title: In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines.
abstract: The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and oncological malignancies. The in vitro cytotoxicity of perifosine, bortezomib and lenalidomide against 6 cell lines derived from hematological malignancies was investigated using trypan blue staining, flow cytometry-based detection of activated caspases, Annexin V assays, immunohistochemistry studies (KI-67 and caspase-3 staining) and the immature-myeloid-information (IMI) technique. Perifosine and bortezomib induced concentration- and time-dependent cytotoxicity in all cell lines tested. Perifosine together with bortezomib largely exerted additive or synergistic effects with combination indices ranging from 1.13 to 0.22 for combined efficacies of 25% to 75% after 24-hour incubation. Lenalidomide-triggered cytotoxicity was low in all cell lines tested with any assay (less than 10% compared to the negative control). Finally, perifosine, but not bortezomib or lenalidomide, significantly increased the number of cells detected in the IMI channel. Perifosine and bortezomib- but not lenalidomide- trigger substantial cytotoxicity by caspase activation and mainly act additively or synergistically. The IMI technique might be a useful tool for studying cytotoxicity of agents like perifosine that interact mainly with the cellular membrane.
authors.affiliation: Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. martin.schmidt-hieber@charite.de
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt-Hieber
authors.forename: Robert
authors.initials: R
authors.lastname: Dabrowski
authors.forename: Andreas
authors.initials: A
authors.lastname: Weimann
authors.forename: Babette
authors.initials: B
authors.lastname: Aicher
authors.forename: Philipp
authors.initials: P
authors.lastname: Lohneis
authors.forename: Antonia
authors.initials: A
authors.lastname: Busse
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Igor W
authors.initials: IW
authors.lastname: Blau
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D019394:Ki-67 Antigen / Q000378:metabolism; D000077269:Lenalidomide; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D019394:Ki-67 Antigen; D011719:Pyrazines; D010767:Phosphorylcholine; C105905:perifosine; D013792:Thalidomide; D000069286:Bortezomib; C505407:CASP3 protein, human; D053148:Caspase 3; D000077269:Lenalidomide