Bee venom and its active component Melittin synergistically potentiate the anticancer effect of Sorafenib against HepG2 cells

Mansour, Ghada H.; El-Magd, Mohammed A.; Mahfouz, Dalia H.; Abdelhamid, Ismail A.; Mohamed, Magda F.; Ibrahim, Nada; Wahab, Abdel; El-Zayat, Emad

doi:10.1016/j.bioorg.2021.105329

Cited by 38 publications

(19 citation statements)

References 54 publications

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“…HepG2 treated with Sorafenib resulted in a decrease in cells in the G0/G1 phase and an increase in cells in the S and G2/M phases compared to the control ( Figure 4 A,B), suggesting that Sorafenib induced S and G2/M phase cell-cycle arrest. The effect observed was in line with a previous report by another group [ 67 , 68 , 69 ]. The selected compounds 2m ’ and 2e exhibited similar cell cycle profiles compared to Sorafenib ( Figure 4 C,D), indicating that the capability to induce S and G2/M phase cell-cycle arrest was recapitulated in these compounds.…”

Section: Resultssupporting

confidence: 93%

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

et al. 2022

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Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m’ and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m’ and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m’ and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m’ and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC.

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Section: Resultssupporting

confidence: 93%

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

et al. 2022

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“…In addition, many studies have demonstrated that MEL—the main component of BV—is responsible for the cytotoxic effect of this extract [ 38 , 41 ], which also explains why Bv-PLA2 alone did not show any cytotoxic effect on HeLa cancer cells in our work. Our findings correlate with those of Mansour et al in 2021, whose in vitro data showed a dose-dependent antiproliferative activity of both BV and MEL on HepG2 cells, with the latter showing the highest cytotoxicity [ 42 ]. This is also consistent with our prior findings regarding A. mellifera syriaca venom, where MEL was proven to be the compound responsible for the cytotoxic effect on HCT116 human colon cancer cells—especially given its synergistic action with Bv-PLA2 [ 6 ].…”

Section: Discussionsupporting

confidence: 92%

Apis mellifera syriaca Venom: Evaluation of Its Anticoagulant Effect, Proteolytic Activity, and Cytotoxicity along with Its Two Main Compounds—MEL and PLA2—On HeLa Cancer Cells

et al. 2022

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Bee venom (BV) is one of the most remarkable natural products that has been a subject of studies since ancient times. Recent studies have shown that Apis mellifera syriaca venom possesses antibacterial as well as cytotoxic effects on cancer cell lines. The venom contains a variety of bioactive molecules—mainly melittin (MEL) and phospholipase A2 (PLA2), as well as other compounds that are not well characterized. In this work, we continue the biological characterization of A. mellifera syriaca venom by testing its anticoagulant effect on human plasma using the prothrombin time (PT) test, as well as assessing its proteolytic activity. In addition, the cytotoxicity of the crude venom—and of its two main components, MEL and PLA2—was tested on HeLa cancer cell lines for the first time. The results obtained showed the capacity of A. mellifera syriaca venom to increase clotting time, thereby proving its anticoagulant effect. Moreover, the venom did not demonstrate a significant proteolytic activity unless administrated at concentrations ≥ 5 mg/mL. Finally, we showed that crude A. mellifera syriaca venom, along with MEL, exhibit a strong in vitro cytotoxic effect on HeLa cancer cell lines, even at low concentrations. In summary, our findings could serve as a basis for the development of new natural-based drug candidates in the therapeutic field.

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“…In addition, it promotes powerful and highly selective cell death in TNBC and HER2-enriched breast cancer and also MDA-MB-231 [ 55 , 56 ]. On HepG2, bee venom and melittin exhibit a synergistic anticancer impact with Sorafenib, suggesting a potential HCC therapeutic method [ 57 ].‏ Also, melittin inhibits tumor cell metastasis by lowering cell motility and migration via the Rac1-dependent pathway, also due to its strong anti-tumor effectiveness and improved biological safety, melittin nano-liposomes would be a good choice for HCC therapy [ 58 ]. In addition to this, bee venom promotes apoptosis in pancreatic cancer cells [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK/ERK pathway

et al. 2022

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Hepatocellular carcinoma (HCC) is one of the world’s most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field’s potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.

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Bee venom and its active component Melittin synergistically potentiate the anticancer effect of Sorafenib against HepG2 cells

Cited by 38 publications

References 54 publications

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

Apis mellifera syriaca Venom: Evaluation of Its Anticoagulant Effect, Proteolytic Activity, and Cytotoxicity along with Its Two Main Compounds—MEL and PLA2—On HeLa Cancer Cells

Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK/ERK pathway

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