In Silico, In Vitro, and In Vivo Antitumor and Anti-Inflammatory Evaluation of a Standardized Alkaloid-Enriched Fraction Obtained from Boehmeria caudata Sw. Aerial Parts.

Paula P De Paiva,Márcia Y Okubo,Ana L T G Ruiz,Rafael R T Zafred,Julia H B Nunes,Mary A Foglio,Paula A Monteiro,Fabiana R Nonato,João E Carvalho,Daniel F Kawano,Ilza M O Sousa

doi:10.3390/molecules25174018

Paula P De Paiva, Márcia Y Okubo + Show 9 more

Open Access

https://doi.org/10.3390/molecules25174018

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Abstract

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeria caudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at low concentrations. Further investigation on NCI-H460 cells showed an irreversible effect on cell proliferation, with cell cycle arrest at G2/M phase and programmed cell death induction. Molecular docking studies of four alkaloids identified in BcAEF with colchicine’s binding site on β-tubulin were performed, suggesting (−)-C (15R)-hydroxycryptopleurine as the main inductor of the observed mitotic death. In vivo studies showed that BcAEF was able to reduce Ehrlich tumor volume progression by 30 to 40%. Checking myeloperoxidase activity, BcAEF reduced neutrophils migration towards the tumor. The in vivo anti-inflammatory activity was evaluated by chemically induced edema models. In croton oil-induced ear edema and carrageenan (CG)-induced paw edema models, BcAEF reduced edema around 70 to 80% together with inhibition of activation and/or migration of neutrophils to the inflammatory area. All together the results presented herein show BcAEF as a potent antitumor agent combining antiproliferative and anti-inflammatory properties, which could be further explored in (pre)clinical studies.

Highlights

Cancer is the second leading cause of death worldwide [1], and the demand for new drugs continues to be a very important research field to pursue
B. caudata alkaloid-enriched fraction (BcAEF) best inhibition outcome was observed on NCI-H460 and K562 human tumor lines
BcAEF showed, in a first evaluation [7], a potent growth inhibitor profile against U251, MCF-7 and NCI-H460 tumor cell lines, to that observed for the ethanolic extract

Summary

Introduction

Cancer is the second leading cause of death worldwide [1], and the demand for new drugs continues to be a very important research field to pursue In this context, plant-derived natural products play an important role, because in general they present anti-inflammatory properties which are interesting in the context of cancer [2,3]. When orally administered, BcEE reduced Ehrlich solid tumor growth with an anti-inflammatory effect, which was evaluated by the carrageenan (CG)-induced paw edema, and croton oil-induced ear edema on mice [7] These results suggested that the antitumor activity of the BcEE could be related to the antiproliferative and anti-inflammatory effects, which may have a straight relationship with the phenanthroquinolizidine alkaloids detected in BcEE. Continuing the study on the pharmacological profile of B. caudata aerial parts, the in silico tubulin interaction (molecular docking studies), in vitro antiproliferative activity (2D model and flow cytometry evaluation), and in vivo antitumor and anti-inflammatory activities of BcAEF are reported for the first time, in order to attest whether the high potency observed in vitro is maintained in vivo

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