A new approach for enhancing differential setectivity of drugs to cancer cells
A new approach for enhancing differential setectivity of drugs to cancer cells
复制标题
DOI：
10.1021/cb6001202
复制
发表时间：
2006-01-01
影响因子：
4
通讯作者：
Krise, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Duvvuri, Muralikrishna;Konkar, Saimidha;Krise, Jeffrey P.
抗癌药物选择性靶向癌细胞的程度是成功治疗结果的关键决定因素。 Hsp90 分子伴侣抑制剂代表了一类重要的新型抗癌药物。我们在此提出了一种新机制，通过该机制可以优化 Hsp90 抑制剂的理化特性，以提高对癌细胞的选择性。这种方法的基础依赖于正常细胞和转化细胞之间存在的不同的细胞内 pH 梯度。使用溶酶体 pH 值可变的细胞进行抗增殖测定，对五种含有碱性或中性特性的 Hsp90 抑制剂进行了评估。具有基本功能的抑制剂在溶酶体 pH 值正常（低）的细胞中活性降低，但在溶酶体 pH 值异常升高的细胞中活性显着增强（与许多类型的癌细胞中记录的情况类似）。相反，中性抑制剂没有观察到这种选择性增强。通过测定相关细胞内区室中抑制剂的浓度，定量证明了所观察到的选择性的机制基础。总的来说，这些发现表明，具有最佳碱性和理化性质的 Hsp90 抑制剂比中性抑制剂对癌细胞的选择性更强。预计这些发现可能适用于其他类别的抗癌剂以改善差异选择性。
The degree to which anticancer agents selectively target cancer cells is a key determinant in successful therapeutic outcomes. Inhibitors of the Hsp90 molecular chaperone represent an important new class of anticancer agents. We propose here a novel mechanism by which physiochemical properties of Hsp90 inhibitors can be optimized to increase selectivity towards cancer cells. The basis for this approach relies on differential intracellular pH gradients that have been shown to exist between normal and transformed cells. Five Hsp90 inhibitors containing basic or neutral properties were evaluated in anti proliferation assays using cells with variable lysosomal pH. Inhibitors with basic functionalities had reduced activity in cells with normal (low) lysosomal pH but showed significantly greater activity in cells with abnormally elevated lysosomal pH (similar to what has been recorded in many types of cancer cells). Conversely, such selectivity enhancement was not observed for neutral inhibitors. The mechanistic basis for the observed selectivity was demonstrated quantitatively by determining the concentration of inhibitors within relevant intracellular compartments. Collectively, these findings suggest that Hsp90 inhibitors with optimal basicity and physicochemical properties have enhanced selectivity toward cancer cells than their neutral counterparts. It is anticipated that these findings may be applicable to other classes of anticancer agents for improvement of differential selectivity.