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...
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| Format: | Article |
| Language: | en_US |
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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 |
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| author | Awuah, Samuel Zheng, Yaorong Bruno, Peter Michael Hemann, Michael Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Awuah, Samuel Zheng, Yaorong Bruno, Peter Michael Hemann, Michael Lippard, Stephen J. |
| author_sort | Awuah, Samuel |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:45:54Z |
| format | Article |
| id | mit-1721.1/106516 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:45:54Z |
| publishDate | 2017 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1065162022-09-30T22:52:32Z A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy Awuah, Samuel Zheng, Yaorong Bruno, Peter Michael Hemann, Michael Lippard, Stephen J. Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Awuah, Samuel Zheng, Yaorong Bruno, Peter Michael Hemann, Michael Lippard, Stephen J. 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. National Cancer Institute (U.S.) (Grant CA034992) 2017-01-17T21:07:03Z 2017-01-17T21:07:03Z 2015-11 2015-09 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/106516 Awuah, Samuel G. et al. “A Pt(IV) Pro-Drug Preferentially Targets Indoleamine-2,3-Dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.” Journal of the American Chemical Society 137.47 (2015): 14854–14857. https://orcid.org/0000-0002-6958-3991 https://orcid.org/0000-0003-3383-0118 https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1021/jacs.5b10182 Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Awuah, Samuel Zheng, Yaorong Bruno, Peter Michael Hemann, Michael Lippard, Stephen J. A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title | A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title_full | A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title_fullStr | A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title_full_unstemmed | A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title_short | A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy |
| title_sort | pt iv pro drug preferentially targets indoleamine 2 3 dioxygenase providing enhanced ovarian cancer immuno chemotherapy |
| url | 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 |
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