In vitro evaluation of Neosetophomone B inducing apoptosis in cutaneous T cell lymphoma by targeting the FOXM1 signaling pathway

• Published in: Journal of dermatological science Vol. 112; no. 2; pp. 83 - 91
• Main Authors: Kuttikrishnan, Shilpa, Masoodi, Tariq, Ahmad, Fareed, Sher, Gulab, Prabhu, Kirti S, Mateo, Jericha M, Buddenkotte, Joerg, El-Elimat, Tamam, Oberlies, Nicholas H, Pearce, Cedric J, Bhat, Ajaz A, Alali, Feras Q, Steinhoff, Martin, Uddin, Shahab
• Format: Journal Article
• Language: English
• Published: Netherlands 01.11.2023
• Subjects: Apoptosis; Aurora Kinase A - metabolism; Aurora Kinase A - therapeutic use; Cell Line, Tumor; Forkhead Box Protein M1 - drug effects; Forkhead Box Protein M1 - metabolism; Humans; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - pathology; Signal Transduction - drug effects; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Terpenes - pharmacology; Terpenes - therapeutic use
• ISSN: 0923-1811; 1873-569X
• DOI: 10.1016/j.jdermsci.2023.10.001

Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.