title: A novel pro-apoptotic effector lactaptin inhibits tumor growth in mice models.
abstract: Lactaptin, a human milk-derived protein, induces apoptosis in cultured tumor cells. We designed a recombinant analog of lactaptin (RL2) and tested its antitumor activity. The sensitivity of hepatocarcinoma A-1 (HA-1), Lewis lung carcinoma, and Ehrlich carcinoma to RL2 were tested to determine the most reliable in vitro animal model. HA-1 cells, which had the highest sensitivity to RL2, were transplanted into A/Sn mice to investigate RL2 antitumor activity in vivo. Investigation of the molecular effects of RL2 shows that RL2 induces apoptotic transformation of HA-1 cells in vitro: phosphatidylserine translocation from inner side of the lipid bilayer to the outer one and dissipation of the mitochondrial membrane potential. Repetitive injections of RL2 (5-50 mg/kg) for 3-5 days effectively inhibited ascites and solid tumor transplant growth when administered intravenously or intraperitoneally, without obvious side effects. The solid tumor inhibitory effect of RL2 (5 i.v. injections, cumulative dose 125 mg/kg) was comparable with that of cyclophosphamide at a therapeutic dose (5 i.v. injections, cumulative dose 150 mg/kg). In combination therapy with cyclophosphamide, RL2 had an additive antitumor effect for ascites-producing tumors. Histomorphometric analysis indicated a three-fold reduction of spontaneous metastases in the liver of RL2-treated mice with solid tumor transplants in comparison with control animals. Repeated RL2 treatment substantially prolonged the lifespan of mice with intravenously injected tumor cells. Recombinant analog of lactaptin effectively induced apoptosis of tumor cells in vitro and suppressed the growth of sensitive tumors and metastases in vivo.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrentiev av. 8, Novosibirsk 630090, Russia. o_koval@ngs.ru
authors.forename: Olga A
authors.initials: OA
authors.lastname: Koval
authors.forename: Alexandr S
authors.initials: AS
authors.lastname: Fomin
authors.forename: Vasily I
authors.initials: VI
authors.lastname: Kaledin
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Semenov
authors.forename: Miraslava O
authors.initials: MO
authors.lastname: Potapenko
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kuligina
authors.forename: Valery P
authors.initials: VP
authors.lastname: Nikolin
authors.forename: Eugeny V
authors.initials: EV
authors.lastname: Nikitenko
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Richter
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002364:Caseins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002364:Caseins; D011994:Recombinant Proteins; C551270:lactaptin, human; D003520:Cyclophosphamide