Wang and colleagues (1) recently reported that the cardiac glycoside bufalin was a potent inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Because these coactivators have been implicated in cancer progression, the authors investigated whether bufalin could also block cancer cell growth in cell culture and animal models. They observed that bufalin inhibited the growth of human MCF-7 breast cancer cells and human A549 lung cancer cells at nanomolar concentrations (3–5 nmol/L); these concentrations also inhibited SRC-3, did not affect the growth of rodent nonmalignant TM4 Sertoli cells, and were below those reported to be tolerated by humans (8.75 nmol/L). They also found that bufalin inhibited tumor growth in mice xenotransplanted with human MDA-MB-231 breast cancer cells. The most relevant conclusion of this work is that bufalin has potential for cancer therapy.
The key feature of an efficient anticancer drug is its ability to kill (or inhibit the growth of) human cancer cells at concentrations that do not significantly affect human nonmalignant cells. Clifford and Kaplan (2) have recently shown, however, that human breast nonmalignant cells were more sensitive than human breast cancer cells (MCF-7 and MDA-MB-231) to bufalin-induced cell growth inhibition and apoptosis. They showed, for instance, that 50 nmol/L bufalin induced apoptosis in human breast nonmalignant cells but not in MCF-7 and MDA-MB-231 breast cancer cells. Yan and colleagues (3) also observed low levels of apoptosis in MCF-7 and MDA-MB-231 cells exposed for 48 hours to 50 nmol/L bufalin.
The inhibition of tumor growth induced by bufalin in the mouse xenograft model (1) is probably an experimental artifact (4, 5). It has been known for some time that rodent cells are much more resistant than human cells to the cytotoxic effects of bufalin and other cardiac glycosides (6). More recently, we observed that the cytotoxic activity of three cardiac glycosides in several human cell lines (originated from malignant and nonmalignant tissues) was approximately 1,000 times higher than in rodent cell lines and that the selectivity of the three cardiac glycosides toward human cancer cells versus human nonmalignant cells was variable and not higher than 10-fold (5). These studies strongly suggest that the antitumor activity of bufalin in mice xenotransplanted with human cancer cells (1) is due to interspecies differences in sensitivity and not to selective inhibition of cancer cell growth.
These data do not support the idea that bufalin has potential for cancer therapy.
See the Response, p. 1157
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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