title: 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.
authors.affiliation: Institute of Human Genetics, University Medical Center, Goettingen, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Marklein
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graab
authors.forename: Ivonne
authors.initials: I
authors.lastname: Naumann
authors.forename: Tiandong
authors.initials: T
authors.lastname: Yan
authors.forename: Rosalie
authors.initials: R
authors.lastname: Ridzewski
authors.forename: Frauke
authors.initials: F
authors.lastname: Nitzki
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005663:Furans / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology; D013449:Sulfonamides / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053148:Caspase 3; D045304:Cytochromes c; D004317:Doxorubicin; D005663:Furans; D007191:Indazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D051028:bcl-2-Associated X Protein; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C513055:ABCB1 protein, human; C494826:BAX protein, human; C522973:PI103; C546842:MTOR protein, human; C505407:CASP3 protein, human; C421109:multidrug resistance-associated protein 1