Abstract
We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
Highlights
Sarcomas are a heterogeneous group of malignant tumors of mesenchymal origin
Our present study was prompted by the observation that PI103 interacts with DOX in the induction of apoptosis and in activation of caspase 3 in 3 different sarcoma cell lines. Since these proapoptotic effects were in contrast to recent data for the dual PI3K/mTOR inhibitor NVP-BEZ23 in sarcoma cells, we investigated the underlying mechanism in more detail
We investigated if the PI103-associated DOX accumulation was responsible for the combined effects of the drugs on apoptosis
Summary
Sarcomas are a heterogeneous group of malignant tumors of mesenchymal origin. More than 50 histological subtypes are known. Sarcomas comprised 1% of malignancies in adults but 15% in patients under 20 years old in North America in 2006 [1] and 8.5% of cancers in European patients aged 15–24 years diagnosed from 1990 to 1994 [2]. Sarcomas are in general more prevalent in children. The most common histological sarcoma subtype in children is rhabdomyosarcoma (RMS) [3]. The treatment of sarcomas usually comprises surgical resection, radiation treatment, and chemotherapy. Chemotherapy of sarcomas frequently involves anthracyclines, which are topoisomerase II (TOP2) inhibitors, in combination with other cytostatic drugs [4,5]. One of the anthracyclines used in the therapy of sarcoma is DOX
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