An inhibitor of topoisomerase II
Etoposide (VP-16) is the first agent recognized as a topoisomerase II inhibitor of anticancer drug with IC50 of 59.2 μM.
The activity of the topoisomerase II enzyme on re-ligation of DNA strands is interrupted by etoposide. A ternary complex with DNA is formed by etoposide, and causes DNA strands to break [1]. The enzyme was more important in cancer cell than healthy cells, because cancer cells divided more rapidly. So etoposide induced apoptosis of the cancer cells [2]. Etoposide exhibited cytotoxic activity against HepG2 and MOLT-3 cancer cells with IC50 of 30.16 μM and 0.051μM [3]. The IC50 values of etoposide against the tumor cell lines of BGC-823, HeLa, and A549 were 43.74 ± 5.13, 209.90 ± 13.42, and 139.54 ± 7.05 μM, respectively [4].
依托泊甙（VP-16）是第一种被认识为拓扑异构酶 II 抑制剂的抗癌药物，其 IC50 值为 59.2 μM。
依托泊甙中断了拓扑异构酶 II 酶在 DNA 重新连接时的活性。依托泊甙形成与 DNA 的三元复合物，并导致 DNA 断裂 [1]。该酶在癌细胞中比健康细胞更重要，因为癌细胞的分裂更为迅速。因此，依托泊甙引发了癌细胞的凋亡 [2]。依托泊甙对 HepG2 和 MOLT-3 癌细胞表现出细胞毒性，其 IC50 分别为 30.16 μM 和 0.051 μM [3]。依托泊甙对 BGC-823、HeLa 和 A549 肿瘤细胞系的 IC50 值分别为 43.74±5.13、209.90±13.42 和 139.54±7.05 μM [4]。
参考文献:
[1]. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010 May 28;17(5):421-33.
[2]. Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA. Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon. 2004 Sep 15;44(4):441-59.
[3]. Pingaew R, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. Design, synthesis and molecular docking studies of novel N-benzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-based triazoles with potential anticancer activity. Eur J Med Chem. 2014 May 6;81C:192-203.
[4]. Xiao L, Zhao W, Li HM, Wan DJ, Li DS, Chen T, Tang YJ. Design and synthesis of the novel DNA topoisomerase II inhibitors: Esterification and amination substituted 4'-demethylepipodophyllotoxin derivates exhibiting anti-tumor activity by activating ATM/ATR signaling pathways. Eur J Med Chem. 2014 Jun 10;80:267-77.
| Kinase experiment [1]: | |
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Topoisomerase II activity assay |
Nuclear extracts are prepared, and nuclei are isolated. The activity of topoisomerase II is calculated from the percentage of decatenation obtained. Tritiated kinoplast DNA (KDNA 0.22 μg) is used as a substrate. Etoposide and topoisomerase II are incubated for 30 min at 37℃ and are stopped with 1% sodium dodecyl sulfate (SDS) and proteinase K (100 μg/mL). The percentages of decatenation and inhibition of topoisomerase II by Etoposide are obtained. |
| Cell experiment [2]: | |
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Cell lines |
BGC-823, HeLa and A549 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
0.5, 1, 10, 20, 50, 100, 200 and 500 μM; 2 d |
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Applications |
The IC50 values of Etoposide against the tumor cell lines of BGC-823, HeLa and A549 were 43.74 ± 5.13 μM, 209.90 ± 13.42 μM and 139.54 ± 7.05 μM, respectively. |
| Animal experiment [3]: | |
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Animal models |
Murine angiosarcoma xenografts ISOS-1 |
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Dosage form |
2.5, 5, 10 mg/kg; i.p.; every day for 5 days |
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Applications |
The dose of 10 mg/kg Etoposide (i.p.) inhibited murine angiosarcoma cell ISOS-1 tumors. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Beauchesne P, Bertrand S, N'guyen MJ, Christianson T, Dore JF, Mornex F, Bonner JA. Etoposide sensitivity of radioresistant human glioma cell lines. Cancer Chemother Pharmacol. 1998;41(2):93-7. [2]. Xiao L, Zhao W, Li HM, Wan DJ, Li DS, Chen T, Tang YJ. Design and synthesis of the novel DNA topoisomerase II inhibitors: Esterification and amination substituted 4'-demethylepipodophyllotoxin derivates exhibiting anti-tumor activity by activating ATM/ATR signaling pathways. Eur J Med Chem. 2014 Jun 10;80:267-77. [3]. Ma G1, Masuzawa M, Hamada Y, Haraguchi F, Tamauchi H, Sakurai Y, Fujimura T, Katsuoka K. Treatment of murine angiosarcoma with etoposide, TNP-470 and prednisolone. J Dermatol Sci. 2000 Nov;24(2):126-33. |
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