title: Triphenylmethyl derivatives enhances the anticancer effect of immunotoxins.
abstract: The combined use of several drugs targeting different cellular functions is one approach to achieve tumor control in cancer. We studied the effects of Pseudomonas exotoxin A (PE)-based immunotoxins (ITs), the 9.2.27PE and the 425.3PE, together with 2 different triphenylmethyl derivatives, triphenylmethyl phosphonates and phosphonochloridates (TPMP)-I-2 and 4BI. Combining the triphenylmethyl derivatives with ITs enhanced the cytotoxic effect of the ITs, with TPMP-I-2 in combination with the 425.3PE (targeting the epidermal growth factor receptor) being the most promising combination. The cytotoxicity involving signs of apoptosis was observed in cancer cells from different origins in vitro. It is interesting to note that treatment with IT, TPMP-I-2, or 4BI alone or in combination resulted in strongly decreased protein levels of stearoyl-CoA desaturase. Stearoyl-CoA desaturase is the rate-limiting enzyme for converting saturated fatty acids into monounsaturated fatty acids needed for membrane genesis. Furthermore, the combination of 425.3PE and TPMP-I-2 prolonged the survival time of nude rats in a simulated micrometastatic cervical cancer model. In addition, we demonstrate that a combination of the 425.3PE and 4BI was more effective in reducing tumor growth in a breast cancer model in nude mice compared with either agent alone.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet and Faculty Division the Norwegian Radium Hospital, University of Oslo, Norway. Karianne.Risberg@rr-research.no
authors.forename: Karianne
authors.initials: K
authors.lastname: Risberg
authors.forename: Ingrid Jenny
authors.initials: IJ
authors.lastname: Guldvik
authors.forename: Rahul
authors.initials: R
authors.lastname: Palchaudhuri
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Xi
authors.forename: Jingfang
authors.initials: J
authors.lastname: Ju
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Andersson
mesh_terms: D036002:ADP Ribose Transferases / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000276:immunology / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005098:Exotoxins / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D063065:Organophosphonates / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011923:Rats, Nude; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis* / Q000235:genetics; D014320:Triphenylmethyl Compounds / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D037521:Virulence Factors / Q000276:immunology / Q000494:pharmacology*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D053148:Caspase 3; D066246:ErbB Receptors; D005098:Exotoxins; D000922:Immunotoxins; D063065:Organophosphonates; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D013230:Stearoyl-CoA Desaturase; D014320:Triphenylmethyl Compounds; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C499321:Parp1 protein, mouse