Shaw Priyanka, Kumar Naresh, Hammerschmid Dietmar, Privat-Maldonado Angela, Dewilde Sylvia, Bogaerts Annemie
Research Group PLASMANT, Department of Chemistry, University of Antwerp, BE-2610 Wilrijk-Antwerp, Belgium.
Laboratory of Protein Science, Proteomics & Epigenetic Signaling, Department of Biomedical Sciences, University of Antwerp, BE-2610 Wilrijk-Antwerp, Belgium.
Cancers (Basel). 2019 Aug 3;11(8):1109. doi: 10.3390/cancers11081109.
Melittin (MEL), a small peptide component of bee venom, has been reported to exhibit anti-cancer effects in vitro and in vivo. However, its clinical applicability is disputed because of its non-specific cytotoxicity and haemolytic activity in high treatment doses. Plasma-treated phosphate buffered saline solution (PT-PBS), a solution rich in reactive oxygen and nitrogen species (RONS) can disrupt the cell membrane integrity and induce cancer cell death through oxidative stress-mediated pathways. Thus, PT-PBS could be used in combination with MEL to facilitate its access into cancer cells and to reduce the required therapeutic dose. The aim of our study is to determine the reduction of the effective dose of MEL required to eliminate cancer cells by its combination with PT-PBS. For this purpose, we have optimised the MEL threshold concentration and tested the combined treatment of MEL and PT-PBS on A375 melanoma and MCF7 breast cancer cells, using in vitro, in ovo and in silico approaches. We investigated the cytotoxic effect of MEL and PT-PBS alone and in combination to reveal their synergistic cytological effects. To support the in vitro and in ovo experiments, we showed by computer simulations that plasma-induced oxidation of the phospholipid bilayer leads to a decrease of the free energy barrier for translocation of MEL in comparison with the non-oxidized bilayer, which also suggests a synergistic effect of MEL with plasma induced oxidation. Overall, our findings suggest that MEL in combination with PT-PBS can be a promising combinational therapy to circumvent the non-specific toxicity of MEL, which may help for clinical applicability in the future.
蜂毒肽（MEL）是蜂毒中的一种小肽成分，据报道在体外和体内均具有抗癌作用。然而，由于其在高治疗剂量下具有非特异性细胞毒性和溶血活性，其临床适用性存在争议。经等离子体处理的磷酸盐缓冲盐水溶液（PT-PBS）是一种富含活性氧和氮物种（RONS）的溶液，它可以破坏细胞膜完整性，并通过氧化应激介导的途径诱导癌细胞死亡。因此，PT-PBS可与MEL联合使用，以促进其进入癌细胞并降低所需的治疗剂量。我们研究的目的是确定MEL与PT-PBS联合使用时，消除癌细胞所需的有效剂量的降低情况。为此，我们优化了MEL阈值浓度，并使用体外、卵内和计算机模拟方法测试了MEL与PT-PBS联合处理对A375黑色素瘤细胞和MCF7乳腺癌细胞的效果。我们研究了MEL和PT-PBS单独及联合使用时的细胞毒性作用，以揭示它们的协同细胞学效应。为了支持体外和卵内实验，我们通过计算机模拟表明，与未氧化的双层相比，等离子体诱导的磷脂双层氧化导致MEL转运的自由能垒降低，这也表明MEL与等离子体诱导的氧化具有协同效应。总体而言，我们的研究结果表明，MEL与PT-PBS联合使用可能是一种有前景的联合疗法，可规避MEL的非特异性毒性，这可能有助于未来的临床应用。
