Glioblastoma multiforme targeted therapy: The Chlorotoxin story

Cohen-Inbar, Or; Zaaroor, Menashe

doi:10.1016/j.jocn.2016.04.012

Cited by 63 publications

(49 citation statements)

References 104 publications

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“…Most of the lethal toxins found in these venoms are, in fact, peptides able to block or modulate ion channels in a myriad of cell surfaces (Pineda et al 2014). Since the role of many different ion channels in cancer pathophysiology has become evident, ion channel toxins from spiders and scorpions have been proposed to be used as anticancer peptides (Bubien et al 2004;Wang and Wang 2016;Nicoletti et al 2017), as molecular probes to elucidate the functional aspects of these channels in cancer progression and migration (Rooj et al 2012;Aissaoui et al 2018) or chemically engineered to be used as tumor imaging agent in both diagnoses and prognoses (Aroui et al 2015;Moore et al 2013;Cohen-Inbar and Zaaroor 2016). New drugs aiming at overcoming resistance through the activation of other mechanisms of cell death, like necroptosis, are currently being investigated.…”

Section: Introductionmentioning

confidence: 99%

The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells

et al. 2018

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Antimicrobial peptides present a broad spectrum of therapeutic applications, including their use as anticancer peptides. These peptides have as target microbial, normal, and cancerous cells. The oncological properties of these peptides may occur by membranolytic mechanisms or non-membranolytics. In this work, we demonstrate for the first time the cytotoxic effects of the cationic alpha-helical antimicrobial peptide LyeTx I-b on glioblastoma lineage U87-MG. The anticancer property of this peptide was associated with a membranolytic mechanism. Loss of membrane integrity occurred after incubation with the peptide for 15 min, as shown by trypan blue uptake, reduction of calcein-AM conversion, and LDH release. Morphological studies using scanning electron microscopy demonstrated disruption of the plasma membrane from cells treated with LyeTx I-b, including the formation of holes or pores. Transmission electron microscopy analyses showed swollen nuclei with mild DNA condensation, cell volume increase with an electron-lucent cytoplasm and organelle vacuolization, but without the rupture of nuclear or plasmatic membranes. Morphometric analyses revealed a high percentage of cells in necroptosis stages, followed by necrosis and apoptosis at lower levels. Necrostatin-1, a known inhibitor of necroptosis, partially protected the cells from the toxicity of the peptide in a concentration-dependent manner. Imaging flow cytometry confirmed that 59% of the cells underwent necroptosis after 3-h incubation with the peptide. It is noteworthy that LyeTx I-b showed only mild cytotoxicity against normal fibroblasts of human and monkey cell lines and low hemolytic activity in human erythrocytes. All data together point out the anticancer potential of this peptide.

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Section: Introductionmentioning

confidence: 99%

The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells

et al. 2018

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“…CTX and CTX‐conjugated nanoparticles have also been used as vehicles to deliver drugs and therapeutic macromolecules (eg, DNA, siRNA) selectively to cancer cells . Despite widespread interest in CTX for its ability to bind preferentially to cancer cells, relatively little is known about its ability to penetrate cells—a desirable pharmaceutical trait that could be utilized in drug development. Fundamental questions that currently remain unanswered include the extent of CTX uptake compared to other CPPs and whether its internalization is a property that can be tuned.…”

Section: Introductionmentioning

confidence: 99%

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

et al. 2017

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Chlorotoxin (CTX), a disulfide-rich peptide from the scorpion Leiurus quinquestriatus, has several promising biopharmaceutical properties, including preferential affinity for certain cancer cells, high serum stability, and cell penetration. These properties underpin its potential for use as a drug design scaffold, especially for the treatment of cancer; indeed, several analogs of CTX have reached clinical trials. Here, we focus on its ability to internalize into cells-a trait associated with a privileged subclass of peptides called cell-penetrating peptides-and whether it can be improved through conservative substitutions. Mutants of CTX were made using solid-phase peptide synthesis and internalization into human cervical carcinoma (HeLa) cells was monitored by fluorescence and confocal microscopy. CTX_M1 (ie, [K15R/K23R]CTX) and CTX_M2 (ie, [K15R/K23R/Y29W]CTX) mutants showed at least a twofold improvement in uptake compared to CTX. We further showed that these mutants internalize into HeLa cells largely via an energy-dependent mechanism. Importantly, the mutants have high stability, remaining intact in serum for over 24 h; thus, retaining the characteristic stability of their parent peptide. Overall, we have shown that simple conservative substitutions can enhance the cellular uptake of CTX, suggesting that such type of mutations might be useful for improving uptake of other peptide toxins.

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“…It was also found that this fraction has the ability to bind and block matrix metalloproteinase‐2 (MMP‐2) from the extracellular matrix. The MMP‐2 activation mechanism is modulated by various proteins that constitute a macromolecular complex for facilitating the migration and invasion of tumor cells (Cohen‐Inbar & Zaaroor, 2016). On the other hand, the use of chlorotoxin conjugated graphene oxide (CTX‐GO) fraction isolated from L. quinquestriatus venom was evaluated in rat glioma C6 cell line (Wang, Gu, Xiao, Ye, & Xu, 2014) (Table 3).…”

Section: Cytotoxicity Of Scorpion Venom: Mechanism Of Actionmentioning

confidence: 99%

Scorpion venoms and associated toxins as anticancer agents: update on their application and mechanism of action

Desales‐Salazar

Khusro²,

Cipriano‐Salazar

et al. 2020

J of Applied Toxicology

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Cancer remains one of the deadliest non‐infectious diseases of the 21st century, causing millions of mortalities per year worldwide. Analyses of conventional treatments, such as radiotherapy and chemotherapy, have shown not only a lower therapeutic efficiency rate but also plethora of side‐effects. Considering the desperate need to identify promising anticancer agents, researchers are in quest to design and develop new tumoricidal drugs from natural sources. Over the past few years, scorpion venoms have shown exemplary roles as pivotal anticancer agents. Scorpion venoms associated metabolites, particularly toxins demonstrated in vitro anticancer attributes against diversified cell lines by inhibiting the growth and progression of the cell cycle, inhibiting metastasis by blocking ion channels such as K+ and Cl−, and/or inducing apoptosis by intrinsic and extrinsic pathways. This review sheds light not only on in vitro anticancer properties of distinct scorpion venoms and their toxins, but also on their mechanism of action for designing and developing new therapeutic drugs in future.

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Glioblastoma multiforme targeted therapy: The Chlorotoxin story

Cited by 63 publications

References 104 publications

The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells

The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells

Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake

Scorpion venoms and associated toxins as anticancer agents: update on their application and mechanism of action

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