Enhanced antitumor activity of xanthohumol, a diacylglycerol acyltransferase inhibitor, under hypoxia.
Cancer chemotherapy for hypoxic tumor cells is thought to be an important issue, since hypoxia is related to tumor growth, apoptosis, angiogenesis and metastasis. Here, the bioactivities of xanthohumol (XN), a diacylglycerol acyltransferase inhibitor, against hypoxic cells were investigated. At first, the inhibitory effects of XN on the formation of lipid droplets in the cytoplasm were evaluated in hypoxia. Hypoxia upregulated the synthesis of triglyceride and promoted the formation of lipid droplets in the cytoplasm, however, the treatment of XN downregulated the triglyceride synthesis and completely canceled the appearance of lipid droplets. Second, the effects of XN on the proliferation and the motility of HT-1080 human fibrosarcoma were investigated. The proliferation of HT-1080 was significantly suppressed in the presence of XN only in hypoxic condition but not in normoxic condition. XN also suppressed the motility of HT-1080 that was enhanced by hypoxia. Since, most cells in solid tumor were thought to be in hypoxic condition and acquired malignancy in response to hypoxia, these data suggest that XN may have potent and specific activities against cancerous cells. Furthermore, these data suggested that lipid metabolism may play an important role for hypoxic tumor cells and proposed a new therapeutic target for cancer chemotherapy.
Goto
Keiko
K
Department of Medical Biochemistry and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Asai
Tomohiro
T
Hara
Shuntaro
S
Namatame
Ichiji
I
Tomoda
Hiroshi
H
Ikemoto
Mamoru
M
Oku
Naoto
N
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D051048:Diacylglycerol O-Acyltransferase; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005354:Fibrosarcoma; D005419:Flavonoids; D006801:Humans; D050356:Lipid Metabolism; D019301:Oleic Acid / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology*; D014280:Triglycerides
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011427:Propiophenones; D014280:Triglycerides; D019301:Oleic Acid; D002784:Cholesterol; D000217:Acyltransferases; D051048:Diacylglycerol O-Acyltransferase; C104536:xanthohumol