PI3K Inhibition Enhances Doxorubicin-Induced Apoptosis in Sarcoma Cells

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.

Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma

“…The mechanism of Bax activation by cotreatment with PI103 and UO126 may be transcription-independent, since PI103 and UO126 acted together to trigger conformational activation of Bax without upregulating the expression levels of Bax. Along these lines, we previously reported that PI3K inhibition enhances Doxorubicin-or TRAIL-induced Bax activation via a conformational change rather than an increase in Bax levels [48][49][50]. Our findings have important implications for the development of experimental treatment strategies for RMS.…”

Genomic Landscape of Human Papillomavirus–Associated Cancers

“…Trials with PI3K/AKT/mTOR inhibitors are underway in both HNSCC and cervical cancer (86, 87) (NCT02113878, NCT02051751, NCT01602315, NCT02145312). Interestingly PI3K/mTOR inhibition has previously been shown to sensitize cancer cells to radiation and chemotherapy (88–90). The FGFR3 mutation at position 249 and FGFR3-TACC3 fusions identified in a number of HPV-positive HNSCC cases have shown promising therapeutic response to FGFR inhibitors in pre-clinical (52) and clinical studies (91, 92).…”

Targeting protein kinases to reverse multidrug resistance in sarcoma

“…PI103, a dual PI3K/mTOR kinase inhibitor, can reverse MDR in fibrosarcoma and rhabdomyosarcoma 97 . A study demonstrated that PI103 increased intracellular doxorubicin accumulation through decreased expression of ABCB1 and ABCC1.…”