The Study of
venom
Venom toxins
is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin.
Chlorotoxin
Glioma, a Difficult to Cure Human Brain Cancer
Amongst primary brain tumors, gliomas can be considered as the most lethal malignant tumors. This is a family of central nervous system (CNS) tumors derived from differentiated glial cells or glioblastoma stem-like cells. It is composed of glioblastoma multiforme (GBM), anaplastic astrocytoma, astrocytoma and oligodendroglioma. The two first gliomas occur at an incidence of 78% of all the primary brain tumors. Gliomas represent very aggressive brain cancers characterized with a fast cell proliferation rate and a strong tendency to invade healthy brain tissue (French Foundation for medical research). Even low-grade gliomas infiltrate the entire brain. The molecular mechanisms of brain tumor invasion are complex. They involve
(i) modification of receptor-mediated adhesive properties of tumors cells;
(ii) degradation and remodeling of the extracellular matrix by tumor-secreted metalloproteinases; and
(iii) creation of an intercellular space for tumor cell invasion. Standard treatment involves surgery whenever the tumor mass is accessible, followed by chemoradiation and adjuvant chemotherapy with temozolomide. In spite of this therapeutic arsenal, the survival rate of patients rarely exceeds sixteen months. At best, 3% of the patients may benefit of a five-year survival time. This fatal outcome points to other major issues with gliomas, which is their resistance to radiation and chemotherapy, and the difficulty to accurately localize them within the tissue. Although it is possible to roughly visualize the tumor with current imaging techniques, it is very tedious to determine the exact boundaries of tumor invasion. In addition, diagnosis of this cancer still requires tissue biopsy and histopathological analyses. Histological features of interest comprise vascular proliferation and focal necrosis.
Mechanism of glioma cell invasion.
Cell invasion is a natural mechanism that plays an important role in embryonic development, wound healing, immune response and tissue repair. In this situation, the cell migrates on the influence of chemical signals, physical cues and physicochemical processes. Unfortunately, when this complex mechanism is affected by deleterious mutations, an uncontrolled cell invasion leads to the development of several pathologies (e.g., arthritis, atherosclerosis, aneurism, chronic obstructive pulmonary disease, etc.). In the case of cancer, it leads to metastasis or an infiltrative tumor. One of the major characteristics of glioma cells is their propensity to invade healthy brain tissue. The principal mode of invasion of a glioma cell is a single cell invasion, which can be decomposed into five steps:
(i) change in glioma cell morphology (formation of membrane protrusions);
(ii) interaction between membrane protrusions and extracellular matrix (ECM) to obtain traction;
(iii) degradation of ECM by matrix metalloprotease (MMP)-proteins among others; (iv) change of shape (contraction) for the cell to cross the “ECM hole”; (v) detachment of the rear end connection (the cell moves forward). The key abilities for glioma cells to invade healthy brain tissue are modification of cell adhesion property, degradation of ECM, and change of shape. The invading tumor cells do not spread anarchically in the brain, the degradation of ECM occurs at the border between the tumor and the healthy tissue. The invading cells spread following existing anatomical structures such as nerves and blood vessels . During the first steps of invasion, glioma cells will interact with ECM and its environment thanks to adhesion proteins, especially integrins, giving the cell traction points to displace. Then, using proteolytic enzymes, such as the MMP proteins, the cells begin to degrade the ECM, to create a space in which through which they can pass. In order to move through the newly created space, glioma cells need a change in shape and volume. At this point, glioma cells use ionic channels (Cl− and K+ channel) to shrink, and so fit the space to pursue the invasion. Because of adhesion molecules and specific cell surface receptors, cancer cells move forward in the invasive direction . When the invasive cells reach a certain distance from the primary tumor mass, they re-enter the cell cycle and form a new tumor mass.
Chlorotoxin, a Natural Peptide Acting as
a Potent Glioma Marker
CTX is a small neurotoxin of 36 amino acids, isolated in 1993 from the venom of the Israeli scorpion Leiurus quinquestriatus . It holds great promise for the treatment of glioma and other solid tumors. CTX has a compact structure, which is maintained by four disulfide bonds that connect the eight cysteine residues present in the sequence. The amino acid sequence of this natural peptide is detailed. The cysteine pattern adopted is of the type C1–C4, C2–C6, C3–C7 and C5–C8. Three small antiparallel β-sheets are packed against an α-helix (Figure 1B). With its compact structure, CTX was proposed to cross the BBB (TransMolecular, Inc., Cambridge, MA, USA; unpublished data). However, the data were not sufficiently substantiated to firmly demonstrate that CTX crosses the BBB rather than the BBTB. Nevertheless, it was clear that CTX diffused deeply into the tumors while other targeting agents such as antibodies could not . Another report showed that in transgenic mice that spontaneously develop brain medulloblastoma cancers, a fluorescently-tagged Cy5.5-CTX labeled cancer cells while no disruption of the BBB was observed (exclusion of blue Evans labeling of brain structures) . Since this is the only study that investigates the issue of the BBB crossing by CTX and that BBB disturbance by tumors may depend on the tumor type and the stage of progression, it remains cautious to state that CTX crosses at least the BBTB. As a component of the scorpion venom, CTX induces paralysis in small insects or other invertebrates that may be stung by the scorpion. When injected in vertebrates, however, no apparent signs of toxicity have been observed. This indicates that the binding of CTX on its cell surface receptor has no cell toxic or unwanted physiological consequences, as observed for many other animal toxins.
Animal Toxins, Wonderful Potent Natural Peptides for Therapy and Diagnosis
Peptides are increasingly considered as good drug candidates for therapeutic applications. In 2009, 438 peptides were considered by the pharmaceutical industry in their development programs. Of these candidates, 72 were in Phase III clinical trials. Forty-eight peptides are now on the market. In 2007, four of them reached global sales over 500 million dollars each: copaxane ($3.33 billions), lupron ($1.88 billions), byetta ($967 millions) and forteo ($709 millions). The majority of these peptides target G protein coupled receptors, although other targets are increasingly common, such as ion channels.A complete report on the development of peptides as therapeutic drugs can be requested from http://www.peptidetherapeutics.org. Obviously, it may seem odd at first glance to consider animal toxins as potential drugs. However, animal venoms are enriched sources of biologically active peptides of about 100 to a 1000 different components. In addition, peptides issued from venoms are tailored by Nature to be extremely stable in vivo. Different from synthetic chemical libraries, all toxins present in venoms are active, often at nanomolar affinities. In addition, while venoms can be toxic, the toxicity is mainly due to a few peptide members or to the synergistic effect of a combination of peptides. As a matter of fact, the vast majority of venom components possesses interesting therapeutic potential that can be usefully exploited. Hence, several toxins are actually in various clinical phases for the treatment of pain, epilepsy, cancer, atherosclerosis and cardiac failure. It might be of interest that many of these natural peptides target ion channels, ionotropic receptors, transporters and G protein coupled receptors. They also have been found to target enzymes, all constituting major pharmacological classes for the treatment of pathological conditions. Other unusual cell targets have been reported. Disintegrins, a group of snake venom toxins, have the potential to block cancer cell migration and invasion via an RGD-dependent sequence that interacts with integrins, a class of membrane proteins required for cell immobilization through interaction with the extracellular matrix
Chlorotoxin
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