Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation.
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduc...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0224253 |
| _version_ | 1818581099459117056 |
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| author | Heather F Sinner Jeremy Johnson Piotr G Rychahou David S Watt Yekaterina Y Zaytseva Chunming Liu B Mark Evers |
| author_facet | Heather F Sinner Jeremy Johnson Piotr G Rychahou David S Watt Yekaterina Y Zaytseva Chunming Liu B Mark Evers |
| author_sort | Heather F Sinner |
| collection | DOAJ |
| description | Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N'-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND-4b, either alone or combined with PI-103 (a dual PI3K/mTOR inhibitor) or SN-38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of CRC cell lines (both commercially-available and novel lines established from our patient population). Treatment with FND-4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in markers of cell proliferation, such as cyclin D1, in all CRC cell lines. Apoptosis was also notably increased in CRC cells treated with FND-4b. Regardless of the genetic profile of the CRC cells, FND-4b treatment alone resulted in decreased cell proliferation. Moreover, the combination of FND-4b with PI-103 resulted in increased cell death in all cell lines, while the combination of FND-4b with SN-38 resulted in increased cell death in select cell lines. Our findings identify FND-4b, which activates AMPK at micromolar concentrations, as a novel and effective inhibitor of CRC growth either alone or in combination with PI-103 and SN-38. |
| first_indexed | 2024-12-16T07:28:06Z |
| format | Article |
| id | doaj.art-842b75fbdbd8447fac5806cc522d06cc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T07:28:06Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-842b75fbdbd8447fac5806cc522d06cc2022-12-21T22:39:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-011410e022425310.1371/journal.pone.0224253Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation.Heather F SinnerJeremy JohnsonPiotr G RychahouDavid S WattYekaterina Y ZaytsevaChunming LiuB Mark EversColorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N'-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND-4b, either alone or combined with PI-103 (a dual PI3K/mTOR inhibitor) or SN-38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of CRC cell lines (both commercially-available and novel lines established from our patient population). Treatment with FND-4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in markers of cell proliferation, such as cyclin D1, in all CRC cell lines. Apoptosis was also notably increased in CRC cells treated with FND-4b. Regardless of the genetic profile of the CRC cells, FND-4b treatment alone resulted in decreased cell proliferation. Moreover, the combination of FND-4b with PI-103 resulted in increased cell death in all cell lines, while the combination of FND-4b with SN-38 resulted in increased cell death in select cell lines. Our findings identify FND-4b, which activates AMPK at micromolar concentrations, as a novel and effective inhibitor of CRC growth either alone or in combination with PI-103 and SN-38.https://doi.org/10.1371/journal.pone.0224253 |
| spellingShingle | Heather F Sinner Jeremy Johnson Piotr G Rychahou David S Watt Yekaterina Y Zaytseva Chunming Liu B Mark Evers Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. PLoS ONE |
| title | Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. |
| title_full | Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. |
| title_fullStr | Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. |
| title_full_unstemmed | Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. |
| title_short | Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation. |
| title_sort | novel chemotherapeutic agent fnd 4b activates ampk and inhibits colorectal cancer cell proliferation |
| url | https://doi.org/10.1371/journal.pone.0224253 |
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