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From Drug Efflux to the Liver X Receptor: Investigations into Novel Methods to Protect Against Chemotherapy-Induced Alopecia
[Thesis]. Manchester, UK: The University of Manchester; 2020.
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Abstract
Chemotherapy-induced alopecia (CIA) is one of the most distressing side effects of cancer treatment. Despite this, there are currently no pharmacological interventions available and there is therefore an urgent need to identify new targets for therapy. It has been previously hypothesised that increasing drug transport out of the hair follicle (HF) could render human scalp HFs resistant to chemotherapy. Recently, it was demonstrated that human scalp HFs express many different members of the ATP-binding cassette (ABC) superfamily, which efflux a wide variety of chemotherapeutic agents from diverse cell types. However, their role in mediating HF resistance to chemotherapy remains unexplored.The primary aim of this study was to investigate the role of ABC transporter expression and activity in the HF as a novel mechanism for protecting against chemotherapy-induced damage and subsequent hair loss.Firstly, this study showed that inhibition of ABCB1 in human HFs ex vivo sensitizes HFs to damage by both 4-hydroxycyclophosphamide (4HC) and Doxorubicin (DOX). Not only does this study indicate that ABCB1 has a role in protecting the human HF from chemotherapy-induced damage, but it also adds to the growing indirect evidence that 4HC is a substrate of ABCB1. Next, outer root sheath (ORS) keratinocytes were examined as a HF-relevant primary cell model to screen for ABC transporter inducing compounds. T0901317 (a LXR agonist), lopinavir (a protease inhibitor) and dexamethasone (a glucocorticoid receptor agonist), increased ABC transporter activity, significantly increased cell survival and attenuated apoptosis on exposure to DOX. T0901317, but not lopinavir, showed a trend towards protection of human HFs ex vivo from DOX-induced apoptosis. However, the protective effect of T0901317 could not be modified by inhibition of ABC transporter activity, which indicated an ABC-independent mechanism of protection. Therefore, the mechanism of protection of ORS keratinocytes from DOX was investigated by RNA-sequencing. It was found that T0901317 exerted protection in a multifaceted manner, including the modulation of fatty acid synthesis, DNA repair and key signalling pathway modulation (NFκB and MAPK). This study showed that despite ABCB1 modulating chemotherapy-induced damage to the human HF, its transcription could not be significantly increased in culture. However, the LXR agonist T0901317 protected primary ORS keratinocytes and human HFs ex vivo from DOX-induced toxicity, through the modulation of DNA double strand break repair and fatty acid synthesis.