Role of Bee Venom and Melittin on Restraining Angiogenesis and Metastasis in γ-Irradiated Solid Ehrlich Carcinoma-Bearing Mice

Abstract

Pathological angiogenesis and apoptosis evasion are common hallmarks of cancer. The present work was an endeavor to evaluate the influence of bee venom (BV) or its major constituent melittin (MEL) as antiapoptotic and angiogenic regulator modifier on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. BV (0.56 mg/kg/day) and MEL (500 µg/kg body weight/day) were injected intraperitoneally to mice bearing 1 cm3 solid tumor of Ehrlich ascites carcinoma (EAC) for 21 consecutive days. Mice were whole-body exposed to 1 Gray (Gy) of γ-radiation (2 fractionated doses). Treatment with BV or MEL markedly suppresses the proliferation of tumor in EAC mice. The concentrations of m-RNA for angiogenic factors (TNF-α, VEGF) as well as MMPs 2 and 9 activities and NO concentration were significantly decreased, combined with improvements in apoptotic regulators (caspase-3 activity) and normal cells redox tone (catalase and free radicals content) compared with EAC mice. Moreover, the histopathological investigation confirms the improvement exerted by BV or MEL in the EAC mice group or EAC + R group. Exposure to γ-radiation sustained the modulatory effect of BV on tumor when compared with EAC + BV mice. Convincingly, the role of BV or MEL as a natural antiangiogenic in the biological sequelae after radiation exposure is verified. Hence, BV and its major constituent MEL might represent a potential therapeutic strategy for increasing the radiation response of solid tumors.

Melittin inhibits the expression of key genes involved in tumor microenvironment formation by suppressing HIF-1α signaling in breast cancer cells

“…3A and 3B). Several studies have reported VEGFA downregulation by Melittin in human cervical carcinoma cells [24], hepatocellular carcinoma cell lines [34], bladder cancer cells [35], lung cancer cells[36] and ehrlich carcinoma mouse model [37]. Inhibition of ERK and mTOR/p70S6K, VEGFR-2 and the COX-2-mediated MAPK signaling pathways has been implicated in these studies.…”

Amygdalin potentiates the anti-cancer effect of Sorafenib on Ehrlich ascites carcinoma and ameliorates the associated liver damage

“…Additionally, degenerative changes such as loss of histo-architecture, due to microvascular fatty changes in addition to mild Kupffer cells activity were also observed. It was also reported that EAC cells can migrate from the peritoneal cavity and reach the liver causing liver injury 32 . EAC-bearing mice treated with Amy and/or Sor showed notable improvement in liver structure, especially in Amy + SorIP co-treated mice.…”

Protective rules of natural antioxidants against gamma‐induced damage—A review

“…Radiation can also increase the oxidative stress in the intestinal epithelial cells (Roy et al., 2016 ). Raised levels of free oxygen radicals in the mitochondria trigger protein DNA and lipid impairments (El Bakary et al., 2020 ).…”

“…According to previous study, it is observed that the administration of Melittin in a dose of (500 μg/kg body weight/day) injected intraperitoneally to mice with 1 cm 3 solid tumor of Ehrlich ascites carcinoma for 21 days, while the mice is undergoing irradiation with gamma (at a dose rate of 0.46 Gy/min), then Melittin in honeybee venom has the potential to inhibit lipid peroxidation and exhibit a substantial hydroxyl radical scavenging activity, along with obstruction of tumor growth, augmentation of tumor cells apoptosis, and specific enhancements in the state of tumor cells penetration and infiltration. A considerable decline in the level of apoptotic molecule (caspase‐3) is also observed along with development in apoptotic regulators (caspase‐3 activity) and free radicals content, and normal cells redox tone catalase (El Bakary et al., 2020 ).…”