Inhibitory Effect of Tumor Cell Proliferation and Induction of G₂/M Cell Cycle Arrest by Panaxytriol

Abstract

Panaxytriol, a polyacetylenic compound, isolated from red ginseng (Panax ginseng C.A. Meyer), was studied to determine its effects on the growth and cell cycle of tumor cell lines. The compound showed both significant cytotoxicity and inhibition of DNA syntheses in various tumor cells tested. For P388D1, a mouse lymphoma cell line, IC₅₀ values for cytotoxicity and inhibition of DNA synthesis were 3.1 and 0.7 μg/ml, respectively. The cytotoxic effect of panaxytriol was both time- and dose-dependent. It also induced the cell cycle arrest of P388D1 at the G₂/M phase, which was measured through flow cytometry. Particularly, the proportion of cells in the G₂/M phase of the cell cycle increased from 9 % to 26 and 48 %, respectively, after 24 and 36 h exposure to panaxytriol at 5 μg/ml. There were corresponding decreases in the proportion of cells at the G₀/G₁ phase. The S phase also decreased during the 36-h treatment.

Key words

Panaxytriol - cytotoxicity - inhibition of DNA synthesis - cell cycle - G₂/M phase - Panax ginseng C.A. Meyer - Araliaceae

References

• 1 Kim H, Lee Y H, Kim S I. A possible mechanism of polyacetylene:membrane cytotoxicity.  The Korean Journal of Toxicology. 1988;  4 95-105
• 2 Kim Y S, Jin S H, Kim S I, Hahn D R. Studies on the mechanism of cytotoxicities of polyacetylenes against L1210 cell.  Archives of Pharmacal Research. 1989;  12 207-13
• 3 Ota T, Maeda M, Odashima S, Ninomiya-Tsuji J, Tatsuka M. G₁ phase-specific suppression of the cdk2 activity by ginsenoside Rh₂ in cultured murine cells.  Pharmacology Letters. 1997;  60 39-44
• 4 Odashima S, Ohta T, Kohno H, Matsuda T, Kitagawa I, Abe H, Arichi S. Control of phenotypic expression of cultured B16 melanoma cells by plant glycosides.  Cancer Research. 1985;  45 2781-4
• 5 Park J A, Lee K Y, Oh Y J, Kim K W, Lee S K. Activation of caspase-2 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis.  Cancer Letters. 1997;  121 73-81
• 6 Matsunaga H, Katano M, Yamamoto H, Mori M, Takata K. Studies on the panaxytriol of Panax ginseng C. A. Meyer. Isolation, determination and antitumor activity.  Chemical & Pharmaceutical Bulletin. 1989;  37 1279-81
• 7 Lee S H, Hwang W I. Inhibitory effect of petroleum ether extract of Panax ginseng root against growth of human cancer cells.  The Korean Journal of Ginseng Science. 1986;  10 141-50
• 8 Sohn J, Lee C H, Chung D J, Park S H, Kim I, Hwang W I. Effect of petroleum ether extract of Panax ginseng roots on proliferation and cell cycle progression of human renal cell carcinoma cells.  Experimental and Molecular Medicine. 1998;  30 47-51
• 9 Katano M, Yamamoto H, Matsunaga H, Mori M, Takara K, Nakamura M. Cell growth inhibitory substance isolated from Panax ginseng root: panaxytriol.  Japanese Journal of Cancer and Chemotherapy. 1990;  17 1045-9
• 10 Matsunaga H, Saita T, Nagumo F, Mori M, Katano M. A possible mechanism for the cytotoxicity of a polyacetylenic alcohol, panaxytriol: inhibition of mitochondrial respiration.  Cancer Chemotherapy and Pharmacology. 1995;  35 291-6
• 11 Matsunaga H, Katano M, Saita T, Yamamoto H, Mori M. Potentiation of cytotoxicity of mitomycin C by a polyacetylenic alcohol, panaxytriol.  Cancer Chemotherapy and Pharmacology. 1994;  33 291-7
• 12 Katano M, Matsunaga H, Yamamoto H. A tumor inhibitory substance isolated from Panax ginseng.  Journal of Japanese Surgery Society. 1988;  89 971-7
• 13 Nakano Y, Matsunaga H, Saita T, Mori M, Katano M, Okabe H. Antiproliferative constituents in umbelliferae plants II. Screening for polyacetylenes in some Umbelliferae plants, and isolation of panaxytriol and falcarindiol from the root of Heracleum moellendorffii .  Biological & Pharmaceutical Bulletin. 1998;  21 257-61
• 14 Kim J S, Lim Y J, Im K S, Jung J H, Shim C J, Lee C O, Hong J, Lee H. Cytotoxic polyacetylenes from the marine sponge Petrosia sp.  Journal of Natural Products. 1999;  62 554-9
• 15 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.  Journal of Immunological Methods. 1983;  65 55-63
• 16 Marshall E S, Mattews J H, Shaw J H, Nixon J, Tumewu P, Finlay G J, Holdaway K M, Baguley B C. Radiosensitivity of new and established human melanoma cell lines: comparison of [³H] thymidine incorporation and soft agar clonogenic assays.  European Journal of Caner. 1994;  30A 1370-6
• 17 Nicoletti I, Migliorati G, Pagliacci M C, Grignari F, Riccardi A. A rapid simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.  Journal of Immunological Methods. 1991;  139 271-9
• 18 Purohit A, Hejaz H AM, Walden L, MacCarthy-Morrogh L, Packham G, Potter B VL, Reed M J. The effect of 2-methoxyoestrone-3-o-sulfamate on the growth of breast cancer cells and induced mammary tumors.  International Journal of Cancer. 2000;  85 584-9
• 19 Moon J, Yu S J, Kim H S, Sohn J. Induction of G₁ cell cycle arrest and p27^KPI1 increase by panaxydol isolated from Panax ginseng .  Biochemical Pharmacology. 2000;  59 1109-16
• 20 Maity A, McKenna W G, Muschel R J. Evidence for post-transcriptional regulation of cyclin B1 mRNA in the cell cycle and following irradiation in HeLa cells.  EMBO Journal. 1995;  14 603-9