Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity.
Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity.
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DOI：
10.1002/cbic.201300625
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发表时间：
2014-03-21
期刊：
影响因子：
3.2
通讯作者：
Hurley, Thomas D.
中科院分区：
文献类型：
--
作者：
Parajuli, Bibek;Georgiadis, Taxiarchis M.;Fishel, Melissa L.;Hurley, Thomas D.
乙醛脱氢酶3A 1（ALDH 3A 1）通过代谢活化形式的氧氮磷杂环药物如环磷酰胺（CP）及其类似物如马磷酰胺（MF）、异环磷酰胺（IFM）、4-氢过氧环磷酰胺（4-HPCP）在许多细胞氧化过程中起重要作用，包括癌症化疗抗性。可以选择性靶向ALDH 3A 1的化合物可以允许描绘其在这些过程中的作用，并可以恢复表达这种同工酶的癌细胞的化学敏感性。在这里，我们报告了ALDH 3A 1选择性抑制剂CB 29的详细动力学和结构表征，CB 29是以前在高通量筛选中鉴定的。动力学和晶体学研究表明，CB 29结合在ALDH 3A 1的醛底物结合位点内。表达ALDH 3A 1的肺腺癌（A549）和胶质母细胞瘤（SF 767）细胞系以及不表达ALDH 3A 1的肺成纤维细胞CCD-13 Lu的细胞增殖不受单独用CB 29及其类似物处理的影响。然而，通过在肿瘤细胞中用CB 29及其类似物治疗，对马磷酰胺的抗增殖作用的敏感性增强。相反，CCD-13 Lu细胞对马磷酰胺的敏感性不受这些相同化合物的影响。CB 29在化学上不同于先前报道的ALDH同工酶的小分子抑制剂，并且在高达250 μM的浓度下不抑制ALDH 1A 1、ALDH 1A 2、ALDH 1A 3、ALDH 1B 1或ALDH 2同工酶。因此，CB 29是ALDH 3A 1的新型小分子抑制剂，其可用作描述ALDH 3A 1在许多代谢途径中的作用的化学工具，包括使ALDH 3A 1阳性癌细胞对氧氮磷杂环类敏感。
Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemo-resistance by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues such as mafosfamide (MF), ifosfamide (IFM), 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 may permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1 selective inhibitor, CB29, previously identified in a high throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as the ALDH3A1 non-expressing lung fibroblast cells, CCD-13Lu, is unaffected by treatment with CB29 and its analogues alone. However, the sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumour cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1 or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which may be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
影响因子：
3
作者：
Moreb, Jan S.;Muhoczy, Dagmara;Zucali, James R.
通讯作者：
Zucali, James R.
影响因子：
4.8
作者：
Lassen, Natalie;Bateman, J. Bronwyn;Vasiliou, Vasilis
通讯作者：
Vasiliou, Vasilis
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
Khanna, May;Chen, Che-Hong;Hurley, Thomas D.
通讯作者：
Hurley, Thomas D.