Abstract 16494: Rapamycin Enhances Protective Effect of Sildenafil against Doxorubicin Cardiotoxicity and Potentiates Cancer Cell Killing
Background: Doxorubicin (DOX) is one of the most widely used chemotherapeutics for the treatment of various cancers. However, its use has been limited due to severe cardiotoxicity. Sildenafil (Sild), a selective PDE-5 inhibitor, induces partial protection against DOX cardiomyopathy. Similarly, rapamycin (Rapa), a selective inhibitor of mTOR, has been shown to protect against myocardial infarction and heart failure. Rapa is also being developed as a therapeutic agent against cancer. Here we test whether the combination of Rapa and Sild will further protect against DOX-induced injury in adult mouse cardiomyocytes while also enhancing DOX anti-cancer effects in breast cancer cells (MDA-MB-231).
Methods and results: Adult cardiomyocytes were isolated from CD-1 mice and subjected to 24 hr treatment with 100 nM Rapa, 10 µM Sild, and 1 µM DOX either alone or in combination. Necrosis was measured using trypan blue and apoptosis was measured using TUNEL after 24 hr treatment. As shown in figs. A and B, Rapa or Sild in combination with DOX each significantly reduced apoptosis and necrosis compared to DOX alone. The combination of Rapa and Sild further reduced apoptosis and necrosis. For the cancer studies, cell viability of MDA-MB-231 was measured using an MTS assay after treatment for 48 hr with 100 nM Rapa, 10 µM Sild, and 0.5 µM DOX either alone or in combination (fig. C). This significantly reduced viability in cells treated with DOX in combination with Rapa and Sild as compared to those treated with DOX only.
Conclusion: Rapa protects cardiomyocytes against DOX toxicity which is further enhanced in combination with Sild. Interestingly, this same combination enhances the cell killing effects of DOX in breast cancer cells. We propose that Rapa and Sild could be a novel translational strategy to reduce DOX cardiotoxicity while enhancing its anti-cancer effect.
- © 2012 by American Heart Association, Inc.