Mechanism of Action of Limonene in Tumor Cells: A Systematic Review and Meta-Analysis

BACKGROUND: Cancer is a complex, multifactorial disease, and a major public health problem, as it is a leading cause of morbidity and mortality worldwide. Although treatments have significantly improved, still more effective drugs are searched. One source for these drugs is natural products (NPs). One NP that has shown anticancer activity is Limonene. However, the mechanisms of limonene's antiproliferative, anticancer and antineoplastic activity are not fully understood. OBJECTIVE: The objective of this study is to undertake a systematic review and meta-analysis of the literature on this subject. METHODS: A comprehensive literature search was performed using the Scopus, MEDLINE-PubMed, Web of Science, and Science Direct databases using the keywords: "limonene", "cancer", "neoplasm", and "tumor". The inclusion criteria were: in vivo and in vitro studies on the use of limonene in cancer published in English, Portuguese and Spanish until December 2019. Review articles, meta-analyses, abstracts, conference papers, editorials/ letters and case reports were excluded. RESULTS: The search identified 3568 articles, of which, 126 were selected for full reading, with 11 papers meeting the review criteria. Six more papers were added from the references of the initial 11 texts, giving a total of 17 papers. There was a high level of agreement in inclusion/exclusion (Kappa index > 80%). The risk of bias in the texts was shown to be high. CONCLUSION: The meta-analysis suggests that limonene acts mainly on tumor regression induced apoptosis and is a promising natural product for use in the treatment of several types of cancer.