Anticancer Effect of Howiinol A and its Mechanism of Action
Titel:
Anticancer Effect of Howiinol A and its Mechanism of Action
Auteur:
Xu, Cheng-Xiong He, Jian-Hua
Verschenen in:
Journal of Asian natural products research
Paginering:
Jaargang 2 (1999) nr. 1 pagina's 1-19
Jaar:
1999-10-01
Inhoud:
Howiinol A (GHM-10) is a kind of phenylethylene pyrone compounds isolated from Goniothalamus howii. By using the techniques of cell growth curve determination, MTT test, soft agar colony assay and experimental therapy of transplantable tumors in mice, it is found that GHM-10 exerts potent inhibitory effect on cancer cells but its influence on normal cells is relatively slight; the sensitivity of a drug-resistant cell line, KB/VCR 2000, to GHM-10 is similar to its parent cell line KB. Remarkable therapeutic effect can be seen in mice bearing H22 hepatoma and Lewis lung cancer and in mice with ascetic sarcoma 180 when GHM-10 is orally or intraperitoneally administered. The IC50s of L1210 cells treated with GHM-10 for 1 and 24 h are 6.85 and 3.32 μg·ml-1 respectively. The ratio of IC50 1 h and IC50 24 h is only 2.06, indicating that the action of GHM-10 is conformed to a cell cycle non-specific cytotoxic agent. By using trypan blue exclusive test and morphological examination, it is demonstrated that the main effect of GHM-10 is to inhibit the cell proliferation. Flow cytometery technique is used to analyze the cell cycle of L1210 cells. The results show that to some extent, GHM-10 blocks the cell cycle transition from G1 phase to S phase. By using [3H] labeled precursor incorporation technique, it is shown that GHM-10 significantly suppresses the biosynthesis of DNA, RNA and protein in L1210 cells, and the DNA synthesis is mostly affected. At 1 h after the cells were treated with GHM-10, these inhibitory effects have already been irreversible, suggesting that GHM-10 may cause structural damage on DNA molecules. However, GHM-10 is unable to intercalate into DNA molecules or to destroy its structure directly. By using single cell gel electrophoresis and alkaline elution technology, it is confirmed that GHM-10 causes DNA molecule damage and single strand breakage in L1210 cells. Further studies show that GHM-10 markedly inhibits DNA dehelix induced by DNA topoisomerase II both inside and outside the cells, indicating that GHM-10 is acting as an inhibitor of DNA topoisomerase II.
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