A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress
Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other g...
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| Format: | Article |
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Springer Nature
2018
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| Online Access: | http://hdl.handle.net/1721.1/116549 https://orcid.org/0000-0003-3383-0118 https://orcid.org/0000-0001-9087-4227 https://orcid.org/0000-0002-1751-7327 https://orcid.org/0000-0002-4812-4171 https://orcid.org/0000-0002-2693-4982 |
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| author | Murai, Junko Pommier, Yves Hemann, Michael T Bruno, Peter Michael Liu, Yunpeng Park, Ga Young Koch, Catherine E. Lippard, Stephen J. Hemann, Michael Eisen, Timothy Jonas Pritchard, Justin R. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Murai, Junko Pommier, Yves Hemann, Michael T Bruno, Peter Michael Liu, Yunpeng Park, Ga Young Koch, Catherine E. Lippard, Stephen J. Hemann, Michael Eisen, Timothy Jonas Pritchard, Justin R. |
| author_sort | Murai, Junko |
| collection | MIT |
| description | Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs. |
| first_indexed | 2024-09-23T15:10:59Z |
| format | Article |
| id | mit-1721.1/116549 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:10:59Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1165492022-10-02T01:12:54Z A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress Murai, Junko Pommier, Yves Hemann, Michael T Bruno, Peter Michael Liu, Yunpeng Park, Ga Young Koch, Catherine E. Lippard, Stephen J. Hemann, Michael Eisen, Timothy Jonas Pritchard, Justin R. Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Bruno, Peter Michael Liu, Yunpeng Park, Ga Young Koch, Catherine E. Eisen, Timothy Pritchard, Justin Robert Lippard, Stephen J. Hemann, Michael Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs. 2018-06-25T14:14:29Z 2018-06-25T14:14:29Z 2017-02 2016-08 2018-06-21T16:24:47Z Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X http://hdl.handle.net/1721.1/116549 Bruno, Peter M, Yunpeng Liu, Ga Young Park, Junko Murai, Catherine E Koch, Timothy J Eisen, Justin R Pritchard, Yves Pommier, Stephen J Lippard, and Michael T Hemann. “A Subset of Platinum-Containing Chemotherapeutic Agents Kills Cells by Inducing Ribosome Biogenesis Stress.” Nature Medicine 23, no. 4 (February 27, 2017): 461–471. https://orcid.org/0000-0003-3383-0118 https://orcid.org/0000-0001-9087-4227 https://orcid.org/0000-0002-1751-7327 https://orcid.org/0000-0002-4812-4171 https://orcid.org/0000-0002-2693-4982 http://dx.doi.org/10.1038/NM.4291 Nature Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Nature PMC |
| spellingShingle | Murai, Junko Pommier, Yves Hemann, Michael T Bruno, Peter Michael Liu, Yunpeng Park, Ga Young Koch, Catherine E. Lippard, Stephen J. Hemann, Michael Eisen, Timothy Jonas Pritchard, Justin R. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title | A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title_full | A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title_fullStr | A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title_full_unstemmed | A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title_short | A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| title_sort | subset of platinum containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress |
| url | http://hdl.handle.net/1721.1/116549 https://orcid.org/0000-0003-3383-0118 https://orcid.org/0000-0001-9087-4227 https://orcid.org/0000-0002-1751-7327 https://orcid.org/0000-0002-4812-4171 https://orcid.org/0000-0002-2693-4982 |
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