FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology

Our plain-English summary of FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology, by J.M. Chan, Y.C. Chang, H.C. Chan, et al (Molecular Medicine, 2024).

The study

• Authors: J.M. Chan, Y.C. Chang, H.C. Chan, H.C. Chan, W.C. Chang, L.F. Wang, T.H. Tsai, Y.J. Chen, W.C. Huang
• Journal: Molecular Medicine
• Published: 2024;30(1):73
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

© 2024. The Author(s).

In plain English

This was a laboratory study. It did not study patients or asbestos exposure. The authors, working in Taiwan, tested FK228 (romidepsin), a histone deacetylase inhibitor, against human malignant pleural mesothelioma. They used two cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid), and two patient-derived tumor grafts (one sarcomatoid, one epithelioid) implanted in immune-deficient mice. CRL-5946 cells had a 2-fold higher level of vimentin, a marker of mesenchymal change, and the non-epithelioid graft a 4-fold higher level. Cisplatin, a standard drug, significantly slowed epithelioid graft growth (p less than 0.05) but only showed a trend in non-epithelioid grafts. FK228 reduced cell survival and colony formation in both cell lines. It significantly reduced average tumor size in mice carrying either graft (7 epithelioid, 5 non-epithelioid). It stalled cells in the division cycle and caused cell death. A caspase blocker partly reversed that cell death in CRL-5946 cells only. FK228 lowered VEGF and PDGF-AA release from CRL-5946 cells. The authors concluded that FK228 shows therapeutic potential for both subtypes.

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 using human mesothelioma cell lines and patient-derived tumor xenografts implanted in mice (animal experiment)
• Who was studied: Two human malignant pleural mesothelioma cell lines: NCI-H28 (CRL-5820, epithelioid) and NCI-H2452 (CRL-5946, non-epithelioid). Two patient-derived xenograft models, #Meso-17 (sarcomatoid) and #Meso-24 (epithelioid), supplied from Toronto General Hospital, Canada, and implanted in 6-week-old male NOD/SCID mice.
• Exposure: No asbestos exposure was studied. The exposures were drugs. In cells: FK228 at 0.1 to 10 nM and cisplatin 2 µg/mL. In mice: cisplatin 3 mg/kg or FK228 2 mg/kg by intraperitoneal injection on Days 0, 7, 14 and 21, compared with saline.
• Main results:
  • Vimentin expression was 2-fold higher in non-epithelioid CRL-5946 cells than in epithelioid CRL-5820 cells.
  • Vimentin expression was 4-fold higher in the non-epithelioid xenograft than in the epithelioid xenograft.
  • In mice, cisplatin significantly inhibited growth of the epithelioid xenograft (p less than 0.05) and showed only a trend toward reducing non-epithelioid tumor burden. In colony tests, non-epithelioid CRL-5946 cells were described as more refractory to cisplatin.
  • Short-term FK228 exposure significantly reduced viability of both CRL-5820 and CRL-5946 cells.
  • FK228 given for 28 days significantly reduced average tumor size in mice with epithelioid xenografts (n = 7) and with non-epithelioid xenografts (n = 5).
  • FK228 caused G2/M phase cell cycle arrest in both cell lines. The arrest was more prominent in CRL-5946 cells.
  • The caspase inhibitor z-VAD partially reversed FK228-induced cell death in CRL-5946 cells but not in CRL-5820 cells. The authors read this as caspase-dependent cell death in CRL-5946.
  • In CRL-5946 cells, FK228 decreased release of VEGF and PDGF-AA and increased ICAM1/CD54, LCN2, MIF, DPP4/CD26 and CCL20.
  • In CRL-5820 cells, FK228 significantly increased IGFBP-3, DPP-4/CD26 and CCL20.
• The authors' conclusion: The authors concluded that FK228 shows therapeutic potential in malignant pleural mesothelioma by killing tumor cells and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes, and that further investigation is needed before clinical use.
• Limitations the authors state:
  • The authors noted a paradoxical result: FK228 increased secretion of DPP4/CD26, LCN-2 and CCL20, markers that are associated with cancer development.
  • The authors stated that the mechanisms behind FK228's changes to the tumor microenvironment still need further research.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Epithelioid, Non-epithelioid, Histology, Prognosis, Biphasic Mesothelioma, Sarcomatoid, Cisplatin.

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