Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway.
Artesunate (ART), a remarkable antimalarial agent, also inhibited the growth of human colorectal carcinoma. As determined by MTT assay, flow cytometry analysis on apoptosis and indirect immunofluorescence analysis on the proliferation-associated marker Ki67, ART suppressed the proliferation and promoted the apoptosis of colorectal cancer cells in a dose-dependent manner. Furthermore, immunofluorescence analysis on beta-catenin and RT-PCR analysis on Wnt/beta-catenin target genes demonstrated ART translocated beta-catenin from nucleus to adherent junctions of membrane and reduced transcription mediated by beta-catenin. These results suggested the anticancer activity of ART correlated with the inhibition of hyperactive Wnt/beta-catenin signaling pathway. In vivo, ART significantly slowed the growth of colorectal tumor xenografts. Bioluminescent imaging also revealed that ART decreased the physiological activity of tumor xenografts and delayed spontaneous liver metastasis. These antitumor effects were related to the membranous translocation of beta-catenin and the inhibition of the unrestricted activation of Wnt/beta-catenin pathway, which was confirmed by the immunohistochemical staining of tumor tissues. These results and the known low toxicity are clues that ART might be a promising candidate drug for the treatment of colorectal carcinoma.
Li
Lin-Na
LN
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China.
Zhang
Hua-Dong
HD
Yuan
Shou-Jun
SJ
Tian
Zeng-Yue
ZY
Wang
Lin
L
Sun
Zhi-Xian
ZX
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D037621:Artemisinins; D012717:Sesquiterpenes; D051153:Wnt Proteins; D051176:beta Catenin; D000077332:Artesunate