Browsing by Author "Alhabib, Ibrahim"

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    Modulating Chemotherapeutic Drug Sensitivity and Counteracting Chemoresistance in Cancer using Frankincense
    (De Montfort University, 2020) Alhabib, Ibrahim
    The development of resistance to chemotherapy is a recurrent and serious problem applicable to many types of cancer including ovarian cancer, which can show intrinsic and acquired resistance to first-line chemotherapy such as platinum-based drugs (e.g. cisplatin, carboplatin) and taxanes (e.g. paclitaxel), and for the anthracyclines (e.g. doxorubicin). Plants have been a source of therapeutic agents for various diseases for thousands of years, the taxanes being an example. Frankincense (from Boswellia sp.) has been used in traditional medicine for centuries. Bioactive components (primarily boswellic acids) responsible for the therapeutic actions of frankincense have been investigated and characterised in many cases, although activity against selected cancer types, ability to synergise with existing therapies and to overcome chemoresistance is not as well explored. The identification of individual components in frankincense that can synergise or otherwise yield unexpected anti-cancer effects may yield useful information that can be exploited for therapy and give additional insight into mechanisms of cancer chemoresistance. This project explores the potential utility and mechanisms of action of 3-O-acetyl-11-keto-β- boswellic acid (AKBA), a bioactive component of frankincense, in counteracting chemoresistance in cancer, using ovarian cancer as the primary model. The work was conducted in vitro using sensitive and resistant ovarian cancer cell lines and a range of cell and molecular biology approaches to determine the effect and mechanisms of action of AKBA on ovarian cancer cells. This included cell viability assay, cell cycle analysis, mitochondrial membrane potential (Δψm) assay (apoptosis) and protein expression analysis to help examine mechanism of action of AKBA. The key finding of this study is the synergistic interaction between AKBA and doxorubicin, which could consequently lead to reduction of doxorubicin dose and the side effects,. The difference between the EC50 values of doxorubicin in the presence or absence of AKBA were statistically significant. Alterations in the Δψm and the inhibition of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway by supressing the expression of multiple proteins seem to be among the mechanisms of action behind the ability of AKBA to sensitise cancer cells to doxorubicin. An apparent antagonistic interaction was reported between AKBA and cisplatin, on A2780, A2780cis and OVCAR4 cells. The same was observed with paclitaxel on A2780cis, however, the resulting interaction on A2780 was additive. Further studies to understand or overcome these antagonistic interactions are required. Despite the limitations, current findings indicate that bioactive components of frankincense could help in overcoming resistance in cancer cells and enhance the efficacy of selected chemotherapy drugs.