Department of Medical Imaging and Clinical Oncology

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Browsing Department of Medical Imaging and Clinical Oncology by Subject "ABT-888 -- Therapeutic use"

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    Evaluation of BCL-2 and PARP-1 as potential therapeutic targets to radiosensitise lung cancer
    (Stellenbosch : Stellenbosch University, 2021-12) Guillaume, Muteba Mpolesha; Akudugu, John M.; Serafin, Antonio M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Nuclear Medicine.
    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.