title: Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum component 2-methoxycinnamaldehyde.
abstract: Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine for various applications. We evaluated the anticancer effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the bark of the plant, and its underlying molecular biomarkers associated with carcinogenesis in human hepatocellular carcinoma SK-Hep-1 cell line. The results show that 2-MCA suppressed proliferation and induced apoptosis as indicated by mitochondrial membrane potential loss, activation of caspase-3 and caspase-9, increase in the DNA content in sub-G1, and morphological characteristics of apoptosis, including blebbing of plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and long comet tail. In addition, 2-MCA also induced lysosomal vacuolation with increased volume of acidic compartments, suppressions of nuclear transcription factors NF-κB, cyclooxygenase-2, prostaglandin E2 (PGE2), and both topoisomerase I and II activities in a dose-dependent manner. Further study reveals the growth-inhibitory effect of 2-MCA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of 2-MCA against SK-Hep-1 cells is accompanied by downregulations of NF-κB-binding activity, inflammatory responses involving cyclooxygenase-2 and PGE2, and proliferative control involving apoptosis, both topoisomerase I and II activities, together with an upregulation of lysosomal vacuolation and volume of acidic compartments. Similar effects (including all of the above-mentioned effects) were found in other tested cell lines, including human hepatocellular carcinoma Hep 3B, lung adenocarcinoma A549, squamous cell carcinoma NCI-H520, colorectal adenocarcinoma COLO 205, and T-lymphoblastic MOLT-3 (results not shown). Our data suggest that 2-MCA could be a potential agent for anticancer therapy.
authors.affiliation: Department of Gastroenterology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, Republic of China.
authors.forename: Daw-Shyong
authors.initials: DS
authors.lastname: Perng
authors.affiliation: Sierra College, Rocklin, CA, USA.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Faculty of Medicine, Medical University of Lublin, Lublin, Poland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cherng
authors.affiliation: Department of Internal Medicine, Antai Tian-Sheng Memorial Hospital, Pingtung, Taiwan, Republic of China.
authors.forename: Jeng-Shing
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Family Medicine, Saint Mary's Hospital Luodong, Yilan, Taiwan, Republic of China.
authors.forename: Kuo-Shen
authors.initials: KS
authors.lastname: Chou
authors.affiliation: Department of Pathology, Lotung Poh-Ai Hospital, Yilan, Taiwan, Republic of China.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Shih
authors.affiliation: Department of Internal Medicine, Saint Mary's Hospital Luodong, Yilan, Taiwan, Republic of China.
authors.forename: Jaw-Ming
authors.initials: JM
authors.lastname: Cherng
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002935:Cinnamomum zeylanicum / Q000737:chemistry*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C017910:2-methoxycinnamaldehyde; D000171:Acrolein; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: 2-methoxycinnamaldehyde; SK-Hep-1 cells; anticancer; topoisomerase I; topoisomerase II