Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells
Neuroblastoma is the most common malignant tumor of infancy and accounts for 10% of all childhood cancers. The high biological and clinical heterogeneity of this tumor leads to differences in clinical outcomes ranging from benign tumors that regress spontaneously to metastatic tumors that are ultima...
محفوظ في:
| المؤلف الرئيسي: | |
|---|---|
| التنسيق: | masterThesis |
| منشور في: |
2021
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| الموضوعات: | |
| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/13649 https://doi.org/10.26756/th.2022.262 http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php |
| الوسوم: |
إضافة وسم
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| _version_ | 1864513452872040448 |
|---|---|
| author | Al Sayyed, Fatima |
| author_facet | Al Sayyed, Fatima |
| author_role | author |
| dc.creator.none.fl_str_mv | Al Sayyed, Fatima |
| dc.date.none.fl_str_mv | 2021 2021-08-04 2022-06-14T06:34:18Z 2022-06-14T06:34:18Z |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10725/13649 https://doi.org/10.26756/th.2022.262 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 | Neuroblastoma -- Treatment Stem cells -- Therapeutic use Chemotherapy Lebanese American University -- Dissertations Dissertations, Academic |
| dc.title.none.fl_str_mv | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| dc.type.none.fl_str_mv | Thesis info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/masterThesis |
| description | Neuroblastoma is the most common malignant tumor of infancy and accounts for 10% of all childhood cancers. The high biological and clinical heterogeneity of this tumor leads to differences in clinical outcomes ranging from benign tumors that regress spontaneously to metastatic tumors that are ultimately fatal. Despite the recent advances, many children continue to suffer from refractory and relapsed diseases, and they often develop metastatic tumors resistant to standard treatments. Amplification of MYC-N proto-oncogene is highly associated with clinically aggressive disease, recurrence and treatment failure. The highly malignant rate in neuroblastoma is likely due to the continuous acquisition of genetic aberrations in undifferentiated neuroblastoma cancer stem cells (CSCs). CSCs play a crucial role in dysregulating different pathways that are involved in metastasis, invasion, angiogenic properties, uncontrolled proliferation, self-renewal capacities and therapeutic resistance. In this study, we investigate the efficacy of two small molecules Ruxolitinib, a JAK/STAT inhibitor, and CHIR-99021, a GSK-3 inhibitor, in targeting pediatric neuroblastoma stem cells by testing them on human MYC-N amplified, IMR-32, and non-MYC-N amplified, SK-N-SH, cell lines. Treating neuroblastoma cells with Ruxolitinib and CHIR-99021 resulted in significant reduction in cellular proliferation, viability, apoptosis and tumorsphere formation capacity in both IMR-32 and SK-N-SH cell lines. Western blot analysis showed significant decrease in stem cell markers SOX-2 and Oct-4, and tumorigenic protein HMGA1, whereas it showed significant increase in apoptotic markers cleaved PARP and cleaved caspase-3. In conclusion, our findings demonstrated that Ruxolitinib and CHIR-99021 could be promising therapies in targeting neuroblastoma CSCs, and that combining these two drugs may have added therapeutic effects in treating this malignant tumor. Further studies are warranted to elucidate the therapeutic mechanism through which these drugs act to target the various tumorigenic pathways. |
| eu_rights_str_mv | openAccess |
| format | masterThesis |
| id | LAURepo_95c0c42fa20eb9955c195d2f7cd49ccc |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/13649 |
| publishDate | 2021 |
| publisher.none.fl_str_mv | Lebanese American University |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem CellsAl Sayyed, FatimaNeuroblastoma -- TreatmentStem cells -- Therapeutic useChemotherapyLebanese American University -- DissertationsDissertations, AcademicNeuroblastoma is the most common malignant tumor of infancy and accounts for 10% of all childhood cancers. The high biological and clinical heterogeneity of this tumor leads to differences in clinical outcomes ranging from benign tumors that regress spontaneously to metastatic tumors that are ultimately fatal. Despite the recent advances, many children continue to suffer from refractory and relapsed diseases, and they often develop metastatic tumors resistant to standard treatments. Amplification of MYC-N proto-oncogene is highly associated with clinically aggressive disease, recurrence and treatment failure. The highly malignant rate in neuroblastoma is likely due to the continuous acquisition of genetic aberrations in undifferentiated neuroblastoma cancer stem cells (CSCs). CSCs play a crucial role in dysregulating different pathways that are involved in metastasis, invasion, angiogenic properties, uncontrolled proliferation, self-renewal capacities and therapeutic resistance. In this study, we investigate the efficacy of two small molecules Ruxolitinib, a JAK/STAT inhibitor, and CHIR-99021, a GSK-3 inhibitor, in targeting pediatric neuroblastoma stem cells by testing them on human MYC-N amplified, IMR-32, and non-MYC-N amplified, SK-N-SH, cell lines. Treating neuroblastoma cells with Ruxolitinib and CHIR-99021 resulted in significant reduction in cellular proliferation, viability, apoptosis and tumorsphere formation capacity in both IMR-32 and SK-N-SH cell lines. Western blot analysis showed significant decrease in stem cell markers SOX-2 and Oct-4, and tumorigenic protein HMGA1, whereas it showed significant increase in apoptotic markers cleaved PARP and cleaved caspase-3. In conclusion, our findings demonstrated that Ruxolitinib and CHIR-99021 could be promising therapies in targeting neuroblastoma CSCs, and that combining these two drugs may have added therapeutic effects in treating this malignant tumor. Further studies are warranted to elucidate the therapeutic mechanism through which these drugs act to target the various tumorigenic pathways.1 online resource (xii, 68 leaves) : ill. (some col.)Bibliography: leaf 54-68.Lebanese American University2022-06-14T06:34:18Z2022-06-14T06:34:18Z20212021-08-04Thesisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttp://hdl.handle.net/10725/13649https://doi.org/10.26756/th.2022.262http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.phpeninfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/136492022-07-06T10:58:54Z |
| spellingShingle | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells Al Sayyed, Fatima Neuroblastoma -- Treatment Stem cells -- Therapeutic use Chemotherapy Lebanese American University -- Dissertations Dissertations, Academic |
| status_str | publishedVersion |
| title | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| title_full | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| title_fullStr | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| title_full_unstemmed | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| title_short | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| title_sort | Investigating The Efficacy of Ruxolitinib and CHIR-99021 in Targeting Pediatric Neuroblastoma Stem Cells |
| topic | Neuroblastoma -- Treatment Stem cells -- Therapeutic use Chemotherapy Lebanese American University -- Dissertations Dissertations, Academic |
| url | http://hdl.handle.net/10725/13649 https://doi.org/10.26756/th.2022.262 http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php |