Evaluation of BCL-2 and PARP-1 as potential therapeutic targets to radiosensitise lung cancer

Guillaume, Muteba Mpolesha (2021-12)

Thesis (MSc)--Stellenbosch University, 2021.

Thesis

ENGLISH SUMMARY : Lung cancer remains the most incident malignancy worldwide, representing 13% of all cancers. It is also the leading cause of death in the world, accounting for 18 18.2% of global cancer-related deaths. The burden of lung cancer in Africa is increasing due to ag ageing an and population growth, increased prevalence of risks factors such as smoking, occupational exposure, infections, lifestyle changes, and environmental pollutants. The efficacy of many therapeutic strategies has been hindered by normal tissue toxicity and treatment resistance. For many cancer patients, radiotherapy has been the chosen therapeutic option to minimise cancer cell spread by shrinking the tumour while ensuring protection of normal tissue. There is evidence that small molecule inhibitor s can effectively target cell survival signa signalling pathways, but cancer cell cells manage to find molecular escape routes to either repair the damage or evade cell death. Combination therapy appears to be an appropriate approach to address these challenges. Therefore, targeting more than one component of the cell survival signa signalling pathways could potentially sensitise cancer cells to irradiation and improve the outcome of radiotherapy. The purpose of this study was to evaluate the role of targeting the anti-apoptotic (B-cell lymphoma 2 (Bcl -2)) pathway and the DNA repair (poly (ADP ADP-ribose) polymerase 1 (PARPPARP-1)) pathway with specific inhibitors in modulating the radiosensitivity of a lung cancer cell line ( and an apparently normal lung cell line ( For this, Bcl -2 and PARP PARP-1 were inhibited using ABT ABT-737 and ABT ABT-888, respectively. At a dose of 2 Gy, the typical fractional dose in conventional radiotherapy, combined inhibition of Bcl-2 and PARP-1 or inhibition of Bcl-2 alone resulted in significant radio-sensitisation in only the A549 cells. However, at a larger radiation dose of 6 Gy (a potentially useful fractional dose in hypo-fractionated radiotherapy), inhibition of Bcl-2 and PARP-1 markedly radio-sensitised the apparently normal (L132) and malignant (A549) cell lines, respectively. These findings suggest that use of Bcl-2 and PARP-1 inhibitors might be beneficial when combined with conventional radiotherapy, but not with hypo-fractionated radiotherapy when large fractional radiation doses are employed. However, validation of these results with a larger panel of cell lines is warranted.

AFRIKAANSE OPSOMMING : Longkanker bly die wêreldwyd mees maligne maligniteit, wat 13% van alle kankersverteenwoordig. Dit is ook die grootste oorsaak van sterftes ter wêreld, wat verantwoordelik is vir 18,2% van die wêreldwye sterftes aan kanker. Die las van longkanker in Afrika neem toe as gevolg van veroudering en bevolkingsaanwas, verhoogde voorkoms van risikofaktore soos rook, blootstelling aan die werk, infeksies, lewenstylveranderinge en omgewingsbesoedeling. Die doeltreffendheid van baie terapeutiese strategieë word belemmer deur normale weefstoksisiteit en behandelingsweerstand. Vir baie kankerpasiënte was radioterapie die gekose terapeutiese opsie om die verspreiding van kankerselle te verminder deur die gewas te laat krimp, terwyl normale weefsel beskerm word. Daar is bewyse dat kleinmolekule kleinmolekule-remmers effektief kan mik op die oorlewingssignale van selle, maar kankerselle slaag daarin om molekulêre ontsnaproetes te vind om die skade te herstel of om die seldood te voorkom. KombinasieKombinasie-terapie blyk 'n gepaste benadering te wees om hierdie uitdagings die hoof te bied. Daarom kan die fokus van meer as een komponent van die seinoorlewings seinweë moontlik kankerselle sensitief maak vir bestraling en die uitkoms van bestraling verbeter. Die doel van hierdie studie was om di e rol van die anti anti-apoptotiese (B B-sel limfoom 2 (BclBcl-2)) pad en die DNA herstel (poly (ADP ADP-ribose) polimerase 1 (PARPPARP-1)) pad met spesifieke inhibeerders te evalueer. in die modulering van die radiosensitiwiteit van 'n longkanker longkanker-sellyn (A549) en 'n skynba ar normale longsellinie (L132). Hiervoor is Bcl -2 en PARP PARP-1 geïnhibeer deur onderskeidelik ABT ABT-737 en ABT ABT-888 te gebruik. By 'n dosis van 2 Gy het die tipiese fraksionele dosis in konvensionele radioterapie, By 'n dosis van 2 Gy het die tipiese fraksionele dosis in konvensionele radioterapie, gekombineerde inhibisie van Bcl-gekombineerde inhibisie van Bcl-2 en PARP2 en PARP-1 of1 of inhibisie van Bcl-inhibisie van Bcl-2 alleen gelei tot 2 alleen gelei tot beduidende radiosensitisering in slegs die A549beduidende radiosensitisering in slegs die A549-selle. By 'n groter bestralingsdosis van 6 Gy selle. By 'n groter bestralingsdosis van 6 Gy ('n potensieel nuttige fraksionele dosis in hipofraktioneerde radioterapie) het die inhibisie van ('n potensieel nuttige fraksionele dosis in hipofraktioneerde radioterapie) het die inhibisie van Bcl -2 en PARPen PARP-1 egter die 1 egter die skynbaar normale (L132) en kwaadaardige (A549) onderskeidelik skynbaar normale (L132) en kwaadaardige (A549) onderskeidelik radiosensitiviseer.radiosensitiviseer. Hierdie bevindings dui daarop dat die gebruik van BclHierdie bevindings dui daarop dat die gebruik van Bcl-2 en PARP2 en PARP-1-remmers voordelig kan remmers voordelig kan wees as dit gekombineer word met konvensionele radioterapie, maar nie met wees as dit gekombineer word met konvensionele radioterapie, maar nie met hipofraktionerende radioterapie wanneer groot fraksionele bestralings dosisse gebruik word nerende radioterapie wanneer groot fraksionele bestralings dosisse gebruik word nie. Validering van hierdie resultate met 'n groter paneel sellyne is egter nodig.nie. Validering van hierdie resultate met 'n groter paneel sellyne is egter nodig.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/123737
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