LyeTxI-b, a Synthetic Peptide Derived From a Spider Venom, Is Highly Active in Triple-Negative Breast Cancer Cells and Acts Synergistically With Cisplatin

Abstract

Breast cancer is the most common cancer that affects women globally and is among the leading cause of women’s death. Triple-negative breast cancer is more difficult to treat because hormone therapy is not available for this subset of cancer. The well-established therapy against triple-negative breast cancer is mainly based on surgery, chemotherapy, and immunotherapy. Among the drugs used in the therapy are cisplatin and carboplatin. However, they cause severe toxicity to the kidneys and brain and cause nausea. Therefore, it is urgent to propose new chemotherapy techniques that provide new treatment options to patients affected by this disease. Nowadays, peptide drugs are emerging as a class of promising new anticancer agents due to their lytic nature and, apparently, a minor drug resistance compared to other conventional drugs (reviewed in Jafari et al., 2022). We have recently reported the cytotoxic effect of the antimicrobial peptide LyeTx I-b against glioblastoma cells (Abdel-Salam et al., 2019). In this research, we demonstrated the cytotoxic effect of the peptide LyeTx I-b, alone and combined with cisplatin, against triple-negative cell lines (MDA-MD-231). LyeTx-I-b showed a selectivity index 70-fold higher than cisplatin. The peptide:cisplatin combination (P:C) 1:1 presented a synergistic effect on the cell death and a selective index value 16 times greater than the cisplatin alone treatment. Therefore, an equi-effective reduction of cisplatin can be reached in the presence of LyeTx I-b. Cells treated with P:C combinations were arrested in the G2/M cell cycle phase and showed positive staining for acridine orange, which was inhibited by bafilomycin A1, indicating autophagic cell death (ACD) as a probable cell death mechanism. Furthermore, Western blot experiments indicated a decrease in P21 expression and AKT phosphorylation. The decrease in AKT phosphorylation is indicative of ACD. However, other studies are still necessary to better elucidate the pathways involved in the cell death mechanism induced by the peptide and the drug combinations. These findings confirmed that the peptide LyeTx I-b seems to be a good candidate for combined chemotherapy to treat breast cancer. In addition, in vivo studies are essential to validate the use of LyeTx I-b as a therapeutic drug candidate, alone and/or combined with cisplatin.

Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma

“…The selective effect of the OGF-Gem conjugate was evaluated against non-tumor-transformed cells in a human embryonic kidney line, HEK-293, and human primary dermal fibroblasts, HDFa. It has to be emphasized that the HEK-293 and HDFa cell lines are commonly used in research to evaluate the selective cytotoxicity against cancer cells compared to non-cancer cells [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. These results demonstrate the selective action of the new OGF-Gem conjugate on pancreatic cancer cells in comparison with classically used chemotherapeutics.…”

Spider venom-derived peptide JZTX-14 prevents migration and invasion of breast cancer cells via inhibition of sodium channels

“…Spider venom is a rich natural product with significant antitumour effects in human lung adenocarcinoma, leukaemia, liver cancer, glioblastoma, and breast cancer ( Gao et al, 2007 ; Liu et al, 2012 ; Lian et al, 2018 ; Barreto Dos Santos et al, 2019 ; Barreto et al, 2020 ; Lopez et al, 2020 ; de Avelar Júnior et al, 2022 ). We isolated and purified natural JZTX-14 from spider venom, which consists of 31 amino acids with three pairs of disulfide bonds.…”