title: Interleukin-6, osteopontin and Raf/MEK/ERK signaling modulate the sensitivity of human myeloma cells to alkylphosphocholines.
abstract: Alkylphosphocholines are highly active against multiple myeloma (MM) cells in vitro and are devoid of myelotoxicity. Little is known about the determinants of MM cell responsiveness or resistance to these drugs. In this study we investigated the effects of disease-relevant cytokines, such as interleukin-6 (IL-6) and osteopontin (OPN), on the in vitro antimyeloma activity of erufosine and perifosine. The role of the Raf/MEK/ERK pathway was also studied. Exogenous IL-6 reduced the cytotoxicity of erufosine against OPM-2 cells and, to a smaller extent, against U-266 cells. This was accompanied by inhibition of apoptosis in OPM-2 cells. The efficacy of perifosine was similarly affected, but to a greater extent. IL-6 slightly enhanced the sensitivity of RPMI-8226 cells to erufosine, thus emphasizing the heterogeneity of MM. Induced overexpression of OPN isoforms made OPM-2 cells less sensitive to erufosine. In all cases of IL-6- or OPN-induced resistance, the effective concentrations of erufosine were still within the clinically achievable range. Like other alkylphosphocholines, erufosine enhanced Raf/MEK/ERK signaling in MM cells but in some cases this contributed to cytotoxicity.
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria. deyanyosifov@abv.bg
authors.forename: Deyan Y
authors.initials: DY
authors.lastname: Yosifov
authors.forename: Christina
authors.initials: C
authors.lastname: Reufsteck
authors.forename: Spiro M
authors.initials: SM
authors.lastname: Konstantinov
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D010755:Organophosphates; D000644:Quaternary Ammonium Compounds; C472787:erucylphospho-N,N,N-trimethylpropylammonium; D053495:Osteopontin; D010767:Phosphorylcholine; C105905:perifosine; D019908:Proto-Oncogene Proteins c-raf