Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms

Fitoterapia. 2018 Feb 21. pii: S0367-326X(18)30132-1. doi: 10.1016/j.fitote.2018.02.025. [Epub ahead of print] de Oliveira Júnior RG1, Christiane Adrielly AF2, da Silva Almeida JRG2, Grougnet R3, Thiéry V1, Picot L4. Author information 1 UMRi CNRS 7266 LIENSs, University of La Rochelle, 17042 La Rochelle, France. 2 Center for Studies and Research of Medicinal Plants, Federal University of San Francisco Valley, 56306-000 Petrolina, Brazil. 3 UMR CNRS 8638 Laboratory of Pharmacognosy, Paris Descartes University, 75006 Paris, France. 4 UMRi CNRS 7266 LIENSs, University of La Rochelle, 17042 La Rochelle, France. Electronic address: laurent.picot@univ-lr.fr. Abstract PURPOSE: Tumor cells are spontaneously or adaptively resistant to chemotherapeutic drugs, eventually leading to the selection of multiresistant cells responsible for tumor growth and metastasis. Chemosensitization of tumor cells to conventional drugs using non-toxic natural products is a recent and innovative strategy aiming to increase the cytotoxic efficiency of anticancer drugs, limit their toxic side effects and delay the appearance of acquired chemoresistance. This systematic review summarizes data obtained from preclinical studies reporting the use of natural products to sensitize tumor cells to chemotherapeutic agents. It also details the cellular and molecular mechanisms involved in chemosensitization. DESIGN: Search terms were combined and used to retrieve English language reports in PubMed, Science Direct and Scopus databases, published until October 2017. All articles were carefully analyzed and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. RESULTS: From a total of 669 articles surveyed, 104 met the inclusion criteria established. The main studied compounds as chemosensitizers were phenolic derivatives (26.9%) and flavonoids (17.3%). Most reports were authored by researchers from China (33.7%) and USA (26.9%). A large number of articles were published from 2011 to 2015 (50.0%), suggesting that the use of natural products as chemosensitizers is a recent issue. In vivo studies were conducted mainly using xenograft models, which were considered of moderate methodological quality. CONCLUSION: Several natural products, belonging to diverse chemical families, are potent chemosentisizers in tumor cells enhancing the cytotoxicity of conventional drugs. These molecules usually have a pleiotropic effect on different molecular targets, acting on several cellular and molecular processes with low selectivity. All studied molecules were obtained from terrestrial plants and major developments should arise from future studies, considering the chemodiversity of molecules purified from other terrestrial taxa and marine organisms. Copyright © 2018 Elsevier B.V. All rights reserved. KEYWORDS: Cancer; Chemosensitization; Chemotherapy; Drug resistance; Natural products PMID: 29476786 DOI: 10.1016/j.fitote.2018.02.025