期刊
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
卷 61, 期 51, 页码 12588-12597出版社
AMER CHEMICAL SOC
DOI: 10.1021/jf4034688
关键词
benzochalcone; tubulin; G2/M arrest; caspase; apoptosis
资金
- Korea Healthcare Technology R&D Project, the Ministry for Health and Welfare [A111778]
- National Research Foundation of Korea (NRF)
- Ministry of Science, ICT and Future Planning [NRF-2012R1A2A2A01]
- KU Research Professor Program of Konkuk University
- Korea Health Promotion Institute [A111778] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The natural chalcones and their derivatives exhibit many biological activities, such as anti-inflammatory and antitumoral. However, the precise Mechanisms of action of benzochalcone derivatives are currently unknown. Here, a set of benzochalcones was synthesized, and the molecular mechanisms underlying inhibition of tumor- growth were investigated. Colony-forming assays revealed that among tested compounds, 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) most effectively inhibited the clonogenicity of Capan-1 human pancreatic cancer cells. HymnPro inhibited cell proliferation in several human solid tumor cell lines and suppressed xenografted tumor growth in nude mice. Mechanistically, HymnPro induced cell cycle arrest at the G(2)/M phase, followed by an increase in apoptotic cell death. These events were associated with the inhibition of tubulin polymerization through binding of HymnPro to tubulin, leading to the formation of abnormal mono- or multipolar mitotic microtubule structures accompanied by spherical arrangement of multinucleated chromosomes. Furthermore, HymnPro activated caspase-2, caspase-9, caspase-3, and caspase-7 and increased the cleavage of poly(ADP-ribose) polymerase (PARP). HymnPro increased the phosphorylation of JNK1/2, Erk1/2, and p38 kinase. Pretreatment with SP600125, U0126, or SB600125 abrogated HymnPro-induced activation of caspases-3 and caspase-7 and the cleavage of PARP, suggesting that MAPK signalings are involved in HymnPro-induced apoptosis. It was concluded that a novel HymnPro compound exerts antitumor activity by disrupting microtubule assembly, which leads to mitotic arrest and sequential activation of the caspase pathway, resulting in apoptosis.
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