WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells

• Published in: Cancer chemotherapy and pharmacology 2025-12, Vol.95 (1), p.22, Article 22
• Main Authors: Oliveira-Silva, João Marcos, Oliveira, Leilane Sales, Chiminazo, Carolina Berraut, Fonseca, Rafael, de Souza, Carlos Vinicius Expedito, Aissa, Alexandre Ferro, de Almeida Lima, Graziela Domingues, Ionta, Marisa, Castro-Gamero, Angel Mauricio
• Format: Article
• Language: English
• Subjects: Acetylation; Antineoplastic drugs; Apoptosis; Apoptosis - drug effects; Cadherins - metabolism; Cancer Research; Cell adhesion; Cell culture; Cell death; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemoresistance; Chemotherapy; Dacarbazine; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Synergism; E-cadherin; Flow cytometry; Histone deacetylase; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Motility; Oncology; Original Article; Pharmacology/Toxicology; Temozolomide; Temozolomide - pharmacology; Therapeutic targets; Tubulin; Tumorigenesis; β-Catenin
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-024-04731-y

Purpose Histone deacetylase 6 (HDAC6) plays a critical role in tumorigenesis and tumor progression, contributing to proliferation, chemoresistance, and cell motility by regulating microtubule architecture. Despite its upregulation in melanoma tissues and cell lines, the specific biological roles of HDAC6 in melanoma are not well understood. This study aims to explore the functional effects and underlying mechanisms of WT161, a selective HDAC6 inhibitor, in melanoma cell lines. Methods Cell proliferation was assessed using both 2D and 3D cell culture systems, including MTT assays, spheroid growth analyses, and colony formation assays. The interaction between WT161 and the chemotherapeutic agents temozolomide (TMZ) or dacarbazine (DTIC) was evaluated using the Chou-Talalay method. Apoptotic cell death was analyzed through flow cytometry, while migration, adhesion, and invasion assays were conducted to evaluate the motility capacities of melanoma cells. Western blot assays quantified α-tubulin acetylation (Lys40), PARP cleavage, and protein levels of β-catenin and E-cadherin. Results WT161 significantly reduced cell growth in both 2D and 3D cultures, decreased clonogenic capacity, and showed synergistic interactions with TMZ and DTIC. The inhibitor also induced apoptotic cell death and enhanced TMZ-induced apoptosis. Additionally, WT161 reduced cell migration and invasion while increasing cell adhesion. These effects were linked to changes in β-catenin and E-cadherin levels, depending on the specific cell type evaluated. Conclusion Our study underscores the pivotal role of HDAC6 in melanoma progression, establishing it as a promising therapeutic target. We provide the first comprehensive evidence of WT161’s anti-melanoma effects, setting the stage for further research into HDAC6 inhibitors as a potential strategy for melanoma treatment. Graphic abstract