@article{8965357eca6f4bd8a0bc284864e119c2,
title = "13-acetoxysarcocrassolide exhibits cytotoxic activity against oral cancer cells through the interruption of the keap1/Nrf2/p62/SQSTM1 pathway: The need to move beyond classical concepts",
abstract = "13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.",
keywords = "13-Acetoxysarcocrassolide, Apoptosis, Keap1/Nrf2/p62/SQSTM1, Oral cancer, Oxidative stress, Reactive oxygen species",
author = "Liu, {Yi Chang} and Peng, {Bo Rong} and Hsu, {Kai Cheng} and Mohamed El-Shazly and Shih, {Shou Ping} and Lin, {Tony Eight} and Kuo, {Fu Wen} and Chou, {Yi Cheng} and Lin, {Hung Yu} and Lu, {Mei Chin}",
note = "Funding Information: We are grateful to the Ministry of Science and Technology (MOST 107-2320-B-259-004-MY3 (Mei-Chin Lu)); Kaohsiung Medical University Hospital (KMUH-107-7M11 and KMUH-108-8M13 (Yi-Chang Liu)); Ministry of Health and Welfare (MOHW108-TDU-B-212-133006 (Yi-Chang Liu)); and E-Da Cancer Hospital {EDCHP 109006 (Hung-Yu Lin)} for financially supporting the work. Funding Information: Funding: We are grateful to the Ministry of Science and Technology (MOST 107-2320-B-259-004-MY3 (Mei-Chin Lu)); Kaohsiung Medical University Hospital (KMUH-107-7M11 and KMUH-108-8M13 (Yi-Chang Liu)); Ministry of Health and Welfare (MOHW108-TDU-B-212-133006 (Yi-Chang Liu)); and E-Da Cancer Hospital {EDCHP 109006 (Hung-Yu Lin)} for financially supporting the work. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = jul,
day = "23",
doi = "10.3390/MD18080382",
language = "English",
volume = "18",
journal = "Marine Drugs",
issn = "1660-3397",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "8",
}