The antitumor triazoloacridone C-1305 is a topoisomerase II poison with unusual properties.
C-1305 [S-[[3-(dimethylamino)propyl]amino]-8-hydroxy-6H-v-triazolo[4,5,1-de]acridin-6-one] is a triazoloacridone with excellent activity in colon cancer models. The mechanism of C-1305 is unknown, although similarities in the chemical structure between C-1305 and amsacrine suggest common cellular targets. Here, we report that C-1305 is a topoisomerase II poison that is able to induce cleavable complexes with topoisomerase II in vitro as well as in living cells. Even at optimal concentrations, C-1305 is a much weaker inducer of cleavable complexes than amsacrine. Because the cytotoxic activities of the two compounds after continuous drug exposure are comparable, these findings suggest that the low levels of cleavable complexes induced by C-1305 may be unusually toxic. In contrast to amsacrine, the cytotoxicity of C-1305 is strongly time-dependent, with at least 24 h of drug exposure required for optimal cytotoxicity. The p53 tumor suppressor is inactivated in the majority of human tumors, including colorectal cancers. We therefore compared the long-term cytotoxic effects of C-1305, amsacrine, and doxorubicin on human cell lines in which the p53 or p21 pathways have been specifically disrupted by targeted homologous recombination. Disruption of p53 and p21 had minor influence on the cytotoxicity of doxorubicin, whereas p53 but not p21 disruption was associated with increased resistance to amsacrine. In marked contrast, disruption of p53 and p21 was associated with increased sensitivity to C-1305. Taken together, our results show that exposure to C-1305 is accompanied by the formation of low levels of potent cleavable complexes that are selectively toxic toward tumor cells with defective p53 function.
Lemke
Krzysztof
K
Laboratory of Biology and Pharmacogenetics of Human Tumors, Centre National de la Recherche Scientifique Unité Mixte Recherche 8113, Ecole Normale Supérieure Cachan, France.
Poindessous
Virginie
V
Skladanowski
Andrzej
A
Larsen
Annette K
AK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000235:genetics; D011929:Razoxane / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D004247:DNA; D004250:DNA Topoisomerases, Type II; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011929:Razoxane; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C488734:C 1305; C421109:multidrug resistance-associated protein 1