Evaluating Synergistic Anti-Cancer Efficacy of Graviola Plant Extracts

评估 Graviola 植物提取物的协同抗癌功效

• 批准号: 2437791
• 金额: --
• 依托单位: Brunel University London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2437791
• 关键词: Evaluating; Synergistic; Anti; Cancer; Efficacy

Cancer remains one of the most serious health risks and cause of death worldwide. The International Agency Research for Cancer (IARC) documented over 14 million new cancer cases and over 8 million cancer deaths worldwide for 2012, forecasting over 21 million new cases and 13 million new cancer deaths worldwide for 2030 (Ferlay et al, 2015). World Health Organisation (WHO) and GLOBOCAN both reported 9.6 million cancer related deaths worldwide for 2018, showing a 20% increase in mortality as compared with 2012 data (Stewart, 2014 and Ferlay et al, 2018). High treatments costs, side-effects, multicausal etiology and the complex pathophysiology of cancer inclusive of an intrinsic and acquired resistance are becoming increasingly problematic for conventional clinical interventions (Yuan et al, 2015, 2017 and 2019). Characteristics of synergy relative to plant extracts (PEs) have been shown to combat the above-mentioned problem effectively utilizing synergistic multi-target effects, pharmacokinetic/physiochemical properties, alongside mechanisms that antagonize resistance and eliminate or neutralize adversely acting substances in vitro and in vivo (Wagner and Ulrich-Merzenic, 2009 and Nandi et al, 2019). The synergistic efficacy of PEs is commonly determined by the widely used Berenbaum's isobole method, able to comparatively determine quantitatively the degree of pharmacological and therapeutic superiority of interacting components relative to the sum of the respective isolate mono constituent of the PEs (Berenbaum 1997). In terms of conventional clinical interventions relative to infectious disease, oncology and immunoinflammatory disease - the common approach is widespread application of ligand specific single target drugs directed by a capital-intensive model. Although highly successful in many cases, a decreasing effectiveness has been noted (Petrelli and Giordano, 2008 and Wagner 2010). Multi component combination therapy provides a novel alternative or complementary approach, where PEs are of particular interest as some cancer types have already shown multi drug resistance (MDR) to chemotherapeutics accounting for 90% of cancer deaths during treatment (Rather et al 2013: Cercek et al 2020). Seed, leaf, fruit-pulp and bark extracts from Annona muricata otherwise known as Graviola, guanabana or soursop (amongst other names) have been shown to possess clinically significant anticancer effects against malignant cells, successful at inducing cell death/apoptosis in cancers resistant to even chemotherapeutic drugs (Chang et al, 2001 and Moghadamtousi, et al 2015). Crude Graviola PEs (GPEs) and partially fractionated GPEs exhibit cytotoxic effects on breast, prostate, pancreas, skin and liver cancer cells in-vitro and in-vivo. Many reports on the purification and characterisation of almost 100 compounds from GPEs are available shown GPEs to be rich in in flavonoids, isoquinoline, alkaloids and annonoaceous acetogenins (Moghadamtousi et al 2015, Sawant and Dongre 2014). Chan et al 2019, after a systematic safety and tolerability review of Graviola leaf extract (GLE) concluded favourable safety and tolerability profile. Annonaceous acetogenins are considered to be the major groups of phytochemicals in GPEs that induce cytotoxicity in cultured cells, mainly via inhibition of mitochondrial complex 1 (McLaughlin 2008). However, many other compounds obtained from GPEs have not been functionally detailed. To note, GPEs development into new drug entities is restricted by its neurotoxic effects and loss in some pharmacotherapeutic effects in vivo effects during extraction/separation processes (Luna Jde et al, 2006). Also use of single or several GPE derived acetogenins lead to toxic side effects and eventually cell death despite expressing greater efficacy (Sun et al, 2014). However, this only fuels the need to synergistic studies on GPEs where flavonoids in presence of acetogenins have recently been shown to have greater significant

癌症仍然是全世界最严重的健康风险和死亡原因之一。国际癌症研究机构（IARC）记录了2012年全球1400多万新发癌症病例和800多万癌症死亡病例，并预测2030年全球将有2100多万新发癌症病例和1300万新发癌症死亡病例（Ferlay等人，2015年）。世界卫生组织（世卫组织）和GLOBOCAN均报告称，2018年全球癌症相关死亡人数为960万，与2012年的数据相比，死亡率增加了20% （Stewart， 2014年和Ferlay等人，2018年）。高昂的治疗费用、副作用、多原因的病因和复杂的癌症病理生理，包括内在和获得性耐药，正成为传统临床干预措施日益严重的问题（Yuan等，2015,2017和2019）。与植物提取物（PEs）相关的协同特性已被证明可以有效地利用协同多靶点效应、药代动力学/物理化学特性，以及体外和体内拮抗耐药性和消除或中和不良作用物质的机制来解决上述问题（Wagner和Ulrich-Merzenic， 2009和Nandi等人，2019）。pe的协同功效通常由广泛使用的Berenbaum's isobole方法来确定，该方法能够比较定量地确定相互作用成分相对于pe各自分离的单一成分之和的药理学和治疗优势程度（Berenbaum 1997）。就传染病、肿瘤学和免疫炎性疾病的常规临床干预而言，常见的方法是在资本密集型模型指导下广泛应用配体特异性单靶点药物。尽管在许多情况下非常成功，但已经注意到有效性正在下降（Petrelli和Giordano， 2008年和Wagner 2010年）。多组分联合治疗提供了一种新的替代或补充方法，pe尤其令人感兴趣，因为一些癌症类型已经显示出对化疗药物的多药耐药性（MDR），占治疗期间癌症死亡的90% （Rather et al . 2013; Cercek et al . 2020）。番荔枝（Annona muricata）的种子、叶子、果肉和树皮提取物，也被称为Graviola、guanabana或soursop（以及其他名称），已被证明对恶性细胞具有临床显着的抗癌作用，在甚至对化疗药物耐药的癌症中成功诱导细胞死亡/凋亡（Chang等人，2001年和Moghadamtousi等人，2015年）。粗粒葡萄籽PEs （GPEs）和部分分离GPEs对乳腺癌、前列腺癌、胰腺癌、皮肤癌和肝癌细胞具有体外和体内细胞毒性作用。关于从gpe中提取的近100种化合物的纯化和表征的许多报告表明，gpe富含类黄酮、异喹啉、生物碱和无机乙酰原素（Moghadamtousi et al . 2015, Sawant and donggre 2014）。Chan等人，2019年，在对紫堇叶提取物（GLE）进行了系统的安全性和耐受性评价后，得出了良好的安全性和耐受性。annoneous acetogenins被认为是gpe中主要的植物化学物质，主要通过抑制线粒体复合体1在培养细胞中诱导细胞毒性（McLaughlin 2008）。然而，从gpe中获得的许多其他化合物的功能尚未详细说明。需要注意的是，GPEs发展成为新药实体受到其神经毒性作用的限制，并且在提取/分离过程中失去了一些体内药物治疗作用（Luna Jde et al, 2006）。此外，使用单一或多种GPE衍生的醋酸原会导致毒副作用，最终导致细胞死亡，尽管表现出更大的功效（Sun et al ., 2014）。然而，这只会刺激对gpe的协同研究的需要，其中黄酮类化合物的存在最近已被证明具有更大的意义