. Five compounds (4f, 4i, 4j, 4k and 4v) switched on caspase-3, an enzyme involved in programmed cell death. Of those five, only 4k significantly reduced the activation and amount of ERK1/2 and AKT, growth and survival signalling proteins, in the mesothelioma cells. In both cancer cell lines, 4k halted cell division at the G2/M stage and triggered cell death. The non-cancerous mesothelial cells were less sensitive to it below 20 micromolar. The authors concluded that 4k is a novel anticancer drug candidate needing further study in living organisms. The article gives different counts of active compounds in different places.

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 cell lines; no human or animal participants
• Who was studied: Three cell lines: MeT-5A mesothelial cells and A549 non-small-cell lung carcinoma cells (both from ATCC), and SPC212 malignant mesothelioma cells (from the University of Fribourg, Switzerland)
• Exposure: 21 1,3-diarylpyrazole acrylamide derivatives (4a to 4v), whose synthesis had been reported previously. They were screened on SPC212 and MeT-5a cells at 50 micromolar for 24 hours and compared with cisplatin at 50 micromolar. Compound 4k was then tested at a range of concentrations (5, 10, 20 and 25 micromolar) for 12 and 24 hours, including on A549 cells. Asbestos was not tested; it is mentioned only in the introduction, describing another study.
• Main results:
  • Six compounds (4i, 4k, 4l, 4m, 4t and 4v) reduced the viability of MeT-5a mesothelial cells in 24 hours. All of these except 4t also reduced the viability of SPC212 mesothelioma cells, as did 4b, 4e, 4f, 4g, 4h, 4j, 4n, 4s and 4u.
  • In SPC212 mesothelioma cells, 4b, 4e, 4f, 4i, 4j, 4k, 4m, 4n and 4v were reported as more cytotoxic than the same concentration of cisplatin in 24 hours. The figure legend and discussion list eight of these, omitting 4b.
  • Of nine compounds tested, five (4f, 4i, 4j, 4k and 4v) induced caspase-3 enzyme activity in SPC212 cells in 24 hours.
  • Among these five, only 4k significantly (P < 0.01) reduced phosphorylation and expression of ERK1/2 and AKT proteins in SPC212 cells. Concentrations of 4k greater than 10 micromolar significantly inhibited these proteins in SPC212 and A549 cells in 24 hours.
  • At 10 and 25 micromolar, 4k caused G2/M phase arrest (a halt in cell division) in SPC212 and A549 cells. SPC212 cells were more susceptible than A549 cells.
  • With AO/EB staining, 4k induced apoptosis at concentrations greater than 5 micromolar in SPC212 cells and greater than 10 micromolar in A549 cells.
  • In non-cancerous MeT-5a cells, 4k-induced cell death occurred at concentrations above 20 micromolar. PARP cleavage was seen at 5, 10 and 20 micromolar in SPC212, A549 and MeT-5a cells respectively.
• The authors' conclusion: The authors concluded that 4k showed cytostatic and apoptotic activity in tumour cells, and that the lower susceptibility of non-tumour cells may imply selectivity of 4k for tumour cells. They called 4k a novel anticancer drug candidate requiring further in vivo research.
• Limitations the authors state:
  • The authors state that key downstream molecules, such as transcription factors in these pathways, still need to be analysed.
  • The authors note that suppressing ERK1/2 activity might induce resistance of cancer cells to anti-cancer drugs.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Lung Cancer, Apoptosis.

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