melitten and Uterine-Cervical-Neoplasms

Cervical cancer has recently become one of the most prevalent cancers among women throughout the world. Traditional cancer therapies generate side effects due to off-target toxicity. Thus, novel cancer medications coupled with suitable drug delivery systems are required to improve cancer therapies. Melittin peptide has a high affinity to disrupt cancer cells. In this study, we designed targeted and redox-responsive Melittin conjugates for cervical cancer and then tested them in vitro. Folic acid and squamous cell carcinoma-specific peptide (CKQNLAEG) were used as targeting agents to design various conjugates. Our findings indicate that both anticancer conjugates were effective against different cancer cell lines, including MCF-7, C33A, and HeLa. Moreover, these conjugates were found to have antioxidant and antibacterial effects as well as reduced hemolytic activity. The CM-Target (N-terminus cysteine modified-Melittin-targeting peptide-functionalized conjugate) has become more stable and acted specifically against squamous cell carcinoma, whereas folic acid (FA)-containing conjugates acted efficiently against all cancer types studied, especially for breast cancer. According to our results, these anticancer conjugates may be possible anticancer drug candidates that have fewer adverse effects.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Female; Folic Acid; HeLa Cells; Humans; Melitten; Oxidation-Reduction; Pharmaceutical Preparations; Uterine Cervical Neoplasms

Melittin's non-specific cytotoxicity and hemolytic activity restrict its clinical use, but polypeptide modification is thoμght to be highly selective and well-tolerated. Here, we synthesized a novel antineoplastic peptide UM-6 based on melittin and explored the mechanism related to its anti-proliferation and metastasis on cervical cancer (CC). In the present study, we demonstrated that UM-6 inhibits viability of CC cell lines Caski and Hela in vitro by inducing apoptosis and autophagy with low toxicity to normal epithelial cells. UM-6 also triggers the Hippo signaling pathway, promoting cytoplasmic retention and phosphorylation-dependent degradation of YAP, as well as inhibiting YAP-TEAD binding and reducing transcriptional activity, suppressing downstream target gene expression. Injection of UM-6 in mice can significantly inhibit the growth of xenograft tumors, and greatly reduce the number, volume, and burden of abdominal tumors in the metastasis models without significant toxicity. These current results suggest that UM-6 has the potential to serve as a new anticancer drug candidate.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Cell Proliferation; Cytoplasm; Epithelial Cells; Female; Gene Expression; HaCaT Cells; HeLa Cells; Heterografts; Hippo Signaling Pathway; Humans; Melitten; Mice; Mice, Inbred BALB C; Mice, Nude; Peptides; Transcription Factors; Transcription, Genetic; Uterine Cervical Neoplasms

Conjugate compounds constitute a new class of molecules of important biological interest mainly for the treatment of diseases such as cancer. The N-terminus region of cationic peptides has been described as important for their biological activity. The aim of this study was to evaluate the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and the effect of conjugating this macromolecule with gallic acid (C7H6O5) in terms of structure, anti-cancer activity, and toxicity. An N-terminus GA-Hecate peptide conjugate was synthesized to provide information regarding the relationship between the amino-terminal region and its charge and the secondary structure and biological activity of the peptide; and the effects of gallic acid on these parameters. Peptide secondary structure was confirmed using circular dichroism (CD). The CD measurements showed that the peptide has a high incidence of α-helical structures in the presence of SDS and LPC, while GA-Hecate presented lower incidence of α-helical structures in the same chemical environment. An evaluation of the anti-cancer activity in HeLa cancer cells indicated that both peptides are active, but that coupling gallic acid at the N-terminus decreased the activity of the free peptide. GA-Hecate showed lower activity in non-tumor keratinocyte cells but higher hemolytic activity. Our findings suggest that the N-terminus of Hecate plays an important role in its activity against cervical cancer by affecting it secondary structure, toxicity, and hemolytic activity. This study highlights the importance of the N-terminus in antitumor activity and could provide an important tool for developing new anti-cancer drugs.

Topics: Amino Acid Sequence; Antineoplastic Agents; Cell Survival; Drug Screening Assays, Antitumor; Erythrocytes; Female; Gallic Acid; HeLa Cells; Hemolytic Agents; Humans; Melitten; Molecular Sequence Data; Uterine Cervical Neoplasms

Melittin (MEL), a major component of bee venom, has been associated with various diseases including arthritis, rheumatism and various cancers. In this study, the anti-angiogenic effects of MEL in CaSki cells that were responsive to the epidermal growth factor (EGF) were examined.. MEL decreased the EGF-induced hypoxia-inducible factor-1α (HIF-1α) protein and significantly regulated angiogenesis and tumor progression. We found that inhibition of the HIF-1α protein level is due to the shortened half-life by MEL. Mechanistically, MEL specifically inhibited the EGF-induced HIF-1α expression by suppressing the phosphorylation of ERK, mTOR and p70S6K. It also blocked the EGF-induced DNA binding activity of HIF-1α and the secretion of the vascular endothelial growth factor (VEGF). Furthermore, the chromatin immunoprecipitation (ChIP) assay revealed that MEL reduced the binding of HIF-1α to the VEGF promoter HRE region. The anti-angiogenesis effects of MEL were confirmed through a matrigel plus assay.. MEL specifically suppressed EGF-induced VEGF secretion and new blood vessel formation by inhibiting HIF-1α. These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression.

Topics: Animals; Cell Line, Tumor; Cell Movement; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Melitten; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Protein Biosynthesis; Protein Stability; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A