Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer

Abstract

Phytochemical complexity of plant extracts may offer health-promoting benefits including chemotherapeutic and chemopreventive effects. Isolation of 'most-active fraction' or single constituents from whole extracts may not only compromise the therapeutic efficacy but also render toxicity, thus emphasizing the importance of preserving the natural composition of whole extracts. The leaves of Annona muricata, commonly known as Graviola, are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. Here, we demonstrate phytochemical synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions. Comparative quantitation of flavonoids revealed enrichment of rutin (~7-fold) and quercetin-3-glucoside (Q-3-G, ~3-fold) in FEF compared to GLE. In vivo pharmacokinetics and in vitro absorption kinetics of flavonoids revealed enhanced bioavailability of rutin in FEF compared to GLE. However, GLE was more effective in inhibiting in vitro prostate cancer proliferation, viability and clonogenic capacity compared to FEF. Oral administration of 100mg/kg bw GLE showed ~1.2-fold higher tumor growth-inhibitory efficacy than FEF in human prostate tumor xenografts although the concentration of rutin and Q-3-G was more in FEF. Contrarily, AEF, despite its superior in vitro and in vivo efficacy, resulted in death of the mice due to toxicity. Our data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment. Hence, our study emphasizes on evaluating the nature of interactions among Graviola leaf phytochemcials for developing favorable dose regimen for prostate cancer management to achieve optimal therapeutic benefits.

The safety and tolerability of Annona muricata leaf extract: a systematic review

“…Of the 12 toxicity tests reported, only one study reported behavioural signs of toxicity in mice at an oral dose of 4000 mg/kg in response to aqueous leaf extract which included paw licking, salivation, stretching and reduced activity . In mice studies, the calculated intraperitoneal LD 50 varied from 155 mg/kg for aqueous leaf extract to 1092 mg/kg for ethanolic leaf extract .…”

Immunomodulatory Efficacy of Standardized Annona muricata (Graviola) Leaf Extract via Activation of Mitogen‐Activated Protein Kinase Pathways in RAW 264.7 Macrophages

“…While the fruit is traditionally used to alleviate the symptoms associated with neuralgia, arthritis, diarrhea, dysentery, fever, malaria, parasites, rheumatism, skin rashes, and worms, the leaves are believed to have antirheumatic and neuralgic effects [4]. Among various bioactive components in Graviola, annonaceous acetogenins have antiproliferative effects and thus possess potential anticancer properties [23, 24]. The ethyl acetate extract of Graviola leaves inhibited the proliferation of A549 cells and human breast cancer cells by arresting the cell cycle and inducing apoptosis [5, 25].…”

“…Additionally, acetogenins displayed antioxidant activity and are considered as a therapeutic candidate for treatment of chronic diseases initiated by oxidative stress [6, 26, 27]. Besides, Graviola leaf contains various phytoconstituents such as alkaloids, flavonol triglycosides, phenolics, cyclopeptides, and essential oils [6, 13, 24]. Recently, we found that Graviola contains high concentrations of rutin, kaempferol-rutinoside, and vitamin U and effectively scavenged peroxyl and nitrogen radicals [14].…”

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

“…A total of 47 entries were found for human structural flavonoid/protein complexes and another ~ 65 structural hits for non-human complexes including molecules that synergistically interact with flavonoids to render them effective putative cancer treatment/prevention compounds for specific cancers such as prostate cancer [12]. The complete library is provided as supplemental materials to this review in Appendix A: Flavonoid/Protein Complexes.…”