Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas
Abstract High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for dec...
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| Format: | Article |
| Language: | English |
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BMC
2020-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-020-01724-6 |
| _version_ | 1811333745724096512 |
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| author | Faiqa Mudassar Han Shen Geraldine O’Neill Eric Hau |
| author_facet | Faiqa Mudassar Han Shen Geraldine O’Neill Eric Hau |
| author_sort | Faiqa Mudassar |
| collection | DOAJ |
| description | Abstract High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for decades; however, pronounced radioresistance is the major obstacle towards the successful radiotherapy treatment. Herein, tumor hypoxia is identified as a significant contributor to the radioresistance of HGGs as oxygenation is critical for the effectiveness of radiotherapy. Hypoxia plays a fundamental role in the aggressive and resistant phenotype of all solid tumors, including HGGs, by upregulating hypoxia-inducible factors (HIFs) which stimulate vital enzymes responsible for cancer survival under hypoxic stress. Since current attempts to target tumor hypoxia focus on reducing oxygen demand of tumor cells by decreasing oxygen consumption rate (OCR), an attractive strategy to achieve this is by inhibiting mitochondrial oxidative phosphorylation, as it could decrease OCR, and increase oxygenation, and could therefore improve the radiation response in HGGs. This approach would also help in eradicating the radioresistant glioma stem cells (GSCs) as these predominantly rely on mitochondrial metabolism for survival. Here, we highlight the potential for repurposing anti-parasitic drugs to abolish tumor hypoxia and induce apoptosis of GSCs. Current literature provides compelling evidence that these drugs (atovaquone, ivermectin, proguanil, mefloquine, and quinacrine) could be effective against cancers by mechanisms including inhibition of mitochondrial metabolism and tumor hypoxia and inducing DNA damage. Therefore, combining these drugs with radiotherapy could potentially enhance the radiosensitivity of HGGs. The reported efficacy of these agents against glioblastomas and their ability to penetrate the blood-brain barrier provides further support towards promising results and clinical translation of these agents for HGGs treatment. |
| first_indexed | 2024-04-13T16:57:29Z |
| format | Article |
| id | doaj.art-393854a4b3dd4a54a214532cb71aebdc |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-13T16:57:29Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-393854a4b3dd4a54a214532cb71aebdc2022-12-22T02:38:46ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-10-0139111710.1186/s13046-020-01724-6Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomasFaiqa Mudassar0Han Shen1Geraldine O’Neill2Eric Hau3Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical ResearchSydney Medical School, University of SydneyChildren’s Cancer Research Unit, The Children’s Hospital at WestmeadTranslational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical ResearchAbstract High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for decades; however, pronounced radioresistance is the major obstacle towards the successful radiotherapy treatment. Herein, tumor hypoxia is identified as a significant contributor to the radioresistance of HGGs as oxygenation is critical for the effectiveness of radiotherapy. Hypoxia plays a fundamental role in the aggressive and resistant phenotype of all solid tumors, including HGGs, by upregulating hypoxia-inducible factors (HIFs) which stimulate vital enzymes responsible for cancer survival under hypoxic stress. Since current attempts to target tumor hypoxia focus on reducing oxygen demand of tumor cells by decreasing oxygen consumption rate (OCR), an attractive strategy to achieve this is by inhibiting mitochondrial oxidative phosphorylation, as it could decrease OCR, and increase oxygenation, and could therefore improve the radiation response in HGGs. This approach would also help in eradicating the radioresistant glioma stem cells (GSCs) as these predominantly rely on mitochondrial metabolism for survival. Here, we highlight the potential for repurposing anti-parasitic drugs to abolish tumor hypoxia and induce apoptosis of GSCs. Current literature provides compelling evidence that these drugs (atovaquone, ivermectin, proguanil, mefloquine, and quinacrine) could be effective against cancers by mechanisms including inhibition of mitochondrial metabolism and tumor hypoxia and inducing DNA damage. Therefore, combining these drugs with radiotherapy could potentially enhance the radiosensitivity of HGGs. The reported efficacy of these agents against glioblastomas and their ability to penetrate the blood-brain barrier provides further support towards promising results and clinical translation of these agents for HGGs treatment.http://link.springer.com/article/10.1186/s13046-020-01724-6High-grade gliomasRadioresistanceHypoxiaHIFsMitochondriaMetabolism |
| spellingShingle | Faiqa Mudassar Han Shen Geraldine O’Neill Eric Hau Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas Journal of Experimental & Clinical Cancer Research High-grade gliomas Radioresistance Hypoxia HIFs Mitochondria Metabolism |
| title | Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas |
| title_full | Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas |
| title_fullStr | Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas |
| title_full_unstemmed | Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas |
| title_short | Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas |
| title_sort | targeting tumor hypoxia and mitochondrial metabolism with anti parasitic drugs to improve radiation response in high grade gliomas |
| topic | High-grade gliomas Radioresistance Hypoxia HIFs Mitochondria Metabolism |
| url | http://link.springer.com/article/10.1186/s13046-020-01724-6 |
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