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Cellular and Molecular Biology 70: Signal Transduction 2

Chlorotoxin, a small peptide derived from scorpion venom, targets cancer cells via a phosphatidylinositol phosphate

Carol A. Grimes, Matthew A. Gonda and Vernon L. Alvarez
Carol A. Grimes
TransMolecular, Inc., Birmingham, AL
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Matthew A. Gonda
TransMolecular, Inc., Birmingham, AL
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Vernon L. Alvarez
TransMolecular, Inc., Birmingham, AL
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DOI:  Published May 2005
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Proc Amer Assoc Cancer Res, Volume 46, 2005

Abstract

5520

Chlorotoxin, also called TM-601, is a 36-amino acid peptide originally derived from the venom of the Giant Israeli scorpion Leiurus quinquestriatus. In previous studies, chlorotoxin appeared to bind specifically to glioblastoma cell lines and glioblastoma sections, but not to normal brain tissue, and tumor-specific binding was later extended to neuroectodermal tissue. In the present study, using colorimetric binding assays, histochemical staining, and FACS analysis, we demonstrate that chlorotoxin binds to multiple human cancer cell lines and tissues, including solid tumors (glioma, lung, breast, prostate, melanoma, colorectal), as well as hematologic tumor cell lines (leukemia, lymphoma, myeloma). Furthermore, we have dissected the amino acid sequence of chlorotoxin and demonstrated that there are two distinct binding domains in this small molecule, designated α and β, each capable of binding tumor cells. The specific target and mechanism of action of chlorotoxin has remained unclear. To address this, multiple human tumor cell lines were used to localize chlorotoxin binding. In all cell lines tested, chlorotoxin binding was predominantly localized to cellular lamellipodia, organelles involved in signal transduction, cell invasion, adhesion, and motility. Because membrane phospholipids are crucial regulatory components of intracellular signaling pathways, the ability of chlorotoxin to bind phosphatidylinositol phosphates was investigated. Using an in vitro binding assay, we illustrate that chlorotoxin binds multiple phosphatidylinositol isoforms and binds with greatest affinity to phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2), a membrane phospholipid vital to the PI3K-Akt pathway that has been implicated in multiple human cancers. This binding could profoundly affect many cellular functions, including subsequent signal transduction events, cell cycle changes, protein and DNA synthesis, and cell movement. In summary, these data provide solid evidence that chlorotoxin binds multiple human cancer types, including solid and hematologic tumors, and that the α and β domains of chlorotoxin facilitate binding of chlorotoxin to cancer cells through a membrane phosphatidylinositol localized to the lamellipodia of cancer cells. 131I-TM-601, a synthetic version of chlorotoxin conjugated to a radioisotope of iodine, is currently in Phase II clinical development for the treatment of malignant brain tumors.

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Cancer Research: 65 (9 Supplement)
May 2005
Volume 65, Issue 9 Supplement
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Chlorotoxin, a small peptide derived from scorpion venom, targets cancer cells via a phosphatidylinositol phosphate
Carol A. Grimes, Matthew A. Gonda and Vernon L. Alvarez
Cancer Res May 1 2005 (65) (9 Supplement) 1300;

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Chlorotoxin, a small peptide derived from scorpion venom, targets cancer cells via a phosphatidylinositol phosphate
Carol A. Grimes, Matthew A. Gonda and Vernon L. Alvarez
Cancer Res May 1 2005 (65) (9 Supplement) 1300;
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