Inhibitory efficacy of bufadienolides on Na(+),K(+)-pump activity versus cell proliferation.
Inhibitory efficacy of bufadienolides on Na(+),K(+)-pump activity versus cell proliferation.
复制标题
蟾蜍二烯内酯对 Na , K 泵活性与细胞增殖的抑制作用
DOI：
10.1016/j.bbrep.2016.03.015
复制
发表时间：
2016-07
影响因子：
2.7
通讯作者：
Schwarz W
中科院分区：
文献类型：
--
作者：
Xu Y;Liu X;Schwarz S;Hu L;Guo D;Gu Q;Schwarz W
蟾蜍二烯内酯是一种细胞毒性药物，可作为抗癌药物的基础。由于结构和功能与强心苷相似，应用受到限制。因此，我们研究了它们的推定抗癌作用与抑制Na+，K+泵的相关性。对天然蟾蜍灵及其三种衍生物进行了检测。采用MTT法检测药物对大鼠肝癌细胞增殖的抑制作用。通过测量爪蟾卵母细胞表达的大鼠α1/β1和α2/β1 Na+，K+泵的泵介导电流来确定Na+，K+泵的抑制。蟾蜍二烯内酯类化合物均抑制细胞增殖和Na+、K+泵活性。活性系数A= 100 × IC 50 Na，K泵/IC 50增殖用于描述作为抗癌药物的药物有效性。天然蟾毒灵对细胞增殖的影响最小，对大鼠α1亚型的A值最低（0.08），α2亚型的A值最低（1.00）。BF 238衍生物获得的A值最高，α1和α2亚型的A值分别为0.88和2.64。因此，我们认为寻找具有高抗癌作用和低亲和力的蟾蜍灵衍生物的Na+，K+泵异构体可能是一个有前途的策略，为开发抗癌药物。蟾蜍二烯内酯对钠泵的作用与其细胞毒性无关。可能存在抗癌作用强、副作用小的蟾蜍二烯内酯。BF 238可能成为进一步研究和开发抗癌药物的基础。
Bufadienolides are cytotoxic drugs that may form the basis for anticancer agents. Due to structural and functional similarity to cardiotonic glycosides, application is restricted. We, therefore, investigated correlation of their putative anticancer effects with inhibition of Na+,K+pumps. The natural bufalin and three derivatives were tested. The anticancer effects of the drugs were checked by observing their inhibitory effects on proliferation of rat liver cancer cells using MTT assay. Inhibition of Na+,K+-pump was determined by measuring pump-mediated current of rat α1/β1 and α2/β1 Na+,K+pumps expressed in Xenopus oocytes. All tested bufadienolides inhibited cell proliferation and Na+,K+pump activity. An activity coefficient A=100xIC50Na,K pump/IC50proliferation was used to describe drug effectivity as anticancer drug. Natural bufalin exhibited lowest effectivity on cell proliferation, and also the A value for rat α1 isoform was the lowest (0.08), the α2 isoform was much less sensitive (A=1.00). The highest A values were obtained for the BF238 derivative with A=0.88 and 2.64 for the α1 and α2 isoforms, respectively. Therefore, we suggest that search for bufalin derivatives with high anticancer effect and low affinity for both Na+,K+pump isoforms may be a promising strategy for development of anticancer drugs. Effects of bufadienolides on Na pump are not correlated with their cytotoxicity. Bufadienolides with high anticancer effect but low side effect may exist. BF238 may form a basis for further anticancer drug research and development.