title: Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a poor prognosis disease lacking adequate therapy. We have previously shown that ascorbic acid administration is toxic to MPM cells. Here we evaluated a new combined therapy consisting of ascorbate/epigallocatechin-3-gallate/gemcitabine mixture (called AND, for Active Nutrients/Drug). In vitro effects of AND therapy on various MPM cell lines revealed a synergistic cytotoxic mechanism. In vivo experiments on a xenograft mouse model for MPM, obtained by REN cells injection in immunocompromised mice, showed that AND strongly reduced the size of primary tumor as well as the number and size of metastases, and prevented abdominal hemorrhage. Kaplan Meier curves and the log-rank test indicated a marked increase in the survival of AND-treated animals. Histochemical analysis of dissected tumors showed that AND induced a shift from cell proliferation to apoptosis in cancer cells. Lysates of tumors from AND-treated mice, analyzed with an antibody array, revealed decreased TIMP-1 and -2 expressions and no effects on angiogenesis regulating factors. Multiplex analysis for signaling protein phosphorylation exhibited inactivation of cell proliferation pathways. The complex of data showed that the AND treatment is synergistic in vitro on MPM cells, and blocks in vivo tumor progression and metastasization in REN-based xenografts. Hence, the AND combination is proposed as a new treatment for MPM.
authors.affiliation: Molecular Histology and Cell Growth Laboratory, San Raffaele Science Institute, Milano, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Volta
authors.forename: Elia
authors.initials: E
authors.lastname: Ranzato
authors.forename: Simona
authors.initials: S
authors.lastname: Martinotti
authors.forename: Simone
authors.initials: S
authors.lastname: Gallo
authors.forename: Maria Veronica
authors.initials: MV
authors.lastname: Russo
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
authors.forename: Bruno
authors.initials: B
authors.lastname: Burlando
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D002392:Catechin; C045651:epigallocatechin gallate; D001205:Ascorbic Acid; D000093542:Gemcitabine