ORCID Profile
0000-0002-2937-6736
Current Organisations
Macquarie University
,
The University of Newcastle
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Publisher: Springer Science and Business Media LLC
Date: 02-2002
Abstract: Cantharidin (Spanish Fly) is a natural toxin and an inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A), which have key roles in cell cycle progression. We have synthesised two series of demethylated cantharidin analogues, one displaying an open-ring lactone configuration in solution (Novo-1 to Novo-5) similar to cantharidin, the other showing a closed-ring lactone configuration (Novo-6 to Novo-10). In the present study, these ten agents were screened for in vitro PP1 and PP2A inhibition and cellular cytotoxicity in nine cancer cell lines of haematopoietic (L1210, HL60), ovarian (A2780, ADDP), osteo (143B), and colon (HCT116, HT29, WiDr, SW480) origin and one normal colon cell line (CCD-018). The open-ring series (IC50, PPI=2.0-4.8 microM, PP2A=0.2-0.5 microM) maintained the PP2A selectivity of cantharidin (IC50, PPI=1.8 microM, PP2A=0.2 microM), although some were less potent. The closed-ring series (IC50, PPI=12.5->1000 microM, PP2A=5->1000 microM) were considerably less potent inhibitors, confirming the need of ring opening for inhibition. The cytotoxicity (IC50, 72 h, MTT assay) of cantharidin ranged from 6-15 microM, while the new analogues ranged from 14 to >1000 microM. Cytotoxicity of the agents did not consistently parallel the in vitro potency of protein phosphatase inhibition. A number of analogues showed colon cancer selectivity, particularly Novo-6, where the cytotoxicity ranged from 14-88 microM in the colon cancer cells and 275-680 microM in all other cell lines including normal colon cells. The reason for this selectivity was not apparent and may involve additional intracellular targets. Cell cycle analysis showed cantharidin to enhance cell cycle progression as evident from an increased S-phase population and enhanced DNA synthesis, culminating in G2/M arrest and apoptosis. With Novo-1 and Novo-6, the cell cycle changes paralleled the cytotoxicity responses, with the predominant effect of G2/M cell cycle arrest followed by cell death. In conclusion, we have synthesised new anticancer agents that show selective cytotoxicity in colon cancer cells while remaining inactive in normal colon cells, and which mediate their effects via the G2/M phase of the cell cycle.
Publisher: Bond University
Date: 08-01-2020
DOI: 10.53300/001C.11636
Abstract: The Australian Financial Services Reform Act 2001 (Cth) requires that licenced banking and financial services providers establish internal dispute resolution (‘IDR’) systems complying with requirements promulgated by the Australian Securities and Investments Commission (‘ASIC’). In addition, licence holders are required to be members of an ASIC approved External Dispute Resolution (‘EDR’) scheme so that if a complaint is not resolved following the use of internal mechanisms, an external dispute resolution facility is available for most banking consumers. In late 2018, a new EDR body was established, the Australian Financial Complaints Authority (‘AFCA’), to deal with external complaints. The 2018 Royal Commission into the banking and finance sector uncovered significant issues in terms of the banking and financial sector and raised a number of serious concerns that were largely linked to how consumers contracted with banks and other organisations however information about existing complaint handling arrangements was limited. In particular, there was little demographic information about consumers who use IDR and EDR arrangements or what factors may be relevant in terms of the settlement of complaints and disputes. In this regard, currently sections 912A(1)(g), (2) of the Corporations Act direct the form of AFSL holders’ IDR and EDR systems, but they do not impose any obligations on AFSL holders in terms of conduct when providing the systems. In terms of consumers more generally, it is unclear how many consumers could be classified as ‘vulnerable’ and may settle a dispute on less favourable terms because the impact of proceeding may place them in an even more disadvantageous position. It is suggested that better reporting in relation to IDR and EDR activity together with targeted independent advocacy services and training of relevant staff in respect of the Australian Consumer Law could assist consumers and enable more effective reporting of misconduct issues.
Publisher: Westburn Publishers
Date: 03-2019
Publisher: Elsevier BV
Date: 10-2000
DOI: 10.1016/S0223-5234(00)00186-0
Abstract: A series of anhydride modified cantharidin analogues have been synthesised and screened for their ability to inhibit protein phosphatase 2A. Surprisingly only analogues capable of undergoing a facile ring opening of the anhydride moiety displayed any significant inhibition. Subsequent NMR experiments indicated that 7-oxobicyclo[2.2.1]heptane-2,3-dicarboxylic acid was the major (sole) species under assay conditions. The ability of these modified anhydro-cantharidin analogues to inhibit protein phosphatase 2A varies from 4 (16) to 100% (8) at 100 microM test concentration.
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1016/S0960-894X(01)00777-6
Abstract: High pressure Diels-Alder reactions of furan and dimethylmaleate, and thiophene and maleimide resulted in two cantharidin analogues, 3 and 6 possessing PP1 selectivity (>40- and >30-fold selectivity) over PP2A. Both compounds exhibited moderate PP1 activity, 3 IC(50) 50 microM and 6 IC(50) 12.5 microM. Interestingly, the corresponding mono-ester derivatives of 3 showed no such selectivity.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2017
Publisher: Informa UK Limited
Date: 09-04-2017
Publisher: CRC Press
Date: 15-04-2017
No related grants have been discovered for Mirella Atherton.