Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids
Abstract Background Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and i...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-06016-7 |
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| author | Ali Mussa Mahasin Hamid Khalid Hajissa Ahmad Hafiz Murtadha Mohammad A. I. Al-Hatamleh Noor Fatmawati Mokhtar Vuk Uskoković Magdalena Plebanski Rohimah Mohamud Rosline Hassan |
| author_facet | Ali Mussa Mahasin Hamid Khalid Hajissa Ahmad Hafiz Murtadha Mohammad A. I. Al-Hatamleh Noor Fatmawati Mokhtar Vuk Uskoković Magdalena Plebanski Rohimah Mohamud Rosline Hassan |
| author_sort | Ali Mussa |
| collection | DOAJ |
| description | Abstract Background Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids. Methods We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, H2O2 levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis. Results We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated H2O2 production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of H2O2 generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced H2O2 production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response. Conclusions This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC. |
| format | Article |
| id | doaj-art-82b2684712af427aa4ceec30861dbf87 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-82b2684712af427aa4ceec30861dbf872025-01-12T12:37:34ZengBMCJournal of Translational Medicine1479-58762025-01-0123111510.1186/s12967-024-06016-7Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroidsAli Mussa0Mahasin Hamid1Khalid Hajissa2Ahmad Hafiz Murtadha3Mohammad A. I. Al-Hatamleh4Noor Fatmawati Mokhtar5Vuk Uskoković6Magdalena Plebanski7Rohimah Mohamud8Rosline Hassan9Department of Haematology, School of Medical Sciences, Universiti Sains MalaysiaDepartment of Pharmaceutics, Xiangya School of Pharmaceutical Sciences, Central South UniversityDepartment of Zoology, Faculty of Science and Technology, Omdurman Islamic UniversityInstitute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Health CampusUPMC Hillman Cancer Center, Division of Malignant Hematology and Medical Oncology, Department of Medicine, University of Pittsburgh School of MedicineInstitute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Health CampusAdvanced Materials and Nanobiotechnology Laboratory, TardigradeNano LLCThe Accelerator for Translation in Clinical Trials (ATRACT) Centre, School of Health and Biomedical Sciences, RMIT UniversityDepartment of Immunology, School of Medical Sciences, Universiti Sains MalaysiaDepartment of Haematology, School of Medical Sciences, Universiti Sains MalaysiaAbstract Background Pharmacological vitamin C (Vit-C), or high-dose Vit-C has recently gained attention as a potential cancer therapeutic. However, the anticancer activity of Vit-C has not been investigated in realistic 3D models of human cancers, especially with respect to breast cancer (BC), and its potential benefits remain under debate. Herein, we investigate the activity and mechanism of action of pharmacological Vit-C on two BC tumor spheroids. Methods We developed two distinct types of BC tumor spheroids from MDA-MB-231 and MCF-7 cells. The spheroids underwent treatment with a range of concentrations of pharmacological Vit-C (1, 5, 10, 15, and 20 mM). Assessments were conducted to determine the cell viability, H2O2 levels, glutathione-to-glutathione disulfide (GSH/GSSG) ratios, and apoptosis. Both flow cytometry analyses of Annexin V/PI staining and caspase3/7 activity assay were used to check apoptosis. Results We showed that Vit-C induced dose-dependent cell death in both types of tumor spheroids, primarily driven by elevated H2O2 production and a concomitant oxidative stress imbalance induced by the GSH depletion. The high levels of H2O2 generated by Vit-C triggered the apoptosis of spheroids. In MCF-7 spheroids, Vit-C-induced H2O2 production was higher, with a more pronounced decrease in the GSH/GSSG ratio, indicating greater susceptibility to oxidative stress-induced cell death. However, MDA-MB-231 spheroids exhibited a more severe cytotoxic response. Conclusions This study reveals that Vit-C induces oxidative stress-mediated cell death in both non-aggressive and aggressive BC spheroids. Unlike traditional in vitro studies, this work provides novel insights into the response of two BC tumor subtypes to Vit-C, demonstrating its potential as a targeted common therapy for BC.https://doi.org/10.1186/s12967-024-06016-7Vitamin CPharmacologyOncologySpheroidsBreast cancerFree radicals |
| spellingShingle | Ali Mussa Mahasin Hamid Khalid Hajissa Ahmad Hafiz Murtadha Mohammad A. I. Al-Hatamleh Noor Fatmawati Mokhtar Vuk Uskoković Magdalena Plebanski Rohimah Mohamud Rosline Hassan Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids Journal of Translational Medicine Vitamin C Pharmacology Oncology Spheroids Breast cancer Free radicals |
| title | Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids |
| title_full | Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids |
| title_fullStr | Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids |
| title_full_unstemmed | Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids |
| title_short | Pharmacological Vitamin C-induced high H2O2 generation mediates apoptotic cell death by caspase 3/7 activation in breast cancer tumor spheroids |
| title_sort | pharmacological vitamin c induced high h2o2 generation mediates apoptotic cell death by caspase 3 7 activation in breast cancer tumor spheroids |
| topic | Vitamin C Pharmacology Oncology Spheroids Breast cancer Free radicals |
| url | https://doi.org/10.1186/s12967-024-06016-7 |
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