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Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity
Thesis (MSc)--Stellenbosch University, 2023.
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Stellenbosch : Stellenbosch University
2023
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| access_status_str | Open Access |
| author | Van Leeuwen, Carmen |
| author2 | Sishi, Balindiwe |
| author_browse | Sishi, Balindiwe Van Leeuwen, Carmen |
| author_facet | Sishi, Balindiwe Van Leeuwen, Carmen |
| author_sort | Van Leeuwen, Carmen |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2023. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/129429 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:43:14.822Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/129429 Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity Van Leeuwen, Carmen Sishi, Balindiwe Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Breast -- Cancer Doxorubicin -- Chemotherapy Glycoproteins -- Physiological transport Signal transducing adaptor proteins UCTD Thesis (MSc)--Stellenbosch University, 2023. Van Leeuwen, C. 2023. Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/5574e333-db57-4712-a6d6-aace250dc7f0 ENGLISH ABSTRACT: Introduction: Cancer and cardiovascular diseases (CVDs) are associated with significant mortality rates. Advances in research has, however, enabled the effective treatment of these non-communicable diseases (NCDs). Doxorubicin (DOX), an established anthracycline drug, is able to perform topoisomerase targeting and DNA intercalation in cancer cells. DOX administration, however, is hampered by its ability to induce cardiotoxic development. Previous research has identified oxidative stress as the key mechanism by which DOX exerts its cardiotoxic effect, however, antioxidant therapies have failed to successfully combat the cardiotoxic effect induced by DOX. GP130 signalling is important in maintaining the integrity of cardiac tissue. The failure of GP130 signalling in cardiac tissue has been indicated to result in the pathophysiologic development of cardiac tissue. This study explored the alterations in GP130 signalling to establish its possible contribution to the pathophysiology associated with DOX-induced cardiotoxicity. Methods and Materials: The development of a DOX induced cardiotoxic in vivo model was attempted in this study. Female Sprague Dawley rats (N = 80) received cumulative intraperitoneal DOX injections (2.5 mg/kg/week) over four and eight weeks, respectively. Mammary gland tumours were instilled by injecting LA7 cells. In this study, comparisons were made between groups that included a control, a treatment control (vehicle), a DOX, a tumour, and a combination of the tumour and DOX treatment. The animals were euthanised and blood and cardiac tissue samples were extracted from the rats for molecular and biochemical analysis. ELISA, Western blotting, and histological analysis were utilised along with the empirical data of the animal study to establish the functional and structural changes in the rat cardiac tissue. Results and Discussion: A tumour-bearing model was developed in this study. DOX administration delayed tumour growth in both Tumour groups. Additionally, the four-week Tumour groups demonstrated that DOX administration also halts tumour growth, indicated by a lower peak tumour volume achieved by the Tumour and DOX group (1291.65 ± 290.64 mm3) compared to the Tumour group (1390.00 ± 416.23 mm3). Data from the Tumour groups demonstrated a comparable decrease in tumour volumes between the Tumour group and the Tumour and DOX group. This result confirmed the possibility of investigating early chronic cardiotoxicity in this model. The eight-week DOX group indicated weight gain at a lower rate compared to the control. ELISA analysis demonstrated that an increased concentration of cardiac troponin I (cTnI) was in circulation in the animals of the four-week (186.50 ± 83.66 ng/ml) and eight-week (187.50 ± 83.50 ng/ml) DOX groups compared to the control, illustrating that increased myocardial damage occurred in these treatment groups. Histomorphological analysis of the cardiac samples indicated that moderate tissue degeneration occurred in the cardiac tissue of the DOX and Tumour and DOX groups, from both time points. Western blotting analysis indicated that dysregulation in GP130 signalling occurred during DOX treatment. AFRIKAANSE OPSOMMING: Inleiding: Kanker en kardiovaskulêre siektes is aanspreeklik vir spanning op globale gesondheidstatistieke. Te danke aan uitgebreide navorsing, is die ontwikkeling van effektiewe behandeling van hierdie siektestoestande moontlik. Doksorubisien (DOX) is 'n antrasiklien behandeling wat instaat is om kankerselle te bestry deur om die herstelpoging van DNS-topoisomerase aktiwiteit af te reguleer asook om DNS struktuur te beskadig. Die behandeling van kanker, met DOX, is wel beperk deur die ontwikkeling van kardiotoksisiteit, wat as newe-effek daarmee gepaard gaan. Navorsing in dié veld van studie kon nog nie die oorsaak van kardiotoksiese ontwikkeling, as gevolg van DOX behandeling, bevestig nie. Oksidatiewe stres is een van die hoof voorgestelde teorieë van hoe DOX hartselle beskadig, maar kliniese studies het geopenbaar dat byvoegende anti-oksidant terapie geen merkwaardige verskil in die ontwikkeling van kardiotoksisiteit gemaak het gedurende DOX behandeling nie. GP130 is verantwoordelik vir die onderhoud van sellulêre integriteit van hartselle. Hierdie studie het die effek van DOX behandeling op GP130 intrasellulêre kommunikasie bestudeer. Metodes: 'n Poging was aangewend om die ontwikkeling van 'n DOX-geïnduseerde kardiotoksiese in vivo model vas te stel. Vroulike Sprague-Dawley-rotte (N = 80) was behandel met kumulatiewe intraperitoneale DOX-inspuitings (2.5 mg/kg/week) vir vier en agt weke onderskeidelik. Borsklier gewasse was ontwikkel deur om die rotte in te spuit met LA7-selle. Vyf eksperimentele groepe was bestudeer en sluit in: 'n kontrole groep, 'n draer (kontrole) groep, 'n DOX groep, 'n tumor groep, en 'n kombinasie groep (tumor en DOX). Die rotte was uitgesit en bloedmonsters sowel as hart organe was gekollekteer vir molekulêre en biochemiese analises. Eksperimentele tegnieke insluitend ELISA, Western blotting en histopatologiese analises te same met hart- en liggamsgewig metings was gebruik om die funksionele en strukturele veranderinge in hartweefsel vas te stel. Resultate en bespreking: 'n Tumor model was ontwikkel in die studie. DOX behandeling het tumor ontwikkeling vertraag in albei tumor groepe. Die vier-week tumor groep het ook aangedui dat DOX behandeling tumor ontwikkeling weerhou, waar die kombinasie (tumor en DOX behandeling) groep 'n laer maksimum tumor volume (1291.65 ± 290.64 mm3) behaal het as die tumor groep (1390.00 ± 416.23 mm3). Data het aangedui dat 'n vergelykbare afname in tumor volume plaasgevind het in die tumor en die kombinasie (tumor en DOX behandeling) groepe. Die agt weke DOX groep het 'n laer toename in liggamsgewig aangedui in vergelyking met die res van die behandelingsgroepe. ELISA analise het geopenbaar dat 'n toename in sirkulerende harttroponien I (cTnI) konsentrasie teenwoordig was in die rotte van beide die vier (186.50 ± 83.66 ng/ml) en agt weke (187.50 ± 83.50 ng/ml) DOX groepe. 'n Toename in cTnI konsentrasie dui aan dat hartspier weefsel beskadig is. Histopatologiese analise van die hartweefsel het aangedui dat matige morfologiese hartskade teenwoordig was in die DOX groepe. Western blotting analise het aangedui dat 'n wanregulering in GP130 intrasellulêre kommunikasie teenwoordig was, as gevolg van DOX behandeling. Masters 2023-11-29T08:24:59Z 2024-02-20T11:18:21Z 2023-11-29T08:24:59Z 2024-02-20T11:18:21Z 2023-09 Thesis https://scholar.sun.ac.za/handle/10019.1/129429 en_ZA Stellenbosch University xi, 145 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Breast -- Cancer Doxorubicin -- Chemotherapy Glycoproteins -- Physiological transport Signal transducing adaptor proteins UCTD Van Leeuwen, Carmen Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title | Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title_full | Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title_fullStr | Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title_full_unstemmed | Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title_short | Understanding the role of GP130 signalling during chemotherapy-induced cardiotoxicity |
| title_sort | understanding the role of gp130 signalling during chemotherapy induced cardiotoxicity |
| topic | Breast -- Cancer Doxorubicin -- Chemotherapy Glycoproteins -- Physiological transport Signal transducing adaptor proteins UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/129429 |
| work_keys_str_mv | AT vanleeuwencarmen understandingtheroleofgp130signallingduringchemotherapyinducedcardiotoxicity |