A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors
Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-01-01
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| Series: | Medical Sciences |
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| Online Access: | http://www.mdpi.com/2076-3271/6/1/3 |
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| author | Molly C. Peters Allyson Minton Otto Phanstiel IV Susan K. Gilmour |
| author_facet | Molly C. Peters Allyson Minton Otto Phanstiel IV Susan K. Gilmour |
| author_sort | Molly C. Peters |
| collection | DOAJ |
| description | Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas. These tumors rely on both polyamine biosynthesis and an upregulated polyamine transport system (PTS) to maintain their high intracellular polyamine levels. We evaluated the effect of a novel arylpolyamine (AP) compound that is cytotoxic upon cellular entry via the increased PTS activity of melanoma cells with different BRAF mutational status. Mutant BRAF melanoma cells demonstrated greater PTS activity and increased sensitivity to AP compared to wild type BRAF (BRAFWT) melanoma cells. Treatment with an inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), further upregulated PTS activity in mutant BRAF cells and increased their sensitivity to AP. Furthermore, viability assays of 3D spheroid cultures of mutant BRAF melanoma cells demonstrated greater resistance to the BRAFi, PLX4720, compared to 2D monolayer cultures. However, co-treatment with AP restored the sensitivity of melanoma spheroids to PLX4720. These data indicate that mutant BRAF melanoma cells are more dependent on the PTS compared to BRAFWT melanoma cells, resulting in greater sensitivity to the PTS-targeted cytotoxic AP compound. |
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| format | Article |
| id | doaj.art-900b7e6e3e884167a5b88c34c912a8c8 |
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| issn | 2076-3271 |
| language | English |
| last_indexed | 2024-12-12T04:07:24Z |
| publishDate | 2018-01-01 |
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| spelling | doaj.art-900b7e6e3e884167a5b88c34c912a8c82022-12-22T00:38:43ZengMDPI AGMedical Sciences2076-32712018-01-0161310.3390/medsci6010003medsci6010003A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma TumorsMolly C. Peters0Allyson Minton1Otto Phanstiel IV2Susan K. Gilmour3Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USALankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USABiomolecular Research Annex, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826-3227, USALankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USAMutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas. These tumors rely on both polyamine biosynthesis and an upregulated polyamine transport system (PTS) to maintain their high intracellular polyamine levels. We evaluated the effect of a novel arylpolyamine (AP) compound that is cytotoxic upon cellular entry via the increased PTS activity of melanoma cells with different BRAF mutational status. Mutant BRAF melanoma cells demonstrated greater PTS activity and increased sensitivity to AP compared to wild type BRAF (BRAFWT) melanoma cells. Treatment with an inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), further upregulated PTS activity in mutant BRAF cells and increased their sensitivity to AP. Furthermore, viability assays of 3D spheroid cultures of mutant BRAF melanoma cells demonstrated greater resistance to the BRAFi, PLX4720, compared to 2D monolayer cultures. However, co-treatment with AP restored the sensitivity of melanoma spheroids to PLX4720. These data indicate that mutant BRAF melanoma cells are more dependent on the PTS compared to BRAFWT melanoma cells, resulting in greater sensitivity to the PTS-targeted cytotoxic AP compound.http://www.mdpi.com/2076-3271/6/1/3polyaminesα-difluoromethylornithinepolyamine transport systemmelanomamutant BRAF |
| spellingShingle | Molly C. Peters Allyson Minton Otto Phanstiel IV Susan K. Gilmour A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors Medical Sciences polyamines α-difluoromethylornithine polyamine transport system melanoma mutant BRAF |
| title | A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors |
| title_full | A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors |
| title_fullStr | A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors |
| title_full_unstemmed | A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors |
| title_short | A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors |
| title_sort | novel polyamine targeted therapy for braf mutant melanoma tumors |
| topic | polyamines α-difluoromethylornithine polyamine transport system melanoma mutant BRAF |
| url | http://www.mdpi.com/2076-3271/6/1/3 |
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