title: 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.
authors: Department of Biology, Georgia State University, Atlanta, GA-30303, USA, Drug Metabolism, Pharmacokinetics & Clinical Pharmacology, Advinus Therapeutics, Karnataka, 560058, India; Department of Pharmaceutical Sciences, Manipal University, Karnataka, 576104, India and Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Chunhua
authors: C
authors: Yang
authors: Department of Biology, Georgia State University, Atlanta, GA-30303, USA, Drug Metabolism, Pharmacokinetics & Clinical Pharmacology, Advinus Therapeutics, Karnataka, 560058, India; Department of Pharmaceutical Sciences, Manipal University, Karnataka, 576104, India and Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Sushma Reddy
authors: SR
authors: Gundala
authors: Drug Metabolism, Pharmacokinetics & Clinical Pharmacology, Advinus Therapeutics, Karnataka, 560058, India; Department of Pharmaceutical Sciences, Manipal University, Karnataka, 576104, India and.
authors: Rao
authors: R
authors: Mukkavilli
authors: Drug Metabolism, Pharmacokinetics & Clinical Pharmacology, Advinus Therapeutics, Karnataka, 560058, India;
authors: Subrahmanyam
authors: S
authors: Vangala
authors: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Michelle D
authors: MD
authors: Reid
authors: Department of Biology, Georgia State University, Atlanta, GA-30303, USA, Drug Metabolism, Pharmacokinetics & Clinical Pharmacology, Advinus Therapeutics, Karnataka, 560058, India; Department of Pharmaceutical Sciences, Manipal University, Karnataka, 576104, India and Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA raneja@gsu.edu.
authors: Ritu
authors: R
authors: Aneja
mesh_terms: D054378:Acetogenins / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D031041:Annona / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018890:Chemoprevention; D004357:Drug Synergism; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D018515:Plant Leaves; D028321:Plant Preparations / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D023041:Xenograft Model Antitumor Assays
chemical_list: D054378:Acetogenins; D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D028321:Plant Preparations