A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy
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. IDO inhibitors can enhance the efficacy o...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Chemical Society (ACS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/106516 https://orcid.org/0000-0002-6958-3991 https://orcid.org/0000-0003-3383-0118 https://orcid.org/0000-0002-2693-4982 |
| Summary: | 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. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigated
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 auto-crine-signaling loop IDO-AHR-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. |
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