A Conjugate between Lqh-8/6, a Natural Peptide Analogue of Chlorotoxin, and Doxorubicin Efficiently Induces Glioma Cell Death 


Glioma is a type of brain tumor that originates in the glial cells, which are the supportive cells of the brain. These tumors can be either benign or malignant, and their symptoms and treatment depend on their location, size, and grade. Gliomas are classified into three main types: astrocytoma, oligodendroglioma, and ependymoma. Glioblastoma is a highly aggressive and malignant form of brain cancer that arises from glial cells. It is the most common type of glioma and has a poor prognosis due to its rapid growth and tendency to spread quickly throughout the brain. Treatment typically involves surgery, radiation therapy, and chemotherapy, but the tumor often recurs despite aggressive treatment. Natural peptides taken out of animal venom often have a high affinity and specificity for cell surface receptors. Several of these receptors are frequently overexpressed in cancer cells. Chlorotoxin is a small peptide toxin found in the venom of the deathstalker scorpion. It has been shown to selectively bind to certain types of cancer cells, including gliomas, and may be used as a diagnostic and therapeutic tool for brain cancer. Chlorotoxin has also been studied for its potential to deliver therapeutic agents directly to cancer cells while sparing healthy cells. Doxorubicin is a chemotherapy drug that is commonly used to treat a variety of cancers, including breast cancer, lymphoma, and leukemia. It works by inhibiting DNA synthesis and damaging cancer cells. However, it can also cause side effects such as nausea, hair loss, and an increased risk of infection.

To this note, Dr. Michel De Waard and co-workers from the Nantes Université, CNRS reported the discovery of a natural peptide analogue of chlorotoxin, Lqh-8/6, Chlorotoxin is a known and effective substance for the detection and treatment of gliomas. Lqh-8/6 and two additional natural counterparts were chemically synthesised, and their capacity to identify, and inhibit in vitro glioma cells was evaluated. The authors demonstrated that a biotinylated form of Lqh-8/6 enables the labeling of glioma cell lines as well as the identification of glioma in brain slices of Fisher rats that had received glioma allografts. The research work is now published in the journal Biomedicines.

The researchers chemically synthesized Lqh-8/6 for the first time using solid-phase peptide synthesis, which is a method of producing peptides by linking amino acids on a solid support. They produced two variants of Lqh-8/6: one with a biotin molecule attached to it, and one with an azide group that can react with an alkyne group by click chemistry. The researchers used the biotinylated Lqh-8/6 to label and detect glioma cells in vitro (in cell culture) and in situ (in brain slices) from rats that had glioma allografts (tumors transplanted from another rat). They found that Lqh-8/6 bound selectively to glioma cells and not to normal brain cells. They also tested the effect of Lqh-8/6 on glioma cell toxicity, migration and invasion. They found that Lqh-8/6 did not cause cell death or affect cell movement, but it significantly reduced cell invasion, which is the ability of tumor cells to spread into surrounding tissues. The researchers then coupled Lqh-8/6 with doxorubicin, an anti-tumor agent that can cause DNA damage and cell death. They used click chemistry to join the azide group on Lqh-8/6 with the alkyne group on doxorubicin, forming a hybrid molecule called Lqh-8/6-doxorubicin. They tested the hybrid molecule on two glioma cell lines: rat F98 and human U-87, which are commonly used in experimental neuro-oncology. They found that Lqh-8/6-doxorubicin caused significant cell death in both cell lines, and induced caspase-3 dependent cell apoptosis (a type of programmed cell death) in human U-87 cells. Finally, they tested the hybrid molecule in vivo (in living animals) by injecting it into rats that had F98 allografts implanted in their brains. They found that Lqh-8/6-doxorubicin significantly delayed tumor growth compared to control groups. The research provides a promising proof-of-concept for developing PDCs based on natural peptides as leads for drug discovery and targeted therapy for glioma and other cancers.

In conclusion, the findings of Dr. Michel De Waard and colleagues supports the hypothesis that peptides from animal venom can be employed as warheads to deliver anti-tumor medicines. An extremely stable disulfide-bridge organized fold and millions of years of evolution are to blame for its stability. They used a natural peptide as an example since its sequence is comparable to that of chlorotoxin, but there is a lot of optimism that other peptides might also have positive targeting effects on malignancies that are unrelated to chlorotoxin. In a statement to Medicine Innovates Dr. Michel De Waard said “Antibody-drug conjugates have become increasingly popular for the treatment of tumors; Here the objective was to demonstrate that natural peptide-drug conjugates can be no less effective for targeting cancer cells and treating tumors with the extra benefit of reduced costs and higher tissue accessibility owing to the small size of these promising new conjugates“.


Dardevet L, Najlaoui F, Aroui S, Collot M, Tisseyre C, Pennington MW, Mallet JM, De Waard M. A Conjugate between Lqh-8/6, a Natural Peptide Analogue of Chlorotoxin, and Doxorubicin Efficiently Induces Glioma Cell Death. Biomedicines. 2022;10(10):2605.

Go To Biomedicines.