New soft alkylating agents with enhanced cytotoxicity against cancer cells resistant to chemotherapeutics and hypoxia
| Autor: | René C.-Gaudreault, Jacques Lacroix, Jean L.C. Rousseau, Eric Petitclerc, Réna G. Deschesnes, Alexandre Patenaude, Marie-France Côté |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
CHO Cells Mitochondrion Microtubules Models Biological Microtubule polymerization Electron Transport Cricetulus Tubulin Cyclosporin a Cricetinae Neoplasms Tumor Cells Cultured Animals Humans Cytotoxicity Antineoplastic Agents Alkylating biology Adenine nucleotide translocator Phenylurea Compounds Molecular biology Cell Hypoxia Mitochondrial respiratory chain Oncology Biochemistry Apoptosis Drug Resistance Neoplasm Cancer cell biology.protein Drug Screening Assays Antitumor HT29 Cells |
| Zdroj: | Cancer research. 67(5) |
| ISSN: | 0008-5472 |
| Popis: | Chloroethylureas (CEU) are soft alkylating agents that covalently bind to β-tubulin (βTAC) and affect microtubule polymerization dynamics. Herein, we report the identification of a CEU subset and its corresponding oxazolines, which induce cell growth inhibition, apoptosis, and microtubule disruption without alkylating β-tubulin (N-βTAC). Both βTAC and N-βTAC trigger the collapse of mitochondrial potential (ΔΨm) and modulate reactive oxygen species levels, following activation of intrinsic caspase-8 and caspase-9. Experiments using human fibrosarcoma HT1080 respiratory-deficient cells (ρ0) and uncoupler of the mitochondrial respiratory chain (MRC) showed that βTAC and N-βTAC impaired the MRC. ρ0 cells displayed an increased sensitivity toward N-βTAC as compared with ρ+ cells but, in contrast, were resistant to βTAC or classic chemotherapeutics, such as paclitaxel. Oxazoline-195 (OXA-195), an N-βTAC derivative, triggered massive swelling of isolated mitochondria. This effect was insensitive to cyclosporin A and to Bcl-2 addition. In contrast, adenine nucleotide translocator (ANT) antagonists, bongkrekic acid or atractyloside, diminished swelling induced by OXA-195. The antiproliferative activities of the N-βTACs CEU-025 and OXA-152 were markedly decreased in the presence of atractyloside. Conversely, pretreatment with cyclosporin A enhanced growth inhibition induced by βTAC and N-βTAC. One of the proteins alkylated by N-βTAC was identified as the voltage-dependent anion channel isoform-1, an ANT partner. Our results suggest that βTAC and N-βTAC, despite their common ability to affect the microtubule network, trigger different cytotoxic mechanisms in cancer cells. The role of mitochondria in these mechanisms and the potential of N-βTAC as a new therapeutic approach for targeting hypoxia-resistant cells are discussed. [Cancer Res 2007;67(5):2306–16] |
| Databáze: | OpenAIRE |
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