Nitric oxide inhibits topoisomerase II activity and induces resistance to topoisomerase II-poisons in human tumor cells.

Abstract

BACKGROUND:

Etoposide and doxorubicin, topoisomerase II poisons, are important drugs for the treatment of tumors in the clinic. Topoisomerases contain several free sulfhydryl groups which are important for their activity and are also potential targets for nitric oxide (NO)-induced nitrosation. NO, a physiological signaling molecule nitrosates many cellular proteins, causing altered protein and cellular functions.

METHODS:

Here, we have evaluated the roles of NO/NO-derived species in the activity/stability of topo II both in vitro and in human tumor cells, and in the cytotoxicity of topo II-poisons, etoposide and doxorubicin.

RESULTS:

Treatment of purified topo IIα with propylamine propylamine nonoate (PPNO), an NO donor, resulted in inhibition of both the catalytic and relaxation activity in vitro, and decreased etoposide-dependent cleavable complex formation in both human HT-29 colon and MCF-7 breast cancer cells. PPNO treatment also induced significant nitrosation of topo IIα protein in these human tumor cells. These events, taken together, caused a significant resistance to etoposide in both cell lines. However, PPNO had no effect on doxorubicin-induced cleavable complex formation, or doxorubicin cytotoxicity in these cell lines.

CONCLUSION:

Inhibition of topo II function by NO/NO-derived species induces significant resistance to etoposide, without affecting doxorubicin cytotoxicity in human tumor cells.

GENERAL SIGNIFICANCE:

As tumors express inducible nitric oxide synthase and generate significant amounts of NO, modulation of topo II functions by NO/NO-derived species could render tumors resistant to certain topo II-poisons in the clinic.

• Authors: Ashutosh Kumar, Marilyn Ehrenshaft, Erik J Tokar, Ronald P Mason, Birandra K Sinha
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1860 Issue 7 Pg. 1519-27 (Jul 2016) ISSN: 0006-3002 [Print] Netherlands
• PMID: 27095671 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier B.V.

Chemical References

• Nitric Oxide Donors
• Topoisomerase II Inhibitors
• Nitric Oxide
• Etoposide
• Doxorubicin
• DNA
• DNA Topoisomerases, Type II

Topics

• Breast Neoplasms (drug therapy, enzymology, pathology)
• Catalysis
• Colorectal Neoplasms (drug therapy, enzymology, pathology)
• DNA (chemistry, metabolism)
• DNA Topoisomerases, Type II (metabolism)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Stability
• Etoposide (pharmacology)
• Female
• HT29 Cells
• Humans
• MCF-7 Cells
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Nucleic Acid Conformation
• Protein Conformation
• Topoisomerase II Inhibitors (pharmacology)