Camptothecin is a specific DNA topoisomerase I (Top1) inhibitor with an IC50 value of 679 nM[1]. Camptothecin is a plant alkaloid that induces DNA breaks and protein-DNA crosslinks[2]. Camptothecin has potent antitumor activity against colorectal, breast, lung and ovarian cancers[3].
In vitro, treatment of breast cancer-derived cells with high TOP1 enzyme activity (luminal subtype MCF7 and HER2 subtype HCC1419) with camptothecin (0.1-5µM) for 72h significantly inhibited cell viability with IC50 values of 0.089μM and 0.067μM, respectively[4]. Treatment of HeLa and HEK293 cells with camptothecin (0.5µM) for 8-24h significantly reduced the accumulation of hypoxia-inducible factor-1α (HIF-1α) but did not affect HIF-1β levels[5].
In vivo, oral treatment of obese mice with camptothecin (1 mg/kg) for 30 days induced the expression and secretion of growth differentiation factor 15 (GDF15) in the liver of mice, thereby reducing food intake, normalizing body weight and reversing metabolic dysfunction[6]. Camptothecin (2 mg/kg) treated mice with melanoma cell metastasis and significantly reduced the number of lung metastases[7].
References:
[1]Luzzio M J, Besterman J M, Emerson D L, et al. Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I[J]. Journal of medicinal chemistry, 1995, 38(3): 395-401.
[2]Stingele J, Jentsch S. DNA–protein crosslink repair[J]. Nature reviews Molecular cell biology, 2015, 16(8): 455-460.
[3]Huang Q, Wang L, Lu W. Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents[J]. European journal of medicinal chemistry, 2013, 63: 746-757.
[4]Tesauro C, Simonsen A K, Andersen M B, et al. Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study[J]. BMC cancer, 2019, 19: 1-15.
[5]Bertozzi D, Marinello J, Manzo S G, et al. The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells[J]. Molecular cancer therapeutics, 2014, 13(1): 239-248.
[6]Lu J F, Zhu M Q, Xie B C, et al. Camptothecin effectively treats obesity in mice through GDF15 induction[J]. PLoS Biology, 2022, 20(2): e3001517.
[7]Schön M, Wienrich B G, Kneitz S, et al. KINK-1, a novel small-molecule inhibitor of IKKβ, and the susceptibility of melanoma cells to antitumoral treatment[J]. Journal of the National Cancer Institute, 2008, 100(12): 862-875.
Camptothecin是一种特异性DNA拓扑异构酶I（Top1）抑制剂，IC50值为679 nM[1]。Camptothecin是一种植物生物碱，诱导DNA断裂和蛋白质-DNA交联[2]。Camptothecin对结直肠癌、乳腺癌、肺癌和卵巢癌具有强大的抗肿瘤活性[3]。
在体外，Camptothecin（0.1-5µM）处理高TOP1酶活性的乳腺癌衍生细胞（管腔亚型MCF7和HER2亚型HCC1419）72h，显著抑制了细胞活力，IC50值分别为0.089μM和0.067μM[4]。Camptothecin（0.5µM）处理HeLa和HEK293细胞8-24h，显著减少了缺氧诱导因子-1α（HIF-1α）蓄积，但不影响HIF-1β水平[5]。
在体内，Camptothecin（1mg/kg）通过口服治疗肥胖小鼠30天，诱导小鼠肝脏表达和分泌生长分化因子15（GDF15），从而减少食物摄入量，使体重正常化并逆转了代谢功能障碍[6]。Camptothecin（2mg/kg）治疗黑色素瘤细胞转移的小鼠，显著减少了肺部转移灶数量[7]。