Abstract 16178: Iloprost Prevents Doxorubicin Mediated Human Cardiac Progenitor Cells Depletion
Introduction: Doxorubicin (DOX) is one of the most effective antitumor agents known for the treatment of a variety of cancers. However, its clinical use is limited by acute and chronic cardiotoxicities. Recently, it has been reported that DOX-induced cardiotoxicity is mediated by depletion in human cardiac progenitor cells (hCPCs). Iloprost, a stable synthetic analogue of prostacyclin (PGI2), has previously been shown to protect against DOX-induced cardiomyocyte injury. We aimed to test the hypothesis that Iloprost could protect CPC pools without compromising the antitumor efficacy of DOX in vitro.
Methods and results: The hCPCs were enzymatically isolated from the atrial appendages of patients during open chest surgery, and then c-Kit positive cells were sorted and expanded for following experiments. The hCPSs were exposed to DOX (1µM) for 24 hours, which decreased the viability (15.8 ± 2.8% of control, n=3, p<0.05) and increased the activity of Caspase-3/7 (31147 ± 1485RFU, vs. control 19983±1369RFU, n=6, p<0.05) and increased the formation of reactive oxygen species (ROS) (180 ± 38% of control, n=3, p<0.05). However, when hCPCs were treated with Iloprost (1µM) at 6 hour intervals before and during DOX exposure, Iloprost prevented hCPCs viability (97.5 ± 4.2%), attenuated apoptosis (22520 ± 1019RFU), and inhibited the formation of ROS (123 ± 23% of control), which correlated with an increased activity of cyclic adenosine monophosphate (cAMP, 501.5 ± 57.7 nM, vs. 193.3 ± 57.7nM of control, n=3, p<0.05). Furthermore, a pre-incubation with CAY10441 (1µM, an IP receptor antagonist) attenuated the protection of Iloprost and activation of cAMP in hCPCs. In addition, Iloprost alone had no effect on the growth of human gastric cancer cell line and did not compromise DOX-induced suppression of its growth.
Conclusion: Iloprost may be used as a protective agent against DOX-induced cardiotoxicity through preserving CPCs without compromising effeccy of DOX.
- © 2012 by American Heart Association, Inc.