Abstract

The effect on the cytotoxicity against breast cancer cell lines of the substitution of 26Met residue in the sequence of the Bovine Lactoferricin-derived dimeric peptide LfcinB (20-30)2: (20RRWQWRMKKLG30)2-K-Ahx with amino acids of different polarity was evaluated. The process of the synthesis of the LfcinB (20-30)2 analog peptides was similar to the original peptide. The cytotoxic assays showed that some analog peptides exhibited a significant cytotoxic effect against breast cancer cell lines HTB-132 and MCF-7, suggesting that the substitution of the Met with amino acids of a hydrophobic nature drastically enhances its cytotoxicity against HTB-132 and MCF-7 cells, reaching IC50 values up to 6 µM. In addition, these peptides have a selective effect, since they exhibit a lower cytotoxic effect on the non-tumorigenic cell line MCF-12. Interestingly, the cytotoxic effect is fast (90 min) and is maintained for up to 48 h. Additionally, through flow cytometry, it was found that the obtained dimeric peptides generate cell death through the apoptosis pathway and do not compromise the integrity of the cytoplasmic membrane, and there are intrinsic apoptotic events involved. These results show that the obtained peptides are extremely promising molecules for the future development of drugs for use against breast cancer.

Highlights

  • Cancer is considered to be the biggest public health problem worldwide [1], being the second most common cause of death in the world

  • In order to identify peptides derived from the dimeric peptide LfcinB (20-30)2 with enhanced anticancer activity against breast cancer cell lines, six dimeric peptides were synthesized via SPPS-Fmoc/tBu, purified by means of RP-Solid Phase Extraction (SPE), and characterized through RP-HPLC and MALDI-TOF MS (Supplementary Materials, Figure S3), Table 1

  • The synthesis of analog peptides was similar to that of the original dimeric peptide 26[M], indicating that the substitution of amino acids does not affect the synthesis of the peptides

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Summary

Introduction

Cancer is considered to be the biggest public health problem worldwide [1], being the second most common cause of death in the world. In 2018, 8.2 million people died from this disease, and 14 million new cases are reported annually [2], with more than 60% occurring in Asia, Africa, and South America. In 2012, the most frequently diagnosed cancers in women were breast, colon, rectum, lung, cervix, and stomach, while for men they were lung, prostate, colon, rectum, stomach, and liver [3]. Breast cancer is the most common cancer type diagnosed worldwide [4]. There are 2.1 million cases annually, and 627,000 deaths of women due to this disease were reported in 2018 [5]. There are therapeutic options such as chemotherapy [6], radiotherapy [7], hormone therapy [8], and surgery [9]

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