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.