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Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells in vitro.

ABSTRACT: The tumorigenic potentials of residual cancer stem-like cells within tumors represent limitations of current cancer therapies. Here, the authors describe the effects of synthesized flexible, ligated, supramolecular self-assembled chair type tetranuclear ruthenium (II) metallacycles (2-5) on glioblastoma and glioma stem like cells. These self-assemblies were observed to be selectively toxic to glioma cells and CD133-positive glioma stem like cells population. Of the self-assembled compounds tested, metallacycle 4 more efficiently induced glioma stem like cells death within a brain cancer cell population and simultaneously inhibited the formation of free-floating gliospheres by reducing the sphere size. Detailed cell death studies revealed that treatment with metallacycle 4 reduced mitochondrial membrane potentials (an indicator of apoptosis) of glioma stem like cells. These results shows the elimination of cancer stem-like cells using an appropriate ligand binding adaptor offers a potential means of developing metal-based compounds for the treatment of chemo-resistant tumors.

SUBMITTER: Elumalai P

PROVIDER: S-EPMC5601131 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells <i>in vitro</i>.

Elumalai Palani P Kaushik Neha N Kim Dong Hwan DH Kim Hyunuk H Lee Su Jae SJ Choi Eun Ha EH Chi Ki-Whan KW Kaushik Nagendra Kumar NK

Oncotarget 20170705 36

The tumorigenic potentials of residual cancer stem-like cells within tumors represent limitations of current cancer therapies. Here, the authors describe the effects of synthesized flexible, ligated, supramolecular self-assembled chair type tetranuclear ruthenium (II) metallacycles (2-5) on glioblastoma and glioma stem like cells. These self-assemblies were observed to be selectively toxic to glioma cells and CD133-positive glioma stem like cells population. Of the self-assembled compounds teste ...[more]

PMID: 28947963

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Project description:Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels and functional p53 have a critical role on cisplatin resistance. In this work, we explored several mechanisms of cisplatin resistance in human glioma. We showed that cellular survival was independent of the p53 status of those cells. In addition, in a host-cell reactivation assay using cisplatin-treated plasmid, we did not detect any difference in DNA repair capacity. We demonstrated that cisplatin-treated U138MG cells suffered fewer DNA double-strand breaks and DNA platination. Interestingly, the resistant cells carried higher levels of intracellular glutathione. Thus, preincubation with the glutathione inhibitor buthionine sulfoximine (BSO) induced massive cell death, whereas N-acetyl cysteine, a precursor of glutathione synthesis, improved the resistance to cisplatin treatment. In addition, BSO sensitized glioma cells to TMZ alone or in combination with cisplatin. Furthermore, using an in vivo model the combination of BSO, cisplatin and TMZ activated the caspase 3-7 apoptotic pathway. Remarkably, the combined treatment did not lead to severe side effects, while causing a huge impact on tumor progression. In fact, we noted a remarkable threefold increase in survival rate compared with other treatment regimens. Thus, the intracellular glutathione concentration is a potential molecular marker for cisplatin resistance in glioma, and the use of glutathione inhibitors, such as BSO, in association with cisplatin and TMZ seems a promising approach for the therapy of such devastating tumors.

Dataset Information

Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells in vitro.

Publications

Flexible ligated ruthenium(II) self-assemblies sensitizes glioma tumor initiating cells <i>in vitro</i>.

Similar Datasets

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