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The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer
Thesis (PhD)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2026
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| _version_ | 1867613868381962240 |
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| access_status_str | Open Access |
| author | Van Heerden, Elizka |
| author2 | Engelbrecht, Anna-Mart |
| author_browse | Engelbrecht, Anna-Mart Van Heerden, Elizka |
| author_facet | Engelbrecht, Anna-Mart Van Heerden, Elizka |
| author_sort | Van Heerden, Elizka |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134851 |
| institution | Stellenbosch University (South Africa) |
| last_indexed | 2026-06-10T12:42:59.065Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2026 |
| publishDateRange | 2026 |
| publishDateSort | 2026 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134851 The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer Van Heerden, Elizka Engelbrecht, Anna-Mart Kaschula, Catherine H. Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Colon (Anatomy) -- Cancer -- Chemotherapy Garlic -- Therapeutic use Phytochemicals Thesis (PhD)--Stellenbosch University, 2025. Van Heerden, E. 2025. The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/4bed8ef5-3905-4a1a-ba4a-4d85b328f46f ENGLISH ABSTRACT: Introduction Despite being a first-line chemotherapeutic for colorectal cancer (CRC), the success of 5-fluorouracil (5-FU) is limited by off-target toxicity, systemic side effects, and drug resistance. As a result, there has been interest in identifying agents to enhance its therapeutic potential. Novel adjunctive therapies such as phytopharmaceuticals are gaining attention due to their bioactive properties and lower toxicity profiles. In recent years, garlic has emerged as a promising candidate due to its potential anti-cancer attributes. Yet, no research has delved into the possible synergism between 5-FU and garlic extract in CRC. Hence, their combined interaction as an innovative therapy for CRC with targeted examination of inflammation, epithelial-to-mesenchymal transition (EMT), and ferroptotic cell death mechanisms were assessed in in vitro and in vivo CRC models. Materials and methods For the in vitro model of our study, colorectal cancer (CRC) cell lines (HCT-116, Caco-2) and a normal human embryonic kidney epithelial cell line (HEK293) were treated with 5-FU, garlic extract, and Z-ajoene, an organosulfur compound (OSC) found in garlic. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to assesscell viability and determine IC₅₀ values. We further evaluated the preferential cytotoxicity of the treatments and subsequently determined the presence and concentrations of synergistic effects. To evaluate for markers of proliferation, EMT, and ferroptosis, Western blots were performed. To further strengthen our results, a scratch assay was performed to determine migration potential, while a clonogenic assay was performed to assess colony formation potential. After ethical approval was obtained from Stellenbosch University (ACU-2024-30779), for the in vivo model of the study, 50 male C57BL/6 mice were used in a colitisassociated cancer (CAC) model induced by the azoxymethane/dextran sulfate sodium (AOM/DSS) model. Following completion of the second DSS cycle, mice were treated for four weeks with 5-FU (50 mg/kg, once weekly) and/or garlic oil (50 mg/kg, three times per week). At the end of the treatment period, the animals were euthanized at week 11. Furthermore, histopathological analysis, colon length measurement, tumor count, and inflammatory marker analysis was performed. Cell proliferation, EMT, and ferroptosis markers were also assessed in the colonic tumors using Western blots. Results We demonstrated that co-treatment with 5-FU and garlic, as either an extract or a pure compound, acted in synergy to enhance cancer cell death with minimal effect on the normal cells in vitro. Western blots revealed that the combination treatment synergistically decreased mesenchymal markers and increased epithelial markers, accompanied by a decrease in cell migration. We also observed that ferroptosis could be a possible method of cell death in CRC cells through increased lipid peroxidation via downregulation of the SLC7A11-GSH-GPX4 axis. Furthermore, our in vivo model revealed that co-treatment successfully decreased the degree of inflammation and attenuated disease severity in CAC. Conclusion In this study, we found for the first time, in an in vitro and in vivo model, that co-treatment of 5-FU with garlic extracts or pure compounds was able to increase ferroptotic cell death and decrease proliferation, inflammation, and metastatic potential of CRC in a synergistic manner. This proof-of-concept provides a rationale for further investigation into a combination-based approach to allow for reduced chemotherapeutic dosing to ultimately enhance patient outcome and quality of life. AFRIKAANSE OPSOMMING: Inleiding Ten spyte daarvan dat 5-fluorourasiel (5-FU) ’n eerstelyn-chemoterapiebehandeling vir kolorektalekanker (KRK) is, word die sukses daarvan beperk deur buite-teiken toksisiteit, sistemiese newe-effekte en geneesmiddelweerstand. Gevolglik is daar toenemende belangstelling om middels te identifiseer wat die terapeutiese potensiaal daarvan kan verbeter. Nuwe aanvullende terapieë, soos fitofarmaseutiese middels, trek toenemend aandag weens hul bioaktiewe eienskappe en laer toksisiteitsprofiele. In die afgelope jare het knoffel na vore getree as ’n belowende kandidaat vanweë sy moontlike teen-kanker eienskappe. Tog is daar nog geen navorsing wat die moontlike sinergisme tussen 5-FU en knoffelekstrak in KRK ondersoek het nie. Daarom is die gekombineerde interaksie as ’n innoverende terapie vir KRK geëvalueer, met ’n doelgerigte ondersoek op inflammasie, epiteel-na-mesenkiemale oorgang (EMT) en ferroptotiese seldood-meganismes in in vitro en in vivo KRK modelle. Materiaal en Metodes Vir die in vitro-model van ons studie was KRK sellelyne (HCT-116, Caco-2) en ’n normale menslike embrioniese nier-epiteelsellyn (HEK293) behandel met 5-FU, knoffelekstrak en Zajoene, ’n organoswaelverbinding (OSV) wat in knoffel voorkom. ’n MTT-toets was uitgevoer om sel-lewensvatbaarheid te bepaal en IC₅₀-waardes vas te stel. Ons het verder die voorkeursitotoksisiteit van die behandelinge geëvalueer en die aanwesigheid en konsentrasies van sinergistiese effekte bepaal. Om merkers van proliferasie, EMT en ferroptose te evalueer, was Western blots uitgevoer. Om ons resultate te versterk, was ’n migrasietoets uitgevoer om migrasiepotensiaal te bepaal, terwyl ’n klonogeniese toets gedoen was om kolonievormingsvermoë te evalueer. Nadat etiese goedkeuring van die Universiteit Stellenbosch verkry was (ACU-2024-30779), was die in vivo-model van die studie uitgevoer met 50 manlike C57BL/6-muise in ’n kolitis-geassosieerde kanker (KGK)-model wat met die asoksimetaan/dekstraansulfaatnatrium (AOM/DSS)-model geïnduseer was. Na voltooiing van die tweede DSS-siklus was muise vir vier weke behandel met 5-FU (50 mg/kg, een keer per week) en/of knoffelolie (50 mg/kg, drie keer per week). Aan die einde van die behandelingsperiode was die diere in week 11 getermineer. Histopatologiese analises kolonlengte-metings, gewastelling en ontleding van inflammatoriese merkers was uitgevoer. Selproliferasie, EMT- en ferroptose-merkers was ook in die kolongewasse ondersoek deur middel van Western blots. Resultate Ons het getoon dat gesamentlike behandeling met 5-FU en knoffel, hetsy as ’n ekstrak of ’n suiwer verbinding, in sinergie opgetree het om gewasseldood te verhoog met minimale effek op normale selle in vitro. Western blots het onthul dat die kombinasiebehandeling mesenkiemale merkers sinergisties verlaag en epiteelmerkers verhoog het, tesame met ’n afname in selmigrasie. Ons het ook waargeneem dat ferroptose ’n moontlike meganisme van seldood in KRK selle kan wees deur verhoogde lipiedperoksidasie via die afregulering van die SLC7A11-GSH-GPX4-as. Verder het ons in vivo-model getoon dat gesamentlike behandeling die graad van inflammasie suksesvol verlaag en die erns van die siekte in KGK verminder het. Gevolgtrekking In hierdie studie het ons vir die eerste keer, in beide in vitro- en in vivo-modelle, bevind dat gesamentlike behandeling van 5-FU met knoffelekstrak of suiwer verbindings in staat was om ferroptotiese seldood te verhoog, asook proliferasie, inflammasie en metastatiese potensiaal van KRK op ‘n sinergistiese manier te verminder. Hierdie konsep-bewys bied ’n grondslag vir verdere ondersoeke na ’n kombinasie-gebaseerde benadering om laer dosisse chemoterapie moontlik te maak en uiteindelik pasiëntuitkomste en lewenskwaliteit te verbeter. Doctoral 2026-01-12T13:48:49Z 2026-01-12T13:48:49Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134851 Stellenbosch University xxv, 154 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Colon (Anatomy) -- Cancer -- Chemotherapy Garlic -- Therapeutic use Phytochemicals Van Heerden, Elizka The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title | The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title_full | The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title_fullStr | The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title_full_unstemmed | The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title_short | The anti-cancer role of Allium sativum L. in combination with the chemotherapeutic agent, 5-fluorouracil, in colon cancer |
| title_sort | anti cancer role of allium sativum l in combination with the chemotherapeutic agent 5 fluorouracil in colon cancer |
| topic | Colon (Anatomy) -- Cancer -- Chemotherapy Garlic -- Therapeutic use Phytochemicals |
| url | https://scholar.sun.ac.za/handle/10019.1/134851 |
| work_keys_str_mv | AT vanheerdenelizka theanticancerroleofalliumsativumlincombinationwiththechemotherapeuticagent5fluorouracilincoloncancer AT vanheerdenelizka anticancerroleofalliumsativumlincombinationwiththechemotherapeuticagent5fluorouracilincoloncancer |