Aronson Matthew R, Dahl Erika S, Halle Jacob A, Simonson Andrew W, Gogal Rose A, Glick Adam B, Aird Katherine M, Medina Scott H
Department of Biomedical Engineering, Penn State University, University Park, PA 16802 USA.
Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033 USA.
Cell Mol Bioeng. 2020 Jun 24;13(5):447-461. doi: 10.1007/s12195-020-00626-z. eCollection 2020 Oct.
Bacteria and cancer cells share a common trait-both possess an electronegative surface that distinguishes them from healthy mammalian counterparts. This opens opportunities to repurpose antimicrobial peptides (AMPs), which are cationic amphiphiles that kill bacteria by disrupting their anionic cell envelope, into anticancer peptides (ACPs). To test this assertion, we investigate the mechanisms by which a pathogen-specific AMP, originally designed to kill bacterial Tuberculosis, potentiates the lytic destruction of drug-resistant cancers and synergistically enhances chemotherapeutic potency.
peptide design, paired with cellular assays, elucidate structure-activity relationships (SAR) important to ACP potency and specificity. Using the sequence MAD1, microscopy, spectrophotometry and flow cytometry identify the peptide's anticancer mechanisms, while parallel combinatorial screens define chemotherapeutic synergy in drug-resistant cell lines and patient derived tumors.
SAR investigations reveal spatial sequestration of amphiphilic regions increases ACP potency, but at the cost of specificity. Selecting MAD1 as a lead sequence, mechanistic studies identify that the peptide forms pore-like supramolecular assemblies within the plasma and nuclear membranes of cancer cells to potentiate death through lytic and apoptotic mechanisms. This diverse activity enables MAD1 to synergize broadly with chemotherapeutics, displaying remarkable combinatorial efficacy against drug-resistant ovarian carcinoma cells and patient-derived tumor spheroids.
We show that cancer-specific ACPs can be rationally engineered using nature's AMP toolbox as templates. Selecting the antimicrobial peptide MAD1, we demonstrate the potential of this strategy to open a wealth of synthetic biotherapies that offer new, combinatorial opportunities against drug resistant tumors.
细菌和癌细胞具有一个共同特征——二者都拥有负电表面，这使它们有别于健康的哺乳动物细胞。这为将抗菌肽（AMPs）改造成抗癌肽（ACPs）创造了机会，抗菌肽是一类阳离子两亲分子，通过破坏细菌的阴离子细胞膜来杀死细菌。为了验证这一观点，我们研究了一种最初设计用于杀死结核杆菌的病原体特异性抗菌肽增强耐药癌细胞裂解破坏并协同增强化疗效力的机制。
肽设计与细胞试验相结合，阐明了对ACPs效力和特异性至关重要的构效关系（SAR）。使用序列MAD1，通过显微镜、分光光度法和流式细胞术确定该肽的抗癌机制，同时并行组合筛选确定耐药细胞系和患者来源肿瘤中的化疗协同作用。
SAR研究表明，两亲区域的空间隔离可提高ACPs的效力，但会牺牲特异性。选择MAD1作为先导序列，机制研究表明该肽在癌细胞的质膜和核膜内形成孔状超分子聚集体，通过裂解和凋亡机制增强细胞死亡。这种多样的活性使MAD1能够与多种化疗药物协同作用，对耐药卵巢癌细胞和患者来源的肿瘤球体显示出显著的联合疗效。
我们表明，可以以自然界的抗菌肽工具箱为模板合理设计癌症特异性ACPs。选择抗菌肽MAD1，我们证明了该策略有潜力开启大量合成生物疗法，为对抗耐药肿瘤提供新的联合治疗机会。
