Rescue of Doxorubicin-Induced Chemoresistance by API 31510 in Chloroleukemia

Abstract 5016

Cancer resistance to single or multiple chemotherapy regimens continues to be a major problem in achieving complete remission. Fundamental knowledge of the mechanistic aspects underlying chemoresistance has yet to yield a practice changing answer to the problem. Thus, models of chemoresistance are necessary to shed light into molecular pathways and translational aspects of chemotherapy induced resistance. A classical example of chemotherapy to which resistance is developed is with use of doxorubicin. Several molecular and cellular aspects of doxorubicin resistance have been elucidated; however overcoming resistance remains elusive, thereby rendering animal models of doxorubicin to test novel drugs vital in solving this problem. In the present study we have used a well-established model of rat chloroleukemia (Science. 1987; 238:1278-80) to study resistance to doxorubicin. As an extension of this study, we derived a novel clone of the parent chloroleukemic cell resistant to doxorubicin. We proceeded to test this clone on the development of chloroleukemia in rats and to compare the cure rates of the parent (doxorubicin sensitive) cell line versus the doxorubicin resistant clone. Animals injected with the parent clone were treated with 1 mg/kg doxorubicin for 3 days. This regimen resulted in a cure rate of 35 percent. In sharp contrast, 100% of the animals injected with the doxorubicin resistant clone did not respond to doxorubicin therapy. Conversely, treatment of animals injected with the parent and doxorubicin-resistant clones exhibited a 50% cure rate when treated with ubidecarenone (API31510) (p<0.01). In vitro investigations revealed that API 31510 induced apoptosis in both chloroleukemic cell lines. The molecular pathways regulating API 31510- induced reversal of doxorubicin resistance were characterized, and shown to be independent from doxorubicin effect on the induction of resistance. The data herein strongly demonstrate that resistance to doxorubicin can be overcome by co-administration with API 31510.