Niclosamide inhibits epithelial-mesenchymal transition with apoptosis induction in BRAF/ NRAS mutated metastatic melanoma cells.

Autor: Thatikonda S; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India; Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA., Pooladanda V; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA; Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA., Tokala R; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Nagula S; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Godugu C; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana 500037, India. Electronic address: chandra.niperhyd@gov.in.
Jazyk: angličtina
Zdroj: Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2023 Jun; Vol. 89, pp. 105579. Date of Electronic Publication: 2023 Mar 03.
DOI: 10.1016/j.tiv.2023.105579
Abstrakt: Malignant melanoma is considered a deadly aggressive form of skin cancer that frequently metastasizes to various distal organs, which harbors mutations of the BRAF or NRAS which occur in 30 to 50% of melanoma patients. The growth factors secreted by melanoma cells contribute to tumor angiogenesis with the acquisition of metastatic potential by epithelial-mesenchymal transition (EMT) and drive melanoma growth toward a more aggressive form. Niclosamide (NCL) is an FDA-approved anthelmintic drug and is reported to have strong anti-cancer properties against various solid and liquid tumors. Its role in BRAF or NRAS mutated cells is unknown. In this context, we uncovered the role of NCL in impeding malignant metastatic melanoma in vitro in SK-MEL-2 and SK-MEL-28 cell lines. We found that NCL induces significant ROS generation and apoptosis through a series of molecular mechanisms, such as depolarization of mitochondrial membrane potential, arresting the cell cycle at the sub G1 phase with a significant increase in the DNA cleavage via topoisomerase II in both cell lines. We also found that NCL potently inhibited metastasis, which was examined by scratch wound assay, Additionally, we found that NCL inhibits the most important markers involved in the EMT signaling cascade that are stimulated by TGF-β such as N-cadherin, Snail, Slug, Vimentin, α-SMA and p-Smad 2/3. This work provides useful insights into the mechanism of NCL in BRAF/NRAF mutant melanoma cells via inhibition of molecular signaling events involved in EMT signaling, and apoptosis induction.
Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest.
(Copyright © 2023. Published by Elsevier Ltd.)
Databáze: MEDLINE