10 research outputs found
Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo
Following recent work on heterometallic titanocene–gold 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 ¼ S–C6H4–COO) 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
Effective Elimination of Cancer Stem Cells by Magnetic Hyperthermia
Cancer
stem cells (CSCs) are a subpopulation of cancer cells that
have stem cell-like properties and are thought to be responsible for
tumor drug resistance and relapse. Therapies that can effectively
eliminate CSCs will, therefore, likely inhibit tumor recurrence. The
objective of our study was to determine the susceptibility of CSCs
to magnetic hyperthermia, a treatment that utilizes superparamagnetic
iron oxide nanoparticles placed in an alternating magnetic field to
generate localized heat and achieve selective tumor cell kill. SPIO
NPs having a magnetite core of 12 nm were used to induce magnetic
hyperthermia in A549 and MDA-MB-231 tumor cells. Multiple assays for
CSCs, including side population phenotype, aldehyde dehydrogenase
expression, mammosphere formation, and <i>in vivo</i> xenotransplantation,
indicated that magnetic hyperthermia reduced or, in some cases, eliminated
the CSC subpopulation in treated cells. Interestingly, conventional
hyperthermia, induced by subjecting cells to elevated temperature
(46 °C) in a water bath, was not effective in eliminating CSCs.
Our studies show that magnetic hyperthermia has pleiotropic effects,
inducing acute necrosis in some cells while stimulating reactive oxygen
species generation and slower cell kill in others. These results suggest
the potential for lower rates of tumor recurrence after magnetic hyperthermia
compared to conventional cancer therapies
In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer
A series
of organometallic ruthenium(II) complexes containing iminophosphorane
ligands have been synthesized and characterized. Cationic compounds
with chloride as counterion are soluble in water (70–100 mg/mL).
Most compounds (especially highly water-soluble <b>2</b>) are
more cytotoxic to a number of human cancer cell lines than cisplatin.
Initial mechanistic studies indicate that the cell death type for
these compounds is mainly through canonical or caspase-dependent apoptosis,
nondependent on p53, and that the compounds do not interact with DNA
or inhibit protease cathepsin B. In vivo experiments of <b>2</b> on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an
impressive tumor reduction (shrinkage) of 56% after 28 days of treatment
(14 doses of 5 mg/kg every other day) with low systemic toxicity.
Pharmacokinetic studies showed a quick absorption of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues
when compared to kidney and liver, which may explain its high efficacy
in vivo
The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance
In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer
A series
of organometallic ruthenium(II) complexes containing iminophosphorane
ligands have been synthesized and characterized. Cationic compounds
with chloride as counterion are soluble in water (70–100 mg/mL).
Most compounds (especially highly water-soluble <b>2</b>) are
more cytotoxic to a number of human cancer cell lines than cisplatin.
Initial mechanistic studies indicate that the cell death type for
these compounds is mainly through canonical or caspase-dependent apoptosis,
nondependent on p53, and that the compounds do not interact with DNA
or inhibit protease cathepsin B. In vivo experiments of <b>2</b> on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an
impressive tumor reduction (shrinkage) of 56% after 28 days of treatment
(14 doses of 5 mg/kg every other day) with low systemic toxicity.
Pharmacokinetic studies showed a quick absorption of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues
when compared to kidney and liver, which may explain its high efficacy
in vivo