A novel SERCA inhibitor demonstrates synergy with classic SERCA inhibitors and targets multidrug-resistant AML.
A novel SERCA inhibitor demonstrates synergy with classic SERCA inhibitors and targets multidrug-resistant AML.
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DOI：
10.1021/mp400458u
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发表时间：
2013-11-04
影响因子：
4.9
通讯作者：
Xing C
中科院分区：
文献类型：
--
作者：
Bleeker NP;Cornea RL;Thomas DD;Xing C
耐药性作为癌症治疗中的主要障碍而存在，并且保留针对耐药性癌症的有效性的药物分子是高度临床优先事项。2-氨基-6-（3，5-二甲氧基苯基）-4-（2-乙氧基-2-氧代乙基）-4H-色烯-3-羧酸乙酯（CXL 017）最近被鉴定为用于治疗多药耐药白血病的有希望的先导化合物，其部分地通过抑制肌浆网/内质网Ca 2 +-ATP酶（SERCA）而发挥其细胞毒性作用。在本文中，使用SERCA 1a、CXL 017的初始实验证明对钙亲和力没有显著影响，与ATP竞争，并诱导ATP酶活性的剂量依赖性降低。在所有测试的CXL中，（−）-CXL 017表现出最大的SERCA抑制作用，IC 50 = 13.5 ± 0.5 μM。抑制剂组合研究用于评估（−）-CXL 017与众所周知的SERCA抑制剂（毒胡萝卜素、环匹阿尼酸和2，5-二叔丁基对苯二酚）之间的潜在相互作用。令人惊讶的是，（-）-CXL 017与每种已知的SERCA抑制剂表现出显著的协同作用，而已知抑制剂的所有组合产生累加效应，表明（-）-CXL 017可能在独特的变构位点结合。用已知的SERCA抑制剂处理亲代（HL 60）和多药耐药（HL 60/MX2）急性髓性白血病细胞显示，所有这些抑制剂对耐药细胞系显示出选择性细胞毒性（7.7至400倍）。在CXL系列中，HL 60/MX2中的SERCA抑制与细胞毒性之间存在正相关性，但HL 60中不存在。（-）-CXL 017还显示出增强毒胡萝卜素在HL 60/MX2细胞中的细胞毒性。鉴于HL 60/MX2中SERCA水平和ER钙含量升高，SERCA可能在该多药耐药细胞系对CXL分子以及已知SERCA抑制剂的附带敏感性中起重要作用。
Drug resistance exists as a major obstacle in the treatment of cancer and drug molecules that retain effectiveness against resistant cancers are a high clinical priority. Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) was recently identified as a promising lead for the treatment of multidrug-resistant leukemia, which elicits its cytotoxic effect, in part, through inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Herein initial experiments with SERCA1a, CXL017 demonstrated no significant effect on calcium affinity, competed with ATP, and induced a dose-dependent decrease in ATPase activity. Among all CXLs tested, (−)-CXL017 exhibited the greatest SERCA inhibition with an IC50 = 13.5 ± 0.5 μM. Inhibitor combination studies were used to assess potential interactions between (−)-CXL017 and well-known SERCA inhibitors: thapsigargin, cyclopiazonic acid, and 2, 5-di-tert-butylhydroquinone. Surprisingly, (−)-CXL017 exhibited marked synergy with each of the known SERCA inhibitors whereas all combinations of the known inhibitors yielded additive effects, indicating that (−)-CXL017 may bind at a unique allosteric site. Treatment of parental (HL60) and multidrug-resistant (HL60/MX2) acute myeloid leukemia cells with the known SERCA inhibitors revealed that all of these inhibitors demonstrate selective cytotoxicity (7.7 to 400 fold) for the resistant cell line. Within the CXL series, a positive correlation exists between SERCA inhibition and cytotoxicity in HL60/MX2 but not HL60. (−)-CXL017 was also shown to enhance the cytotoxicity of thapsigargin in HL60/MX2 cells. Given the elevated SERCA levels and ER calcium content in HL60/MX2, SERCA likely plays a significant role in the collateral sensitivity of this multidrug-resistance cell line to CXL molecules as well as known SERCA inhibitors.
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影响因子：
4
作者：
Das, Sonia G.;Hermanson, David L.;Xing, Chengguo
通讯作者：
Xing, Chengguo
影响因子：
2.9
作者：
Inesi, Giuseppe;Lewis, David;Prasad, Anand
通讯作者：
Prasad, Anand
影响因子：
4.8
作者：
Eckenrode, Emily F.;Yang, Jun;White, Carl
通讯作者：
White, Carl
影响因子：
3.6
作者：
Hermanson, David;Addo, Sadiya N.;Xing, Chengguo
通讯作者：
Xing, Chengguo
DOI：
10.1046/j.0014-2956.2001.02589.x
发表时间：
2001-12-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Bilmen, JG;Khan, SZ;Michelangeli, F
通讯作者：
Michelangeli, F