Abstract
Glioblastoma is an aggressive cancer, against which medical professionals are still quite helpless, due to its resistance to current treatments. Scorpion toxins have been proposed as a promising alternative for the development of effective targeted glioblastoma therapy and diagnostic. However, the exploitation of the long peptides could present disadvantages. In this work, we identified and synthetized AaTs-1, the first tetrapeptide from Androctonus australis scorpion venom (Aa), which exhibited an antiproliferative effect specifically against human glioblastoma cells. Both the native and synthetic AaTs-1 were endowed with the same inhibiting effect on the proliferation of U87 cells with an IC50 of 0.56 mM. Interestingly, AaTs-1 was about two times more active than the anti-glioblastoma conventional chemotherapeutic drug, temozolomide (TMZ), and enhanced its efficacy on U87 cells. AaTs-1 showed a significant similarity with the synthetic peptide WKYMVm, an agonist of a G-coupled formyl-peptide receptor, FPRL-1, known to be involved in the proliferation of glioma cells. Interestingly, the tetrapeptide triggered the dephosphorylation of ERK, p38, and JNK kinases. It also enhanced the expression of p53 and FPRL-1, likely leading to the inhibition of the store operated calcium entry. Overall, our work uncovered AaTs-1 as a first natural potential FPRL-1 antagonist, which could be proposed as a promising target to develop new generation of innovative molecules used alone or in combination with TMZ to improve glioblastoma treatment response. Its chemical synthesis in non-limiting quantity represents a valuable advantage to design and develop low-cost active analogues to treat glioblastoma cancer.
Highlights
Glioblastoma is the most aggressive primary brain tumor, reaching 50–60% of gliomas.It is classified as grade IV based on its level of malignancy by the World Health Organization [1]
The number of cells in the G0/G1, S, and G2/M phases was 7.5%, 64%, and 18.5%, respectively (Supplementary Materials Figure S4C). All these results supported that the antiproliferative effect of australis Tetrascorpin-1 (AaTs-1) on U87 cells is neither due to the induction of apoptosis nor to the cell cycle arrest but rather by another mechanism; we investigated the role of some important and studied markers linked to the growth of U87 glioblastoma cells in vitro such as the epidermal growth factor receptor (EGFR) [23], the tumor suppressor protein p53 [24,25], AKT (Protein kinase B); ERK1/2 (Extracellular-signal-Regulated Kinases 1 and 2); p38 (p38 mitogen-activated protein kinase) and JNK (Jun N-terminal Kinases) [26]
Given that AaTs-1 represents only 0.87% of the Androctonus australis scorpion venom, we chemically synthesized the tetrapeptide on Wang resin by means of Fmoc/But procedure in order to be further studied
Summary
Glioblastoma is the most aggressive primary brain tumor, reaching 50–60% of gliomas. It is classified as grade IV based on its level of malignancy by the World Health Organization [1]. Radiation therapy associated to daily chemotherapy is the second line of standard treatment for patients less than 70 years [3]. There is an urgent need to find or produce more effective drugs against glioblastoma [9] In this context, scientists are currently focused on searching for active biomolecules to develop targeted therapies. Scientists are currently focused on searching for active biomolecules to develop targeted therapies Scorpion toxins, such as Chlorotoxin (Cltx), purified from. Only TM-601, a synthetic version of chlorotoxin, has reached the phase III clinical trials [12] It crosses the blood-brain barrier and binds to malignant brain tumor cells, without affecting healthy tissue [12]. (AaTs-1), bearing antiproliferative activity against human U87 glioblastoma cells
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