Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism.

Abstract

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.

• Authors: Brian T Kalet, Meagan B McBryde, Joaquin M Espinosa, Tad H Koch
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 18 Pg. 4493-500 (Sep 06 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17696516 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Topoisomerase II Inhibitors
• Formaldehyde
• Doxorubicin
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Cycle (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type II (genetics, physiology)
• Doxorubicin (analogs & derivatives, pharmacology)
• Formaldehyde (analogs & derivatives, pharmacology)
• Humans
• Models, Molecular
• Myocytes, Cardiac (cytology, drug effects)
• Topoisomerase II Inhibitors