Sensitivierung von Sarkomzellen gegenüber Doxorubizin

Doxorubicin is one of the most effective cytostatic agents and is widely used in a variety of tumor entities. Despite being one of the drugs of choice in sarcoma treatment, doxorubicin sometimes does not show any efficacy. Therefore, this drug remains a controversial treatment option in sarcoma, especially in rhabdomyosarcoma, the most common sarcoma of childhood. The aim of this study was to enhance the response of sarcoma cells towards doxorubicin. For this purpose, doxorubicin was applied in combination with drugs, which have been described to increase TOP2a expression. Additionally, we used the dual PI3K and mTOR inhibitor PI103, which enhances the antitumoral effects of doxorubicin in glioblastoma and neuroblastoma cells. As evidenced by means of proliferation and apoptosis assays, PI103 sensitized rhabdomyosarcoma cells towards doxorubicin-mediated antiproliferative and proapoptotic effects. When analysing the proapoptotic effect in more detail, we found that the enhancement of doxorubicin-induced apoptosis is independent of TOP2a expression. Furthermore, the enhancement of doxorubicin-induced apoptosis does not include inhibition of mTOR. Interestingly, PI103 inhibits the expression of the multidrug efflux transporters MDR1 and MRP1, as evidenced by qRT-PCR analyses. This results in intracellular accumulation of doxorubicin, which however does not explain the cooperative proapoptotic effect. Instead, the combination treatment of doxorubicin plus PI103 induces the activation of Bax and of the mitochondrial apoptosis pathway, and of caspase 3. The latter effect is also being observed in a first experiment in vivo in mice, which have been transplanted with human rhabdomyosarcoma cells. In summary, these data show that PI103 sensitizes sarcoma cells towards doxorubicin treatment via the mitochondrial apoptosis signalling pathway.