Correction published on 15 January 2021, see
Cancers 2021, 13(2), 303.
The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells
1
Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan
2
Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
3
Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan
4
Research Center of Chinese Herbal Medicine, China Medical University, Taichung 40402, Taiwan
5
Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung 40402, Taiwan
6
Department of Medical Research, Chi Mei Medical Center, Tainan 71004, Taiwan
7
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71004, Taiwan
8
School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
9
Department of Veterinary Medicine, National Chiayi University, Chiayi 60054, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(10), 2936; https://doi.org/10.3390/cancers12102936
Received: 7 September 2020
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Revised: 5 October 2020
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Accepted: 7 October 2020
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Published: 12 October 2020
Simple Summary
Melanoma is the most dangerous type of skin cancer that develops from the pigment-producing cells known as melanocytes. One of the primary causes of melanoma is ultraviolet light (UV) exposure in those with low levels of the skin pigment melanin. Flavokawain B (FKB) is a naturally occurring chalcone, which is known to possess anti-proliferative pharmacological activity on various cancer cells. However, the effect of FKB on the anti-melanoma pharmacological role has not been investigated. Therefore, in this study, we explored the anti-melanoma properties of FKB on human melanoma cells and the cell death mechanisms that were mediated through the induction of reactive oxygen species (ROS) were investigated via in vitro and in vivo approaches. Our study results support promising application prospects of FKB in the treatment of human melanoma cancer.
Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.
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Keywords:
flavokawain B; melanoma cells; apoptosis; autophagy; ROS
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MDPI and ACS Style
Hseu, Y.-C.; Chiang, Y.-C.; Vudhya Gowrisankar, Y.; Lin, K.-Y.; Huang, S.-T.; Shrestha, S.; Chang, G.-R.; Yang, H.-L. The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells. Cancers 2020, 12, 2936. https://doi.org/10.3390/cancers12102936
AMA Style
Hseu Y-C, Chiang Y-C, Vudhya Gowrisankar Y, Lin K-Y, Huang S-T, Shrestha S, Chang G-R, Yang H-L. The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells. Cancers. 2020; 12(10):2936. https://doi.org/10.3390/cancers12102936
Chicago/Turabian StyleHseu, You-Cheng, Yu-Chi Chiang, Yugandhar Vudhya Gowrisankar, Kai-Yuan Lin, Sheng-Teng Huang, Sirjana Shrestha, Geng-Ruei Chang, and Hsin-Ling Yang. 2020. "The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells" Cancers 12, no. 10: 2936. https://doi.org/10.3390/cancers12102936
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