CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells

Our plain-English summary of CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells, by S. Jamal, V.T. Cheriyan, M. Muthu, et al (PloS One, 2014).

The study

• Authors: S. Jamal, V.T. Cheriyan, M. Muthu, S. Munie, E. Levi, A.E. Ashour, H.I. Pass, A. Wali, M. Singh, A.K. Rishi
• Journal: PloS One
• Published: 2014;9(3):e89146
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.

In plain English

This was a laboratory study of mesothelioma cells grown in dishes. No patients were treated, and asbestos exposure itself was not studied. The authors tested three experimental compounds called CARP-1 functional mimetics (CFM-1, CFM-4 and CFM-5) on human malignant pleural mesothelioma cell lines, mainly H2461 (epithelioid) and H2373 (sarcomatoid). They compared the compounds with the chemotherapy drug cisplatin. At the higher dose tested, after 24 hours, CFM-1 reduced growth of both cell lines by about 50%, and CFM-4 or CFM-5 caused about 90% loss of viability. Cisplatin caused a 10–20% loss at 24 hours and a 50% loss at 48 hours. Combining cisplatin with a CFM did not increase growth inhibition. The compounds increased signs of programmed cell death (apoptosis). At a lower dose, CFM-4 and CFM-5 reduced cell migration and colony growth, and CFM-4 significantly reduced the number of cells crossing a matrix-coated membrane. The authors concluded that these compounds have potential as a new class of anti-mesothelioma agents.

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) cell culture experiment; described by the authors as a proof-of-concept study
• Who was studied: Human malignant pleural mesothelioma cell lines (H2373, H2714, H2461), mainly H2461 (epithelioid) and H2373 (sarcomatoid), plus murine mesothelioma AB12 cells; no human or animal subjects
• Exposure: Treatment of cells with the experimental compounds CFM-1, CFM-4 and CFM-5, compared with cisplatin (and adriamycin in some tests), and with cisplatin combined with CFMs; asbestos exposure was not studied
• Main results:
  • In both cell lines, CFM-1 at the higher dose for 24 h caused approximately 50% growth inhibition. CFM-4 or CFM-5 caused about 90% loss of viability. Cisplatin caused 10–20% loss at 24 h and 50% loss at 48 h.
  • Combining cisplatin with any of the CFMs did not produce greater growth inhibition in the mesothelioma cells.
  • CFM-4 increased levels of cleaved (activated) caspase-3, a marker of apoptosis, in the mesothelioma cells.
  • CFM-4 activated JNK1/2 in the mesothelioma cells; cisplatin, CFM-1 and CFM-5 did not.
  • In H2373 cells, CFM-4 or CFM-5 reduced the number and size of colonies in soft agar compared with untreated controls.
  • In H2373 cells, CFM-4 or CFM-5 reduced the activities of MMP-1, -8 and -9.
  • CFM-4 significantly reduced the number of mesothelioma cells that crossed matrigel-coated membranes in the invasion assay.
  • CFM-4 produced robust serine phosphorylation of podoplanin in the mesothelioma cells.
• The authors' conclusion: The authors concluded that CFMs activate multiple growth-inhibitory and apoptosis pathways in mesothelioma cells. They wrote that this underscores the compounds' potential as a new class of anti-mesothelioma agents.
• Limitations the authors state:
  • The authors stated that the extent to which raised DR4 and DR5 levels contributed to the effects of CFMs remained to be clarified.
  • The authors stated that it remained to be clarified whether CFM-4 damaged cellular DNA, and whether the pathways it activated drive cell death or act as defenses.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis, Podoplanin (D2-40), Prognosis, Metastasis.

Related studies

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• Podoplanin overexpression in human mesothelioma cell lines enhances the tumorigenic phenotype — E. Yamaki, T. Yajima, et al. (2013)
• Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis — A. Raza, B.A. Jacobson, et al. (2012)
• Podoplanin: An emerging cancer biomarker and therapeutic target — H. Krishnan, J. Rayes, et al. (2018)
• Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma — M. Moriya, T. Yamada, et al. (2014)
• Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model — S. Abe, M.K. Kaneko, et al. (2016)

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