22 research outputs found
Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens
Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies
Heterometallic titaniumāgold complexes inhibit renal cancer cells in vitro and in vivo
Following recent work on heterometallic titanoceneāgold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba Ā¼ SāC6H4āCOO) bound to gold(I)-phosphane fragments through a thiolate group [(h-C5H5)2TiMe(m-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(h-C5H5)2TiMe(m-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(h-C5H5)2Ti {OC(O)-4-C6H4-P(Ph2)AuCl}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds
Inhibition of Protein Kinase CĪ± by Dequalinium Analogues:Ā Dependence on Linker Length and Geometry
Direct Electrochemical Measurements of Reactive Oxygen and Nitrogen Species in Nontransformed and Metastatic Human Breast Cells
The production of reactive oxygen
and nitrogen species (ROS and
RNS) in human cells is implicated in various diseases, including cancer.
Micrometer-sized electrodes coated with Pt black and platinized Pt
nanoelectrodes have previously been used for the detection of primary
ROS and RNS in biological systems. In this Article, we report the
development of platinized carbon nanoelectrodes with well-characterized
geometry and use them as scanning electrochemical microscopy (SECM)
tips to measure ROS and RNS inside noncancerous and metastatic human
breast cells. By performing time-dependent quantitative amperometric
measurements at different potentials, the relative concentrations
of four key ROS/RNS in the cell cytoplasm and their dynamics were
determined and used to elucidate the chemical origins and production
rates of ROS/RNS in nontransformed and metastatic human breast cells