Surgery (RMH) - Research Publications
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ItemRepurposing FDA-approved drugs as inhibitors of therapy-induced invadopodia activity in glioblastoma cells(SPRINGER, 2023-06-01)Glioblastoma (GBM) is the most prevalent primary central nervous system tumour in adults. The lethality of GBM lies in its highly invasive, infiltrative, and neurologically destructive nature resulting in treatment failure, tumour recurrence and death. Even with current standard of care treatment with surgery, radiotherapy and chemotherapy, surviving tumour cells invade throughout the brain. We have previously shown that this invasive phenotype is facilitated by actin-rich, membrane-based structures known as invadopodia. The formation and matrix degrading activity of invadopodia is enhanced in GBM cells that survive treatment. Drug repurposing provides a means of identifying new therapeutic applications for existing drugs without the need for discovery or development and the associated time for clinical implementation. We investigate several FDA-approved agents for their ability to act as both cytotoxic agents in reducing cell viability and as ‘anti-invadopodia’ agents in GBM cell lines. Based on their cytotoxicity profile, three agents were selected, bortezomib, everolimus and fludarabine, to test their effect on GBM cell invasion. All three drugs reduced radiation/temozolomide-induced invadopodia activity, in addition to reducing GBM cell viability. These drugs demonstrate efficacious properties warranting further investigation with the potential to be implemented as part of the treatment regime for GBM.
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ItemNo Preview AvailableThe renin-angiotensin system in central nervous system tumors and degenerative diseases(IMR PRESS, 2021-09-30)Despite their differences, central nervous system (CNS) tumors and degenerative diseases share important molecular mechanisms underlying their pathologies, due to their common anatomy. Here we review the role of the renin-angiotensin system (RAS) in CNS tumors and degenerative diseases, to highlight common molecular features and examine the potential merits in repurposing drugs that inhibit the RAS, its bypass loops, and converging signaling pathways. The RAS consists of key components, including angiotensinogen, (pro)renin receptor (PRR), angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (AT1R), ATII receptor 2 (AT2R) and the Mas receptor (MasR). The RAS is integral to systemic and cellular pathways that regulate blood pressure and body fluid equilibrium and cellular homeostasis. The main effector of the RAS is ATII which exerts its effect by binding to AT1R and AT2R through two competitive arms: an ACE1/ATII/AT1R axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/AT2R and/or ATII/ACE2/Ang(1-7)/MasR axis that potentiates neuroprotection pathways. Alterations of these axes are associated with cellular dysfunction linked to CNS diseases. The generation of ATII is also influenced by proteases that constitute bypass loops of the RAS. These bypass loops include cathepsins B, D and G and chymase and aminopeptidases. The RAS is also influenced by converging pathways such as the Wnt/β-catenin pathway which sits upstream of the RAS via PRR, a key component of the RAS. We also discuss the co-expression of components of the RAS and markers of pluripotency, such as OCT4 and SOX2, in Parkinson's disease and glioblastoma, and their potential influences on transduction pathways involving the Wnt/β-catenin, MAPK/ERK, PI3K/AKT and vacuolar (H+) adenosine triphosphatase (V-ATPase) signaling cascades. Further research investigating modulation of the ACE1/ATII/AT1R and ACE2/Ang(1-7)/MasR axes with RAS inhibitors may lead to novel treatment of CNS tumors and degenerative diseases. The aim of this review article is to discuss and highlight experimental and epidemiological evidence for the role of the RAS, its bypass loops and convergent signaling pathways in the pathogenesis of CNS tumors and degenerative diseases, to direct research that may lead to the development of novel therapy.
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ItemExtracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression(MDPI, 2022-03)Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs' specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.
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ItemInhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs(MDPI, 2020-10)Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy.
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ItemTherapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System(MDPI, 2019-11)Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection and adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs can be identified by embryonic stem cell markers, express components of the renin-angiotensin system (RAS) and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB patients rarely develop distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the RAS to improve overall symptom-free survival and maintain quality of life.
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ItemEVALUATION OF TUMOR AND TISSUE DISTRIBUTION OF PORPHYRINS FOR USE IN PHOTODYNAMIC THERAPY(CHURCHILL LIVINGSTONE, 1992-03)A range of pure, monomeric porphyrins were synthesised and their localising capacities compared to HpD and Hp at 6 h and 24 h post injection in the mouse C6 intracerebral glioma model as well as in normal brain, skin, muscle, kidney, spleen, liver, lung and whole blood. The partition coefficients were examined between PBS and 2-octanol over the pH range 7.4-6.6 and pH profiles were established. A parabolic relationship was observed between log (porphyrin tumour concentration) at pH 7.4, with maximal tumour localisation at log (partition coefficient), pi, of approximately zero. Porphyrins with side chains with nett cationic character also exhibited up upward (parabolic) dependence on pi for most tissues studied, with maximal porphyrin localisation at pi of 0-0.5. In contrast, those porphyrins with nett anionic character exhibited a downward (negative) parabolic trend for all eight tissues studied, with minimal porphyrin localisation at pi of approximately zero. Four porphyrins (4, 11, 12, 13) exhibited similar or better tumour localisation than HpD, and two (11 and 12) offer promise as lead compounds for the design of improved porphyrins for use in PDT.
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ItemEVALUATION OF A MORPHOLINOTHIOLPORPHYRIN FOR USE IN PHOTODYNAMIC THERAPY(STOCKTON PRESS, 1994-09)The photonecrotic effectiveness of a morpholinothiolporphyrin derived from haematoporphyrin was measured in an animal model of cerebral glioma. The dose administered was 20 mg kg-1 and the laser dose varied from 0 to 200 J cm-2. The tumour necrosis was at least as good as that of HpD, and this therapeutic response may be attributed to the targeting of specific 'photopotent' subcellular sites.
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ItemEvaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma(NATURE PUBLISHING GROUP, 1996-02)A series of monomeric porphyrins (2-8) based on porphyrin C (1) have been tested as sensitisers for photodynamic therapy (PDT) of cerebral glioma using the in vitro/in vivo C6 intracerebral animal tumour model. The in vivo screening, consisting of cytotoxicity, phototoxicity (red light) and subcellular localisation studies, revealed two sensitisers (porphyrin 7, molecular weight 863 Da and porphyrin 8, molecular weight 889 Da), which had greater photoactivity than porphyrin C and similar photoactivity to haematoporphyrin derivative (HpD) although at a 5-fold higher dose than HpD. Both sensitisers showed intracellular localisation to discrete organelle sites and exhibited considerably less 'dark' cytotoxicity than HpD. The kinetics of uptake of porphyrins 7 and 8 was studied in the mouse C6 glioma model as well as in biopsy samples from normal brain, liver, spleen and blood. Maximal drug uptake levels in tumour occurred 9 and 6 h after intraperitoneal injection for 7 and 8 respectively, at which time the tumour to normal brain ratios were 15:1 and 13:1 respectively. The effect of PDT using porphyrin 7 activated by the gold metal vapour laser tuned to 627.8 nm was studied in Wistar rats bearing intracerebral C6 glioma. At a drug dose of 10 mg porphyrin 7 kg-1 body weight and laser doses of up to 400 J cm-2 light, selective tumour kill with sparing of normal brain was achieved, with a maximal depth of tumour kill of 1.77+/-0.40. mm. Irradiation following a higher drug dose of 75 mg porphyrin 7 kg-1 body weight resulted in a greater depth of tumour kill, but also significantly increased the likelihood and extent of necrosis in normal brain.
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ItemA comprehensive meta-analysis of circulation miRNAs in glioma as potential diagnostic biomarker(PUBLIC LIBRARY SCIENCE, 2018-02-14)Glioma is the most common malignant intracranial tumour. Recently, several publications have suggested that miRNAs can be used as potential diagnostic biomarkers of glioma. Here we performed a meta-analysis to identify the diagnostic accuracy of differentially expressed circulating miRNAs in gliomas. Using PubMed, Medline and Cochrane databases, we searched for studies which evaluated a single or panel of miRNAs from circulating blood as potential biomarkers of glioma. Sixteen publications involving 23 studies of miRNAs from serum or plasma met our criteria and were included in this meta-analysis. The pooled diagnostic parameters were calculated by random effect models and overall diagnostic performance of altered miRNAs was illustrated by the summary receiver operator characteristic (SROC) curves. The pooled sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) from each study were calculated. The pooled PLR, NLR and Diagnostic Odds Ratio were 6.39 (95% CI, 4.61-8.87), 0.15 (95% CI, 0.11-0.21) and 41.91 (95% CI, 23.15-75.88), respectively. The pooled sensitivity, specificity and area under the curve (AUC) were 0.87 (95% CI, 0.82-0.91), 0.86 (95% CI, 0.82-0.90) and 0.93 (95% CI, 0.91-0.95), respectively. This meta-analysis demonstrated that circulating miRNAs are capable of distinguishing glioma from healthy controls. Circulating miRNAs are promising diagnostic biomarkers for glioma and can potentially be used as a non-invasive early detection.
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ItemThe role of interleukin-6-STAT3 signalling in glioblastoma(SPANDIDOS PUBL LTD, 2018-10)Glioblastoma is the most common type of malignant brain tumor among adults and is currently a non-curable disease due primarily to its highly invasive phenotype, and the lack of successful current therapies. Despite surgical resection and post-surgical treatment patients ultimately develop recurrence of the tumour. Several signalling molecules have been implicated in the development, progression and aggressiveness of glioblastoma. The present study reviewed the role of interleukin (IL)-6, a cytokine known to be important in activating several pro-oncogenic signaling pathways in glioblastoma. The current study particularly focused on the contribution of IL-6 in recurrent glioblastoma, with particular focus on glioblastoma stem cells and resistance to therapy.