Evaluating Synergistic Anti-Cancer Efficacy of Graviola Plant Extracts

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