Selwyn F. Mapolie

A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy

Malignant melanoma is an aggressive skin cancer and it is reported to be the most treatment-resistant human cancer. Here we describe the anti-tumour activity of a novel binuclear palladacycle complex (AJ-5) in vertical growth phase (ME1402) and metastatic (WM1158) melanoma cell lines. We show that compared to normal control cell lines, AJ-5 is more effective in inhibiting the proliferation of ME1402 and WM1158 melanoma cells with IC50 values of 0.19 and 0.20μM, respectively. Flow cytometry analyses showed that AJ-5 induced apoptosis (sub-G1 peak) which was confirmed by Annexin V-FITC/propidium iodide double-staining, nuclear fragmentation and an increase in the levels of PARP cleavage. Furthermore, AJ-5 was shown to induce both intrinsic and extrinsic apoptotic pathways as measured by PUMA, Bax and active caspases. Interestingly, AJ-5 treatment also simultaneously induced the formation of autophagosomes and led to an increase in the autophagy markers LC3II and Beclin1. Inhibition of autophagy reduced AJ-5 cytotoxicity suggesting that AJ-5 induced autophagy was a cell death and not cell survival mechanism. Moreover we show that AJ-5 induces the ATM-CHK2 DNA damage pathway and that its anti-tumour function is mediated by the p38 and ERK1/2 signalling pathways. Importantly, AJ-5 treatment efficiently reduced tumour growth in melanoma bearing mice and induced high levels of autophagy and apoptosis markers. Together these findings suggest that AJ-5 may be an effective chemotherapeutic drug in the treatment of melanoma, a highly aggressive and intractable cancer.

Composite polyester membranes with embedded dendrimer hosts and bimetallic Fe/Ni nanoparticles: synthesis, characterisation and application to water treatment

This study describes the preparation, characterization and evaluation of new composite membranes with embedded dendrimer hosts and Fe/Ni nanoparticles. These new reactive membranes consist of films of cyclodextrin–poly(propyleneimine) dendrimers (β-CD–PPI) that are deposited onto commercial polysulfone microporous supports and crosslinked with trimesoyl chloride (TMC). The membranes were subsequently loaded with Fe/Ni nanoparticles and evaluated as separation/reactive media in aqueous solutions using 2,4,6-trichlorophenol as model pollutant. The morphology and physicochemical properties of the composite membranes were characterised using high-resolution transmission electron microscopy (HR-TEM), atomic force microscopy and measurements of contact angle, water intake, porosity and water permeability. The sorption capacity and catalytic activity of the membranes were evaluated using ion chromatography, atmospheric pressure chemical ionisation-mass spectrometry and UV–Vis spectroscopy (UV–Vis). The sizes of the embedded Fe/Ni nanoparticles in the membranes ranged from 40 to 66xa0nm as confirmed by HR-TEM. The reaction rates for the dechlorination of 2,4,6-trichlorophenol ranged from 0.00148 to 0.00250xa0min−1. In all cases, we found that the reaction by-products consisted of chloride ions and mixtures of compounds including phenol (m/zxa0=xa093), 2,4-dichlorophenol (m/zxa0=xa0163) and 4-chlorophenol (m/zxa0=xa0128). The overall results of this study suggest that β-CD–PPI dendrimers are promising building blocks for the synthesis of composite and reactive membranes for the efficient removal of chlorinated organic pollutants from water.

The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells

Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.

Cyclometallated platinum(II) complexes of benzylidene-2,6-di-isopropylphenylamine containing bidentate phosphines: synthesis, structural properties and reactivity studies

The reaction of the cyclometallated complex [PtCl(N^C)(dmso)], 1 (N^C represents the cyclometallated Schiff base, benzylidene-2,6-diisopropylphenylamine), with 1,1-bis(diphenylphosphino)ferrocene, dppf, bis(diphenylphosphino)methane, dppm, or 1,2-bis(diphenylphosphino)ethane, dppe, in a 2u2009:u20091 ratio or an equimolar ratio using acetone as the solvent produced the corresponding binuclear or mononuclear diphosphine platinum complexes. In the case of the mononuclear complexes, the diphosphines act as either a bidentate ligand or a monodentate ligand depending on the size of the bite angle of the diphosphines, while in the case of the binuclear complexes, the diphosphines act as a bridging ligand between the two metal centres. The solid state structures of some of the binuclear as well as mononuclear species are reported. The mononuclear derivatives were found to show different behaviour in solution and in the solid state when compared to the binuclear analogues. This behaviour is also influenced by the nature of the diphosphine ligands employed.

Platinacycloalkane complexes containing [P,N] bidentate ligands: synthesis and decomposition studies

A new series of platinacyclopentanes (2a-2f) and platinacycloheptanes (3a-3f) of the type [Pt(N^P)(CH2)n] (n = 4, 6) were obtained by the reaction of [Pt(COD)(CH2)n] with the appropriate iminophosphine ligand (1a-1f). These complexes were characterised using a variety of spectroscopic and analytical techniques. X-ray structure analysis of complex 2a revealed a slightly distorted square planar geometry around platinum as a consequence of the ring strain imposed by the [P,N] chelate ring formed and the metallocycloalkane. Thermal decomposition analyses of the platinacycloalkanes revealed that the platinacyclopentanes are markedly stable, with the decomposition reaction requiring temperatures higher than 100 °C to occur. The major products obtained from the thermal decomposition reactions were 1-butene (for platinacyclopentanes) and 1-hexene (for platinacycloheptanes).

Nanostructured β-Cyclodextrin-Hyperbranched Polyethyleneimine (β-CD-HPEI) Embedded in Polysulfone Membrane for the Removal of Humic Acid from Water

The synthesis of a new β-cyclodextrin-hyperbranched polyethyleneimine (β-CD-HPEI)/polysulfone (PSf) membranes via interfacial polymerization of trimesoyl chloride and β-CD-HPEI is described in this paper. The membranes were characterized by atomic force microscopy (AFM), high resolution scanning electron microscopy (HR-SEM) and contact-angle measurements. Water permeability and rejection data were obtained using a cross-flow filtration system at 0.69 MPa. The membranes were hydrophilic (25° to 63°), showed high humic acid rejection (>80%), and maintained a constant flux throughout the filtration. The modified membranes were rougher than the pristine PSf membranes but they exhibited better antifouling properties due to the hydrophilic surface which acted as a barrier against humic acid deposition. The modification of PSf with β-CD-HPEI resulted in enhanced hydrophilicity and water permeability while still maintaining high humic acid rejection. Supplemental materials are available for this article. Go to the publishers online edition of Separation Science & Technology to view the supplemental file.

Abstract B38: A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas

Cisplatin and second-generation alternatives to cisplatin, represent some of the most active and clinically useful agents in the treatment of cancer. However, their application in the clinic is marred by side-effects and drug resistance. We have identified the binuclear palladacycle, AJ-5, as a lead anticancer compound with potent activity against advanced melanomas and estrogen receptor -positive and -negative breast cancers. AJ-5 displayed an IC50 of 0.2μM in melanoma and breast cancer cell lines which was 50 fold less than that for cisplatin and our in vivo results show that it efficiently reduces melanomas in nude mice without any obvious side effects. AJ-5 also showed activity against breast cancer stem cells which are associated with drug-resistance and often not targeted by traditional chemotherapeutic agents. This study investigates the potential of AJ-5 as an anti-cancer agent in sarcomas, which are a heterogeneous group of neoplasms that account for approximately 21% of paediatric malignancies and treatment outcomes for patients with metastatic disease are dismal. Cytotoxicity assays were performed and sub-micromolar IC50 concentrations were obtained for rhabdomyosarcoma, chondrosarcoma, liposarcoma, synovial sarcoma and osteosarcoma. Clonogenic assays show that AJ-5 greatly compromises the long-term ability of the sarcoma cells to survive and proliferate. To determine the underlying molecular mechanisms by which AJ-5 exerts its cytotoxicity, western blot analyses were performed with antibodies to key proteins involved in the DNA damage response in rhabdomyosarcoma cell lines. The results show that AJ-5 induces high levels of γH2AX, a marker of double-stranded DNA breaks, and that it may exert it9s cytotoxicity through the p38 MAP kinase stress pathway. Furthermore, Annexin VFITC/propidium iodide staining, Caspase Glo assays and western blotting demonstrated that AJ-5 induce intrinsic and extrinsic apoptosis more effectively than doxorubicin, a drug currently used in the treatment of rhabdomyosarcomas. AJ-5 treatment also led to autophagy as confirmed by the formation of autophagosomes, increased levels of LC3-II and the presence of LC3 puncta. Finally, pharmacokinetic studies show that AJ-5 has a promising half-life of 11.2 hours in mice and in addition its volume of distribution is high and its clearance is low while its intraperitoneal absorption is good. Thus the PK data correlates well with our observed efficacy of the drug in our mouse model. Together these findings suggest that AJ-5 may be an effective chemotherapeutic for treating a range of drug-resistant and advanced cancers. Citation Format: Jenna Bleloch, Reyna Ballim, Angelique Blanckenberg, Selwyn Mapolie, Serah Kimani, Sharon Prince. A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B38.