Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma
The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effect...
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Taylor & Francis Group
2017-07-01
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| Series: | Journal of Radiation Research and Applied Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1687850717300262 |
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doaj-bffb1019dfdc44d5b1c86afc7875988a2020-11-25T00:54:19ZengTaylor & Francis GroupJournal of Radiation Research and Applied Sciences1687-85072017-07-0110320421310.1016/j.jrras.2017.04.008Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinomaSuraj Radhamani, Ph.D0Rejitha Suraj, Ph.D1Terri Meehan-Andrews, Ph.D2Jasim Al-Rawi3Christopher Bradley, Ph.D4School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, AustraliaSchool of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, AustraliaLa Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, AustraliaSchool of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, AustraliaSchool of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, AustraliaThe DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present two novel benzoxazines (LTU28 and LTU31) and analyse their ability to cause sensitization of cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them with LTU28 concomitantly with radiation. The mechanism of action by LTU28 appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis. LTU31 showed an inhibition in the phosphorylation of BRCA1, thereby blocking DNA repair by homologous recombination.http://www.sciencedirect.com/science/article/pii/S1687850717300262RadiosensitizingDNA-PKBRCA1Apoptosis |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Suraj Radhamani, Ph.D Rejitha Suraj, Ph.D Terri Meehan-Andrews, Ph.D Jasim Al-Rawi Christopher Bradley, Ph.D |
| spellingShingle |
Suraj Radhamani, Ph.D Rejitha Suraj, Ph.D Terri Meehan-Andrews, Ph.D Jasim Al-Rawi Christopher Bradley, Ph.D Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma Journal of Radiation Research and Applied Sciences Radiosensitizing DNA-PK BRCA1 Apoptosis |
| author_facet |
Suraj Radhamani, Ph.D Rejitha Suraj, Ph.D Terri Meehan-Andrews, Ph.D Jasim Al-Rawi Christopher Bradley, Ph.D |
| author_sort |
Suraj Radhamani, Ph.D |
| title |
Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma |
| title_short |
Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma |
| title_full |
Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma |
| title_fullStr |
Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma |
| title_full_unstemmed |
Radiosensitizing activity of novel small molecule BRCA1 and DNA-PK inhibitors in lung and colon carcinoma |
| title_sort |
radiosensitizing activity of novel small molecule brca1 and dna-pk inhibitors in lung and colon carcinoma |
| publisher |
Taylor & Francis Group |
| series |
Journal of Radiation Research and Applied Sciences |
| issn |
1687-8507 |
| publishDate |
2017-07-01 |
| description |
The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present two novel benzoxazines (LTU28 and LTU31) and analyse their ability to cause sensitization of cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them with LTU28 concomitantly with radiation. The mechanism of action by LTU28 appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis. LTU31 showed an inhibition in the phosphorylation of BRCA1, thereby blocking DNA repair by homologous recombination. |
| topic |
Radiosensitizing DNA-PK BRCA1 Apoptosis |
| url |
http://www.sciencedirect.com/science/article/pii/S1687850717300262 |
| work_keys_str_mv |
AT surajradhamaniphd radiosensitizingactivityofnovelsmallmoleculebrca1anddnapkinhibitorsinlungandcoloncarcinoma AT rejithasurajphd radiosensitizingactivityofnovelsmallmoleculebrca1anddnapkinhibitorsinlungandcoloncarcinoma AT terrimeehanandrewsphd radiosensitizingactivityofnovelsmallmoleculebrca1anddnapkinhibitorsinlungandcoloncarcinoma AT jasimalrawi radiosensitizingactivityofnovelsmallmoleculebrca1anddnapkinhibitorsinlungandcoloncarcinoma AT christopherbradleyphd radiosensitizingactivityofnovelsmallmoleculebrca1anddnapkinhibitorsinlungandcoloncarcinoma |
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