title: Zinc enhances temozolomide cytotoxicity in glioblastoma multiforme model systems.
abstract: Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients positively respond to it. It has been shown that zinc metal reestablishes chemosensitivity but this effect has not been tested with TMZ. Using both in vitro and in vivo experimental approaches, we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and Caspase-3 expression and a decrease in growth fraction as manifested by low ki67 and lower colony formation. Analysis of GBM as intracranial xenografts in athymic mice and administration of concurrent TMZ and zinc yielded results consistent with those of the in vitro analyses. The co-treatment resulted in significant reduction in tumor volume in TMZ/zinc treated mice relative to treatment with TMZ alone. Our results suggest that zinc may serve as a potentiator of TMZ therapy in GBM patients.
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Toren
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Pismenyuk
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Yalon
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Freedman
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Fisher
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Moshe
authors.affiliation: YachayTech University, Urcuquí, Ecuador.
authors.forename: Juergen K V
authors.initials: JK
authors.lastname: Reichardt
authors.affiliation: Department of Pediatric Neurosurgery, Dana Children's Hospital, Tel-Aviv-Sourasky Medical Center, Israel.
authors.forename: Shlomi
authors.initials: S
authors.lastname: Constantini
authors.affiliation: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Mardor
authors.affiliation: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Last
authors.affiliation: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Guez
authors.affiliation: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Dianne
authors.initials: D
authors.lastname: Daniels
authors.affiliation: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Moria
authors.initials: M
authors.lastname: Assoulin
authors.affiliation: Pediatric Hemato-Oncology, Edmond and Lilly Safra Children's Hospital and Cancer Research Center, Sheba Medical Center, Tel Hashomer Affiliated to The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Ruty
authors.initials: R
authors.lastname: Mehrian-Shai
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000077204:Temozolomide; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; D019394:Ki-67 Antigen; D051028:bcl-2-Associated X Protein; D003606:Dacarbazine; D053148:Caspase 3; D015032:Zinc; D000077204:Temozolomide
keywords: chemosensitivity; glioblastoma multiforme; proliferation; temozolomide; zinc