Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism.
The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. The IC(50) for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Growth inhibition by doxazolidine correlates better with growth inhibition by DNA cross-linking agents than with growth inhibition by doxorubicin. Doxorubicin induces G2/M arrest in HCT-116 colon cancer cells and HL-60 leukemia cells through a well-documented topoisomerase II dependent mechanism. Doxazolidine fails to induce a G2/M arrest in HCT-116 cells but induces apoptosis 4-fold better than doxorubicin. The IC(50) for doxazolidine growth inhibition of HL-60/MX2 cells, a topoisomerase II deficient derivative of HL-60 cells, is 1420-fold lower than the IC(50) for doxorubicin, and doxazolidine induces apoptosis 15-fold better. Further, doxazolidine has little effect in a topoisomerase II activity assay. These data indicate that doxorubicin and doxazolidine induce apoptosis via different mechanisms and doxazolidine cytotoxicity is topoisomerase II independent.
Kalet
Brian T
BT
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA.
McBryde
Meagan B
MB
Espinosa
Joaquin M
JM
Koch
Tad H
TH
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005557:Formaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D005557:Formaldehyde; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II
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