This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Patenaude, A. Articles by C.-Gaudreault, R. Search for Related Content PubMed PubMed Citation Articles by Patenaude, A. Articles by C.-Gaudreault, R.

New Soft Alkylating Agents with Enhanced Cytotoxicity against Cancer Cells Resistant to Chemotherapeutics and Hypoxia

¹ Unité de Biotechnologie et de Bioingénierie, CHUQ, Hôpital Saint-François d'Assise and ² Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada

Requests for reprints: René C.-Gaudreault, or Alexandre Patenaude, Unité de Biotechnologie et de Bioingénierie, Centre de recherche, CHUQ, Hôpital Saint-François d'Assise, Québec, Québec, Canada G1L 3L5. Phone: 418-525-4444, ext. 52363 or 53401; Fax: 418-525-4372; E-mail: rene.c-gaudreault{at}crsfa.ulaval.ca, or alexandre.patenaude{at}crchul.ulaval.ca.

Chloroethylureas (CEU) are soft alkylating agents that covalently bind to ß-tubulin (ßTAC) 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 ß-tubulin (N-ßTAC). Both ßTAC and N-ßTAC trigger the collapse of mitochondrial potential (_m) and modulate reactive oxygen species levels, following activation of intrinsic caspase-8 and caspase-9. Experiments using human fibrosarcoma HT1080 respiratory-deficient cells (⁰) and uncoupler of the mitochondrial respiratory chain (MRC) showed that ßTAC and N-ßTAC impaired the MRC. ⁰ cells displayed an increased sensitivity toward N-ßTAC as compared with ⁺ cells but, in contrast, were resistant to ßTAC or classic chemotherapeutics, such as paclitaxel. Oxazoline-195 (OXA-195), an N-ßTAC 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-ßTACs CEU-025 and OXA-152 were markedly decreased in the presence of atractyloside. Conversely, pretreatment with cyclosporin A enhanced growth inhibition induced by ßTAC and N-ßTAC. One of the proteins alkylated by N-ßTAC was identified as the voltage-dependent anion channel isoform-1, an ANT partner. Our results suggest that ßTAC and N-ßTAC, 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-ßTAC as a new therapeutic approach for targeting hypoxia-resistant cells are discussed. [Cancer Res 2007;67(5):2306–16]

This article has been cited by other articles:

				N. R. Khawaja, M. Carre, H. Kovacic, M. A. Esteve, and D. Braguer Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria Mol. Pharmacol., October 1, 2008; 74(4): 1072 - 1083. [Abstract] [Full Text] [PDF]

				L. S. Li, J. C. Morales, A. Hwang, M. W. Wagner, and D. A. Boothman DNA Mismatch Repair-dependent Activation of c-Abl/p73{alpha}/GADD45{alpha}-mediated Apoptosis J. Biol. Chem., August 1, 2008; 283(31): 21394 - 21403. [Abstract] [Full Text] [PDF]