HIF-1 Offers Target for Digoxin in Cancer Therapy
Several cardiac glycosides, including digoxin, inhibited HIF-1-dependent gene transcription
WEDNESDAY, Jan. 7 (HealthDay News) -- Cardiac glycosides -- used in treating congestive heart failure and arrhythmias -- appear to be strong inhibitors of hypoxia-inducible factor 1α (HIF-1α) synthesis, providing evidence that supports the use of drugs like digoxin for cancer treatment, according to research published Dec. 16 in the Proceedings of the National Academy of Sciences.
Huafeng Zhang, Ph.D., of the Johns Hopkins University School of Medicine in Baltimore, and colleagues write that HIF-1 regulates the expression of hundreds of genes in response to hypoxia. The investigators screened more than 3,000 drugs and found that 20 inhibited HIF-1-dependent gene transcription by more than 88 percent at a concentration of 0.4 μM. Eleven of these were cardiac glycosides, they report.
In mice given xenografts of P493-Myc cells, which are transformed human B-lymphocytes, daily digoxin injections inhibited the growth of the xenografts in a dose-dependent manner, the authors report. This effect paralleled the inhibition of HIF-1α protein expression in the tumors, they write. In another experiment, the researchers began digoxin treatment 11 days after cell implantation in the mice, and tumor growth stopped within seven days.
"Knowledge of the relevant therapeutic target of digoxin in human cancer will allow this drug to be used in a more rational manner. Specifically, our findings suggest that immunohistochemical analysis of HIF-1α in tumor biopsy sections may identify a subset of breast and lung cancer patients in current and future trials who are most likely to respond favorably to the inclusion of digoxin in combination chemotherapy regimens, the authors write.