A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy

被引：144
作者：
Awuah, Samuel G. [1 ]
Zheng, Yao-Rong [1 ]
Bruno, Peter M. [2 ]
Hemann, Michael T. [2 ]
Lippard, Stephen J. [1 ,2 ]
机构：
[1] MIT, Dept Chem, Cambridge, MA 02139 USA
[2] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA
来源：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2015年 / 137卷 / 47期
关键词：
INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION; DENDRITIC CELLS; TRYPTOPHAN CATABOLISM; IDO EXPRESSION; T-CELLS; INHIBITION; MECHANISMS; CISPLATIN; THERAPY; STRATEGIES;
D O I：
10.1021/jacs.5b10182
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. ID inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigate Pt(IV)-(D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer "immuno-chemotherapy". Compound 2 effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, inhibiting IDO by transcriptional deregulation of the autocrine-signaling loop IDOAHR-IL6, which blocks kynurenine production and promotes T-cell proliferation. Additionally, 1 and 2 display low toxicity in mice and are stable in blood. To our knowledge, this construct is the first Pt drug candidate with immune checkpoint blockade properties.
引用
收藏
页码：14854 / 14857
页数：4
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