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

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 30; no. 1; pp. 73 - 14
• Main Authors: Chan, James Mei-Lin, Chang, Yuan-Ching, Chan, Hua-Chen, Chan, Hsiu-Chuan, Chang, Wei-Chin, Wang, Liu-Fang, Tsai, Tung-Hu, Chen, Yu-Jen, Huang, Wen-Chien
• Format: Journal Article
• Language: English
• Published: England BioMed Central 31.05.2024; BMC
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Cancer; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-dependent kinases; Cytotoxicity; Depsipeptides - pharmacology; Depsipeptides - therapeutic use; Epigenetics; Epithelioid; Epithelioid Cells - pathology; Female; Human malignant pleural mesothelioma (hMPM); Humans; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - pathology; Mesothelioma, Malignant - drug therapy; Mesothelioma, Malignant - pathology; Mice; Non-epithelioid; Pleural Neoplasms - drug therapy; Pleural Neoplasms - pathology; Response rates; Romidepsin (FK228); Sarcomatoid; Xenograft Model Antitumor Assays; Sarcomatoid; Non-epithelioid; Human malignant pleural mesothelioma (hMPM); Romidepsin (FK228); Epithelioid
• DOI: 10.1186/s10020-024-00835-6
• ISSN: 1528-3658; 1076-1551

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.