Bufalin Is a Steroid Receptor Coactivator Inhibitor—Response

We would like to thank Calderón-Montaño and colleagues (1) for their letter expressing their opinions about our characterization of bufalin as a potential “proof-of-principle” compound for depleting SRC-3 and killing cancer cells (2). First, the issue of whether bufalin is able to selectively kill cancer cells over nonmalignant cells is raised in this letter, and a recent paper from Clifford and Kaplan (3) is cited as evidence that bufalin preferentially kills nonmalignant cells over cancer cells at high concentrations (>100 nmol/L). However, this study contrasts with numerous other studies that have reported that bufalin can selectively kill cancer cells over normal cells when low nanomolar concentrations are used (4, 5). Furthermore, more than “50 publications” describe the induction of apoptosis as a key mechanism underlying the anticancer effects of bufalin, in contrast with what is implied in the letter by Calderón-Montaño and colleagues (1). This disconnect by the commenter to published data is disconcerting.

While immortalized mouse cell lines may be less sensitive to bufalin and other cardiac glycosides than human cell lines, mouse toxicity to bufalin in vivo still limits the dose of bufalin that can be given to animals. Indeed, dose-limiting toxicity forced us to develop a bufalin nanoparticle complex to avoid cardiotoxicity in our mouse xenograft model. We also partly address this concern in the last paragraph of our paper, where we acknowledged the fact that the generally narrow therapeutic window for many cardiac glycosides could limit their use as anticancer agents in humans. In contrast with other cardiac glycosides though, bufalin possesses anticancer properties at concentrations below its maximum tolerated dose in humans. As long as it is tested below this concentration, mouse xenograft models should be appropriate models to test bufalin for its anticancer properties against human cancer cells. In fact, in what other animal model would you ever test human cells other than the “mouse model”—a model that many other laboratories have employed in testing drugs?

See the original Letter to the Editor, p. 1156