Melittin Suppresses VEGF-A-Induced Tumor Growth by Blocking VEGFR-2 and the COX-2-Mediated MAPK Signaling Pathway

Huh, Jungwon; Kang, Jung Won; Nam, Dongwoo; Baek, Yong-Hyeon; Choi, Dong‐Hee; Park, Dong-Suk; Lee, Jae-Dong

doi:10.1021/np300446c

Cited by 53 publications

(46 citation statements)

References 40 publications

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“…MEL also decreased the expression of VEGF receptor-2, COX-2, and prostaglandin E2 in VEGF-A-transfected HUVECs. These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase, whereas it increased the phosphorylation of p38 MAPK [68]. …”

Section: Anticancer Effects Of Bv and Its-conjugatesmentioning

confidence: 99%

Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy

et al. 2017

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Melittin (MEL), a major peptide component of bee venom, is an attractive candidate for cancer therapy. This agent has shown a variety of anti-cancer effects in preclinical cell culture and animal model systems. Despite a convincing efficacy data against variety of cancers, its applicability to humans has met with challenges due to several issues including its non-specific cytotoxicity, degradation and hemolytic activity. Several optimization approaches including utilization of nanoparticle based delivery of MEL have been utilized to circumvent the issues. Here, we summarize the current understanding of the anticancer effects of bee venom and MEL on different kinds of cancers. Further, we also present the available information for the possible mechanism of action of bee venom and/or MEL.

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Section: Anticancer Effects Of Bv and Its-conjugatesmentioning

confidence: 99%

Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy

et al. 2017

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“…As a typical PFT, melittin can destabilize and create pores inside the cell membranes. By this direct lytic action to the membranes and via additional mechanisms involved in apoptosis, cell cycle arrest or necrosis, melittin can kill tumor cells and significantly inhibit tumor growth (7, 8). These anti-tumor effects are, however, available only with high (above micro-molar) concentration of melittin.…”

Section: Introductionmentioning

confidence: 99%

Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity

et al. 2016

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Purpose To investigate the applicability of fusion biotoxins combining pore-forming toxins (PFTs) and ribosome-inactivating proteins (RIPs) for the anti-cancer treatment. Methods Membrane active PFTs tend to destabilize cell membranes of tumor cells, but lack a warhead inducing significant cause of cell death. Cell-impermeable RIPs possess a powerful warhead, yet not able to enter the tumor cells. To address these challenges for anti-tumor effects, we introduced a fusion strategy of conjugating melittin (a PFT) and gelonin (a type 1 RIP) via chemical and recombinant methods, followed by in vitro assays and in vivo animal studies. Results In vitro characterization results confirmed that the chimeric gelonin-melittin fusion proteins retained equivalent intrinsic activity to that of unmodified gelonin in inhibiting protein translation. However, chemically conjugated gelonin-melittin (cGel-Mel) and recombinant chimeric gelonin-melittin fusion (rGel-Mel) exhibited greater cell uptake, yielding a significantly enhanced cytotoxic activity over treatment of gelonin, melittin or physical mixture of gelonin and melittin. Remarkably, cGel-Mel and rGel-Mel displayed 32- and 10-fold lower IC50 than gelonin in the cell lines. The superior anti-tumor efficacy of multivalent cGel-Mel to monovalent rGel-Mel suggested that valency could be a crucial factor for the extent of melittin-mediated cell uptake. Tumoricidal effects observed from animal studies were in good accordance with our findings from the cellular assays. Conclusions This study successfully demonstrated that fusion of biotoxins could provide a simple yet effective way to synergistically augment their anti-tumor activity.

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“…Classical members of MAPK signalling include stress activated protein-kinase 2 (p38), c-Jun N-terminus kinase (JNK) and extracellular signal-regulated kinase (ERK1/2), which play crucial roles in the migration of various cells under VEGF stimulation (Huh et al 2012, Jeong et al 2014. The present study demonstrated that VEGFA enhanced the phosphorylation of p38 protein in hDPSCs.…”

Section: Discussionmentioning

confidence: 51%

Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways

et al. 2019

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Aim To investigate the effects of vascular endothelial growth factor A (VEGFA) and the underlying molecular mechanisms on the migration of human dental pulp stem cells (hDPSCs). Methodology The expression of VEGFA in inflammatory pulp tissue and lipopolysaccharide (LPS)‐stimulated dental pulp cells was examined by immunofluorescence staining and qRT‐PCR. The migration of hDPSCs was detected using transwell migration and wound healing assays. The activation of FAK, PI3K, Akt and p38 signalling was evaluated by Western blot analysis. Silence RNA (siRNA) technology was utilized to knockdown the expression of VEGFR1 (Flt‐1) and VEGFR2 (Flk‐1/KDR). PF573228 (inhibitor of FAK), LY294002 (inhibitor of PI3K), SB203580 (inhibitor of p38) and SU5416 (inhibitor of VEGFR2) were employed to investigate the effect of VEGFA on the migratory mechanism of hDPSCs. Data were analysed statistically using the Student’s t‐test or one‐way ANOVA. Results The expression levels of VEGFA in inflammatory pulp tissue in vivo and LPS‐stimulated dental pulp cells in vitro were significantly greater than those in the control groups (P < 0.05). Vascular endothelial growth factor A promoted the migration of hDPSCs in a concentration‐dependent manner. Several signalling pathways, including FAK, PI3K, Akt and p38, were activated by VEGFA in a dose‐ and time‐dependent manner in hDPSCs. The VEGFA‐induced migration of hDPSCs was significantly inhibited with drug inhibitors such as PF573228, LY294002, SB203580 or SU5416 (P < 0.05). These signalling pathways activated by VEGFA stimulation were significantly suppressed by pre‐treatment with inhibitor of VEGFR2 (SU5416) or transfection with siRNA of VRGFR2 (P < 0.05) but not VEGFR1 siRNA. Conclusions Vascular endothelial growth factor A/VEGFR2 axis promoted the migration of hDPSCs via the FAK/PI3K/Akt and p38 MAPK signalling pathways. These findings reveal a novel molecular mechanism for cell migration of hDPSCs, which may contribute to the remodelling of pulp tissue and dentine.

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Melittin Suppresses VEGF-A-Induced Tumor Growth by Blocking VEGFR-2 and the COX-2-Mediated MAPK Signaling Pathway

Cited by 53 publications

References 40 publications

Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy

Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy

Preparation and Characterization of Gelonin-Melittin Fusion Biotoxin for Synergistically Enhanced Anti-Tumor Activity

Vascular endothelial growth factor A/Vascular endothelial growth factor receptor 2 axis promotes human dental pulp stem cell migration via the FAK/PI3K/Akt and p38 MAPK signalling pathways

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