Introduction: Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored.
Methods: The effect of seven dietary phytochemicals, quercetin (0-100 μM), curcumin (0-80 μM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0-200 μM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue assay.
Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of sensitising tumour cells to therapeutic agents. βIII-tubulin is associated with aggressive tumours and chemotherapy resistance in a range of cancers including NSCLC.
View Article and Find Full Text PDFPatients whose leukemias harbor a rearrangement of the (/) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target -rearranged (KMT2A-r) leukemia cells.
View Article and Find Full Text PDFBackground: The development of high-throughput drug screening (HTS) using primary cultures provides a promising, clinically translatable approach to tailoring treatment strategies for patients with cancer. However, this has been challenging for solid tumors because of often limited amounts of tissue available. In most cases, in vitro expansion is required before HTS, which may lead to overgrowth and contamination by non-neoplastic cells.
View Article and Find Full Text PDFDiffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease.
View Article and Find Full Text PDFBackground: Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency.
Methods: PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis.
A series of 3-aryl-5,7-dimethoxyquinolin-4-ones 8 and 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones 13 were synthesized in good yields. Demethylation under a range of conditions afforded the corresponding 5-hydroxy and 5,7-dihydroxy derivatives. Biological evaluation against a range of cancer cells lines showed that the quinolin-4-one scaffold was more cytotoxic than the reduced 2,3-dihydroquinolin-4-one scaffold.
View Article and Find Full Text PDFCo-crystallisation of diphenyl phosphate (Hdpp) with anticancer active Pt(IV) complexes of the type cis,trans,cis-[PtCl(2)(OH)(2)(am(m)ine)(2)] has produced a new type of supramolecular adduct with short hydrogen bonds from the Hdpp molecules to the hydroxide ligands in all cases. X-ray crystallographic analysis showed within the adduct cis,trans-[PtCl(2)(en)(OH(2))(2)](dpp)(2) (1) a hydrogen bond length of 2.341(6) Å; the shortest O ··· O distance reported in the literature.
View Article and Find Full Text PDFAurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439.
View Article and Find Full Text PDFThe development of complexes that allow the monitoring of the release and distribution of fluorescent models of anticancer drugs initially bound to cobalt(III) moieties is reported. Strong quenching of fluorescence upon ligation to cobalt(III) was observed for both the carboxylate- and the hydroximate-bound fluorophores as was the partial return of fluorescence following addition of ascorbate and cysteine. The extent of the increase in the fluorescence intensity observed following addition of these potential reductants is indicative of the fluorophore being displaced from the complex by the action of ascorbate or cysteine, by ligand exchange.
View Article and Find Full Text PDFThe potential for cobalt(III) complexes in medicine, as chaperones of bioactive ligands, and to target tumours through bioreductive activation, has been examined over the past 20 years. Despite this, chemical properties such as reduction potential and carrier ligands required for optimal tumour targeting and drug delivery have not been optimised. Here we review the chemistry of cobalt(III) drug design, and recent developments in the understanding of the cellular fate of these drugs.
View Article and Find Full Text PDFFe(III)-salen (N,N-bis(salicylidene)-ethane-1,2-diimine) complexes of simple hydroxamic acids and the MMP (matrix metalloproteinase) inhibitor marimastat have been evaluated as hypoxia activated drug carriers. The aceto- (aha), propion- (pha), benzohydroxamato (bha), and marimastat complexes were prepared and characterised by single crystal X-ray diffraction and electrochemical analysis. The hydroxamato ligands form a bidentate chelate to Fe(III) with the remaining octahedral coordination sites occupied by the tetradentate salen ligand.
View Article and Find Full Text PDFWe report a potential means of selectively delivering matrix metalloproteinase (MMP) inhibitors to target tumour sites by use of a bioreductively activated Co(III) carrier system. The carrier, comprising a Co(III) complex of the tripodal ligand tris(methylpyridyl)amine (tpa), was investigated with the antimetastatic MMP inhibitor marimastat (mmstH(2)). The X-ray crystal structure of [Co(mmst)(tpa)]ClO(4) x 4H(2)O was determined and two-dimensional NMR revealed the existence of two isomeric forms of the complex in solution.
View Article and Find Full Text PDFCo(III) complexes of simple hydroxamic acids have been evaluated as models of hypoxia activated prodrugs containing MMP inhibitors. The complexes are based upon a proposed carrier system comprising the tripodal tetradentate ligand tris(2-methylpyridyl)amine (tpa) with the hydroxamate functionality occupying the remaining coordination sites of the Co centre. Acetohydroxamato (aha), propionhydroxamato (pha), and benzohydroxamato (bha) complexes were synthesised and characterised by single crystal X-ray diffraction.
View Article and Find Full Text PDFComplexes of salicylhydroxamic acid (shaH) with palladium(II) and platinum(II) were investigated. The synthesis of [Pt(sha)(2)] was attempted via a number of methods, and ultimately (1)H NMR investigations revealed that salicylhydroxamate would not coordinate to chloro complexes of platinum(II). However, [Pt(sha-H)(PPh(3))(2)] was successfully synthesized and the crystal structure determined (orthorhombic, space group Pca2(1) a = 17.
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