Dual drug targeting to kill colon cancers
Abstract Introduction Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic acti...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-07-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.4641 |
| _version_ | 1811330918461210624 |
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| author | Silvia Paola Corona Francesca Walker Janet Weinstock Guillaume Lessene Maree Faux Antony W. Burgess |
| author_facet | Silvia Paola Corona Francesca Walker Janet Weinstock Guillaume Lessene Maree Faux Antony W. Burgess |
| author_sort | Silvia Paola Corona |
| collection | DOAJ |
| description | Abstract Introduction Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair‐wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. Objectives To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. Methods The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro‐cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. Results Colon cancer cells in non‐adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro‐apoptotic Bcl‐2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. Conclusion By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro‐survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro‐survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations. |
| first_indexed | 2024-04-13T16:11:12Z |
| format | Article |
| id | doaj.art-b8858d210b854fbcb0fff27274dc6cfd |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-13T16:11:12Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-b8858d210b854fbcb0fff27274dc6cfd2022-12-22T02:40:14ZengWileyCancer Medicine2045-76342022-07-0111132612262610.1002/cam4.4641Dual drug targeting to kill colon cancersSilvia Paola Corona0Francesca Walker1Janet Weinstock2Guillaume Lessene3Maree Faux4Antony W. Burgess5Structural Biology Division WEHI Parkville AustraliaStructural Biology Division WEHI Parkville AustraliaStructural Biology Division WEHI Parkville AustraliaDepartment of Medical Biology University of Melbourne Parkville AustraliaStructural Biology Division WEHI Parkville AustraliaStructural Biology Division WEHI Parkville AustraliaAbstract Introduction Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair‐wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. Objectives To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. Methods The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro‐cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. Results Colon cancer cells in non‐adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro‐apoptotic Bcl‐2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. Conclusion By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro‐survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro‐survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations.https://doi.org/10.1002/cam4.4641adenomaapoptosispro‐survival inhibitorssignaling |
| spellingShingle | Silvia Paola Corona Francesca Walker Janet Weinstock Guillaume Lessene Maree Faux Antony W. Burgess Dual drug targeting to kill colon cancers Cancer Medicine adenoma apoptosis pro‐survival inhibitors signaling |
| title | Dual drug targeting to kill colon cancers |
| title_full | Dual drug targeting to kill colon cancers |
| title_fullStr | Dual drug targeting to kill colon cancers |
| title_full_unstemmed | Dual drug targeting to kill colon cancers |
| title_short | Dual drug targeting to kill colon cancers |
| title_sort | dual drug targeting to kill colon cancers |
| topic | adenoma apoptosis pro‐survival inhibitors signaling |
| url | https://doi.org/10.1002/cam4.4641 |
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