Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G0/G1 cell cycle arrest and apoptosis
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AbstractLow selectivity is one of the major problems of currently used anticancer drugs, therefore, there is a high demand for novel, selective antitumor agents. In this study, the anticancer effects and mechanisms of guttiferone K (GUTK), a novel polyprenylated acylphloroglucinol derivative isolated from Garcinia cowa Roxb., were examined for its development as a novel drug targeting colon cancer. GUTK concentration- and time-dependently reduced the viability of human colon cancer HT-29 cells (IC50 value 5.39 +/- 0.22 mu M) without affecting the viability of normal human colon epithelial CCD 841 CoN cells and induced G0/G1 cell cycle arrest in HT-29 cells by down-regulating cyclins D1, D3 and cyclin-dependent kinases 4 and 6, while selectively restoring p21Waf1/Cip1 and p27Kip1 to levels comparable to those observed in normal colon cells, without affecting their levels in normal cells. GUTK (10.0 mu M) induced cleavage of PARP, caspases-3, -8 and -9 and chromatin condensation to stimulate caspase-3-mediated apoptosis. The addition of a JNK inhibitor, SP600125, partially reversed GUTK-induced caspase-3 activity, indicating the possible involvement of JNK in GUTK-induced apoptosis. Furthermore, GUTK (10 mg/kg, i.p.) significantly decreased the tumor volume in a syngeneic colon tumor model when used alone or in combination with 5-fluorouracil without toxicity to the mice. Immunohistochemical staining of the tumor sections revealed a mechanism involving an increase in cleaved caspase-3 and a decrease in cell proliferation marker Ki-67. Our results support GUTK as a promising novel, potent and selective antitumor drug candidate for colon cancer.
All Author(s) ListKan WLT, Yin C, Xu HX, Xu G, To KKW, Cho CH, Rudd JA, Lin G
Journal nameInternational Journal of Cancer
Detailed descriptionTo ORKTS: doi:10.1002/ijc.27694
Year2013
Month2
Day1
Volume Number132
Issue Number3
PublisherWILEY-BLACKWELL
Pages707 - 716
ISSN0020-7136
eISSN1097-0215
LanguagesEnglish-United Kingdom
Keywordsanti-tumor; apoptosis; cell cycle; colon cancer; guttiferone K
Web of Science Subject CategoriesOncology; ONCOLOGY

Last updated on 2020-27-05 at 03:51