title: Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential.
abstract: Brain tumors are fast proliferating and destructive within the brain microenvironment. Effective chemotherapeutic strategies are currently lacking which combat this deadly disease curatively. The glioma-specific chloride ion channel represents a specific target for therapy. Chlorotoxin (CTX), a peptide derived from scorpion venom, has been shown to be specific and efficacious in blocking glioma Cl(-) channel activity. Here, we report on two new derivatives (termed CA4 and CTX-23) designed and generated on the basis of the peptide sequence alignments of CTX and BmKCT. The novel peptides CA4 and CTX-23 are both effective in reducing glioma cell proliferation. In addition, CTX, CA4 and CTX-23 impact on cell migration and spheroid migration. These effects are accompanied by diminished cell extensions and increased nuclear sizes. Furthermore, we found that CA4 and CTX-23 are selective with low toxicity against primary neurons and astrocytes. In the ex vivo VOGiM, which maintain the entire brain tumor microenvironment, both CTX and CA4 display anti-tumor activity and reduce tumor volume. Hence, CTX and CA4 reveal anti-angiogenic properties with endothelial and angiogenic hotspots disrupting activities. These data report on the identification of two novel CTX derivatives with multiple anti-glioma properties including anti-angiogenesis.
authors.affiliation: Translational Neurooncology Lab, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Tengfei
authors.initials: T
authors.lastname: Xu
authors.affiliation: Translational Neurooncology Lab, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072 P.R. China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: Translational Research Center, Department of Cardiology and Angiology, Universitätsklinikum Erlangen, Schwabachanlage 12, 91054 Erlangen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dietel
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072 P.R. China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Gynecology and Obstetrics, &Comprehensive Cancer Center Erlangen-EMN, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, Erlangen, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, Erlangen, Germany.
authors.forename: Jana K
authors.initials: JK
authors.lastname: Wrosch
authors.affiliation: Translational Neurooncology Lab, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: Translational Neurooncology Lab, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Ilker Y
authors.initials: IY
authors.lastname: Eyupoglu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072 P.R. China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Translational Neurooncology Lab, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen - Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Nicolai E
authors.initials: NE
authors.lastname: Savaskan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D012604:Scorpion Venoms; C091539:Chlorotoxin
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