PLGA-DS reverses chemoresistance in malignant mesothelioma by targeting hypoxia induced cancer stem cells
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AbstractBackground: Malignant Mesothelioma (MM) is a malignancy related to asbestos exposure which causes a wide variety of molecular aberrations. MM has a very dismal treatment outcome with an overall survival of fewer than 12 months, with less than five drugs available for its treatment. MM recurrence is unavoidable due to chemoresistance. Long-term inflammation triggered by asbestos activates a key transcription factor, nuclear factor-κB (NF-κB), which is further upregulated in cancer stem cells (CSCs) by hypoxia. Both hypoxia and NF-κB pathway plays a pivotal role in the maintenance of stemness in hypoxia-induced CSCs leading to upregulation of anti-apoptotic signalling, chemo-radiation resistance and metastasis. Therefore, the development of drugs targeting hypoxia-NF-κB-CSCs axis is of clinical significance for MM treatment. Our previous studies have shown that Disulfiram (DS), a clinically used anti-alcoholism drug, in combination with Copper (II) (Cu) has substantial toxicity in CSCs in a wide range of cancer types. The clinical application of DS in Cancer is limited by its very short half-life (< 2 minutes) in the bloodstream. MM is Cancer which mainly infiltrates local organs and tissues with rare distant metastasis. Considering this growing feature of MM, we developed a biodegradable and controlled released poly (lactic-co-glycolic acid) microparticle-encapsulate disulfiram (PLGA-DS) for local treatment of MM. This study aims to examine the anti-MM effect of PLGA-DS and elucidate its molecular mechanisms. Methodologies: In order to determine drug sensitivity, stemness, apoptosis, invasiveness and NFκB status, the following methodologies were performed in this study: MTT cytotoxicity assay, flow cytometry, analysis of CSC markers, hypoxic cell cultures, western blot, stable transfection of MM cell line with NFκB, CRISPR-Cas9 knock out of NF-kB-p65, CSC sphere reformation, invasion and migration assay. Results and conclusions: Two MM cell lines were examined and cultured in a hypoxic environment. MM cell lines were highly resistant to Pemetrexed (PMT) and Cisplatin (CIS), the first-line chemotherapeutic agents for MM. Hypoxia cultured MM cells showed high NF-κB activity and CSC markers and manifested strong migration/invasion ability. The NF-κB-p65 over expressed transfected cell lines did not demonstrate CSC traits along with no increase in resistance to first line drugs. PLGA-DS/Cu completely abolished CSC population in a culture which is demonstrated by sphere reformation assays and flow cytometry analysis of CSC markers such as CD24, CD133 and ABCG2. PLGA-DS/Cu also inhibited the hypoxiainduced NF-kB expression and blocked the migration and invasion ability of MM cells. It showed substantial toxicity to MM cell lines and reversed hypoxia-induced chemoresistance. Also, PLGA-DS/Cu potentiated the cytotoxic effect of Cisplatin/Pemetrexed in vitro. Isobologram analysis indicates moderate synergistic effect between PLGA-DS and cisplatin and pemetrexed in MSTO 211 and JU77 cell lines, respectively. As an FDA approved a drug with all preclinical safety data available, further studies may quickly translate it into MM clinical treatment. This is very promising in vitro data and indicate that PLGA-DS could be a promising formulation for localised MM treatment.
PublisherUniversity of Wolverhampton
TypeThesis or dissertation
DescriptionA thesis submitted in fulfilment of the requirement of the University of Wolverhampton for the degree Master of Philosophy.
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