Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017)
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. It has the lowest survival rate in children, and only 5.4% of elders survive. For the past 40 years, chemotherapy remains the common treatment for AML with minimal lifestyle improvements largely due to better risk classificati...
محفوظ في:
| المؤلف الرئيسي: | |
|---|---|
| التنسيق: | masterThesis |
| منشور في: |
2017
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| الموضوعات: | |
| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/7184 https://doi.org/10.26756/th.2018.35 http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php |
| الوسوم: |
إضافة وسم
لا توجد وسوم, كن أول من يضع وسما على هذه التسجيلة!
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| _version_ | 1864513481722560512 |
|---|---|
| author | Assaf, Nicole |
| author_facet | Assaf, Nicole |
| author_role | author |
| dc.creator.none.fl_str_mv | Assaf, Nicole |
| dc.date.none.fl_str_mv | 2017 2017-09-12 2018-03-06T08:40:17Z 2018-03-06T08:40:17Z 2018-03-06 |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10725/7184 https://doi.org/10.26756/th.2018.35 http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php |
| dc.language.none.fl_str_mv | en |
| dc.publisher.none.fl_str_mv | Lebanese American University |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Acute myeloid leukemia -- Treatment Arginine -- Therapeutic use Dissertations, Academic Lebanese American University -- Dissertations |
| dc.title.none.fl_str_mv | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| dc.type.none.fl_str_mv | Thesis info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/masterThesis |
| description | Acute myeloid leukemia (AML) is the most common acute leukemia in adults. It has the lowest survival rate in children, and only 5.4% of elders survive. For the past 40 years, chemotherapy remains the common treatment for AML with minimal lifestyle improvements largely due to better risk classifications and enhancements in supportive care. Hence, novel approaches for targeting AML cells are needed. A common mutation in cancer is amino acid auxotrophy, particularly arginine, which is needed for the production of many metabolites and also involved in immunoregulation and protein modification. We have previously shown that AML cells were auxotrophic for arginine and highly sensitive to arginine deprivation induced by a PEGylated human recombinant Arginase I cobalt [HuArgI (Co)-PEG5000], hence demonstrating that arginine deprivation may constitute an attractive strategy for the selective targeting of AML cells. In this study, we aim to further investigate the mechanisms of HuArgI (Co)-PEG5000 induced cytotoxicity in AML cells. We have demonstrated that arginine depletion is cytotoxic in a time-dependent manner. We have also demonstrated that autophagy is significantly activated following arginine deprivation starting at 12 hours and continuing up to 72 hours following arginine deprivation. Inhibition of autophagy using Chloroquine, rescued AML cells from arginine deprivation-induced cytotoxicity indicating that the observed cell death following arginine deprivation is due to the prolonged over-activation of autophagy (death by autophagy). Finally, combining HuArgI(Co)-PEG5000-induced arginine deprivation with Anthrax lethal toxinmediated inhibition of the MAPK pathway has revealed a synergistic cytotoxic effect on selective AML cell lines that are usually sensitive to MAPK inhibition. |
| eu_rights_str_mv | openAccess |
| format | masterThesis |
| id | LAURepo_57fd64d61a129378ffe59a247a591ec6 |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/7184 |
| publishDate | 2017 |
| publisher.none.fl_str_mv | Lebanese American University |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017)Assaf, NicoleAcute myeloid leukemia -- TreatmentArginine -- Therapeutic useDissertations, AcademicLebanese American University -- DissertationsAcute myeloid leukemia (AML) is the most common acute leukemia in adults. It has the lowest survival rate in children, and only 5.4% of elders survive. For the past 40 years, chemotherapy remains the common treatment for AML with minimal lifestyle improvements largely due to better risk classifications and enhancements in supportive care. Hence, novel approaches for targeting AML cells are needed. A common mutation in cancer is amino acid auxotrophy, particularly arginine, which is needed for the production of many metabolites and also involved in immunoregulation and protein modification. We have previously shown that AML cells were auxotrophic for arginine and highly sensitive to arginine deprivation induced by a PEGylated human recombinant Arginase I cobalt [HuArgI (Co)-PEG5000], hence demonstrating that arginine deprivation may constitute an attractive strategy for the selective targeting of AML cells. In this study, we aim to further investigate the mechanisms of HuArgI (Co)-PEG5000 induced cytotoxicity in AML cells. We have demonstrated that arginine depletion is cytotoxic in a time-dependent manner. We have also demonstrated that autophagy is significantly activated following arginine deprivation starting at 12 hours and continuing up to 72 hours following arginine deprivation. Inhibition of autophagy using Chloroquine, rescued AML cells from arginine deprivation-induced cytotoxicity indicating that the observed cell death following arginine deprivation is due to the prolonged over-activation of autophagy (death by autophagy). Finally, combining HuArgI(Co)-PEG5000-induced arginine deprivation with Anthrax lethal toxinmediated inhibition of the MAPK pathway has revealed a synergistic cytotoxic effect on selective AML cell lines that are usually sensitive to MAPK inhibition.N/A1 hard copy: xi, 55 leaves; 31 cm. available at RNL.Bibliography : leaves 48-55.Lebanese American University2018-03-06T08:40:17Z2018-03-06T08:40:17Z20172018-03-062017-09-12Thesisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttp://hdl.handle.net/10725/7184https://doi.org/10.26756/th.2018.35http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.phpeninfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/71842021-03-19T10:43:19Z |
| spellingShingle | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) Assaf, Nicole Acute myeloid leukemia -- Treatment Arginine -- Therapeutic use Dissertations, Academic Lebanese American University -- Dissertations |
| status_str | publishedVersion |
| title | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| title_full | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| title_fullStr | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| title_full_unstemmed | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| title_short | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| title_sort | Mechanisms of human recombinant arginase I (Co) - PEG5000 [Huarg I (Co) - PEG5000] - induced cytotoxicity on AML cells. (c2017) |
| topic | Acute myeloid leukemia -- Treatment Arginine -- Therapeutic use Dissertations, Academic Lebanese American University -- Dissertations |
| url | http://hdl.handle.net/10725/7184 https://doi.org/10.26756/th.2018.35 http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php |