The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo

Our plain-English summary of The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo, by W. Blum, T. Henzi, L. Pecze, et al (Oncotarget, 2019).

The study

• Authors: W. Blum, T. Henzi, L. Pecze, K.L. Diep, C.G. Bochet, B. Schwaller
• Journal: Oncotarget
• Published: 2019;10(65):6944-6956
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is one of the most aggressive cancer types with a patient's life expectancy of typically less than one year upon diagnosis. The urgency of finding novel therapeutic approaches to treat mesothelioma is evident. Here we tested the effect of the plant-growth regulator forchlorfenuron (FCF), an inhibitor of septin function(s) in mammalian cells, on the viability and proliferation of MM cell lines, as well as other tumor cell lines derived from lung, prostate, colon, ovary, cervix and breast. Exposure to FCF strongly inhibited proliferation of human and mouse (most efficiently epithelioid) MM cells and all other tumor cells in a concentration-dependent manner and led to cell cycle arrest and cell death. The role of septin 7 (SEPT7), a presumably essential target of FCF in MM cells was confirmed by an shRNA strategy. FCF was robustly inhibiting tumor cell growth in vitro at low micromolar (IC50: ≈20-60µM) concentrations and more promisingly also in vivo. Initial experiments with FCF analogous revealed the importance of FCF's chloride group for efficient cell growth inhibition. FCF's rather low systemic toxicity might warrant for an extended search for other related and possibly more potent FCF analogues to target MM and putatively other septin-dependent tumors.

Copyright: © 2019 Blum et al.

In plain English

In this laboratory study, the authors tested whether forchlorfenuron (FCF), a plant-growth regulator used on fruit, affects malignant mesothelioma cells. Asbestos exposure itself was not studied. In culture, the concentration needed to halve growth ranged from 19 micromolar (ZL55) to 56 micromolar (JL-1) across the mesothelioma cell lines. In two non-cancerous mesothelial cell lines it was 76 and 62 micromolar. Reducing septin 7, the protein FCF is thought to act on, also stopped growth and killed cells, including non-cancerous mouse mesothelial cells. In a small mouse experiment, tumor signal rose 6.05-fold in control mice (n=4) and 3.13-fold in FCF-treated mice (n=3), with a reported p-value of 0.063. Treated mice showed partial hair loss and heavy constipation; a few became hypothermic and were euthanized. Related compounds without FCF's chloride group worked much less well. The authors noted that the tumors in their mouse model were in the abdomen, while most mesotheliomas occur in the pleural (chest) cavity. They concluded that further work on modified FCF might lead to compounds with stronger effects on mesothelioma cells and fewer side effects.

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 study: cell-culture experiments on mesothelioma and other cell lines, plus a small (pilot) experiment in mice
• Who was studied: Mostly human malignant mesothelioma cell lines (epithelioid, biphasic and sarcomatoid), two mouse mesothelioma cell lines (AB12; RN5, established in asbestos-exposed C57Bl/6J mice), immortalized non-tumorigenic human and mouse mesothelial cell lines, cell lines from other solid tumors, and BALB/c mice injected with AB12 cells; University of Fribourg, Switzerland
• Exposure: Forchlorfenuron (FCF), a septin inhibitor, at 6.25 to 200 micromolar in cell culture and by intraperitoneal injection in mice; also shRNA knockdown of septin 7 and synthesized FCF analogues. Asbestos exposure was not studied.
• Main results:
  • In MSTO-211H mesothelioma cells, the FCF concentration giving 50% growth inhibition (IC50) was about 22 micromolar
  • Across the mesothelial-origin cell lines, IC50 values ranged from 19 micromolar (ZL55) to 56 micromolar (JL-1)
  • The non-tumorigenic mesothelial lines Met-5A and LP9/TERT-1 had higher IC50 values (76 and 62 micromolar), meaning they were less sensitive than the mesothelioma lines
  • In the mouse mesothelioma lines AB12 and RN5, IC50 values were 47 and 43 micromolar
  • A confluent layer of immortalized mouse mesothelial iMeso-WT1 cells tolerated up to 100 micromolar FCF without evidence of cytotoxicity; 200 micromolar caused massive cell death
  • In cell lines from tumors of the lung, prostate, colon, ovary, cervix and breast, 100 micromolar FCF inhibited proliferation by more than 80% in all lines
  • Reducing septin 7 by shRNA stopped growth and killed cells in RN5 mesothelioma cells and in two immortalized mouse mesothelial lines; the effect was even more pronounced in the immortalized lines
  • In BALB/c mice injected with AB12 mesothelioma cells, the bioluminescence (tumor) signal increased 6.05-fold in control mice (n=4) and 3.13-fold in FCF-treated mice (n=3), p=0.063 (t-test)
  • Mice given FCF intraperitoneally showed partial alopecia and heavy constipation; a few became hypothermic and were euthanized
  • Among FCF-related compounds, only those containing the chloride group efficiently blocked mesothelioma cell proliferation
• The authors' conclusion: The authors concluded that more thorough investigation of FCF modifications might lead to new analogues with possibly stronger effects on mesothelioma cells and fewer side effects
• Limitations the authors state:
  • The mouse model used tumors in the peritoneal (abdominal) cavity, whereas most mesotheliomas are in the pleural cavity
  • Off-target effects of FCF, such as mitochondrial fragmentation at concentrations thought to target only septins, have been reported before
  • The apparent greater resistance of spindle-shaped cells may partly reflect epithelioid cells changing shape after treatment

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Life Expectancy, Epithelioid.

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