Repurposing NFκB and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas

Luan César Silva; Gabriell Bonifácio Borgato; Vivian Petersen Wagner; Manoela Domingues Martins; Márcio Ajudarte Lopes; Alan Roger Santos-Silva; Gilberto De Castro; Luiz Paulo Kowalski; Cristiane Helena Squarize; Pablo Agustin Vargas; Rogerio Moraes Castilho

Repurposing NFκB and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas

Am J Cancer Res. 2023 Apr 15;13(4):1547-1559. eCollection 2023.

Affiliations

¹ Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas Piracicaba, São Paulo, Brazil.
² Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry Ann Arbor, Michigan, USA.
³ Academic Unit of Oral and Maxillofacial Medicine and Pathology, Department of Clinical Dentistry, University of Sheffield Sheffield, UK.
⁴ Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul Porto Alegre, Rio Grande do Sul, Brazil.
⁵ Serviço de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo São Paulo, SP, Brazil.
⁶ Department of Head and Neck Surgery, University of Sao Paulo Medical School and Head and Neck Surgery and Otorhinolaryngology Department, A C Camargo Cancer Center São Paulo, Brazil.

PMID: 37168350
PMCID: PMC10164805

Abstract

Drug resistance remains a major obstacle in the treatment of mucoepidermoid carcinomas (MEC) leading to tumor recurrence, disease progression, and metastasis. Emerging evidence suggests that drug resistance is mediated by the presence of a highly adaptative subpopulation of cancer cells known as cancer stem cells (CSC). We have previously reported that solid tumors use NFkB signaling as a chemotherapy-resistant mechanism. We have also shown that interfering with the epigenome of solid tumors is an effective strategy to control the population of CSC. Here, we sought to investigate the effects of the NFkB inhibitor emetine and the HDAC inhibitor SAHA on the biology of MEC CSC and assessed whether this combination therapy would favor the standard of care therapy comprised of the administration of Cisplatin (CDDP). Our findings suggested that the administration of low concentrations of emetine and SAHA is more effective in disrupting CSC in MEC, while the administration of emetine in combination with CDDP constitutes an effective therapy to target non-CSC MEC tumor cells.

Keywords: Head and neck tumors; NFκB; cancer stem cells; chemotherapy; epigenetic; salivary gland cancer; target therapy.