José Miguel P Ferreira de Oliveira1, Conceição Santos2, Eduarda Fernandes3. 1. LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, 4050-313 Porto, Portugal. Electronic address: jmoliveira@ff.up.pt. 2. Integrated Biology and Biotechnology Laboratory, Department of Biology, Faculty of Sciences, University of Porto, Rua Campo Alegre, 4169-007 Porto, Portugal; LAQV, REQUIMTE, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal. Electronic address: csantos@fc.up.pt. 3. LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, 4050-313 Porto, Portugal. Electronic address: egracas@ff.up.pt.
Abstract
BACKGROUND: The ability of cancer cells to divide without restriction and to escape programmed cell death is a feature of the proliferative state. Citrus flavanones are flavonoids with potential multiple anticancer actions, from antioxidant and chemopreventive, to anti-inflammatory, anti-angiogenic, cytostatic and cytotoxic in different cancer models. PURPOSE: This review aims to summarize the current knowledge on the antiproliferative actions of the citrus flavanones hesperidin (HSD) and hesperetin (HST), with emphasis on cell cycle arrest and apoptosis. METHODS: Cochrane Library, Scopus, Pubmed and Web of Science collection databases were queried for publications reporting antiproliferative effects of HSD and HST in cancer models. RESULTS: HSD and HST have been proven to delay cell proliferation in several cancer models. Depending on the compound, dose and cell line studied, different effects have been reported. Cell cycle arrest associated with cytostatic effects has been reported in cells with increased levels of p53 and also cyclin-dependent kinase inhibitors, as well as decreased levels of specific cyclins and cyclin-dependent kinases. Moreover, apoptotic effects have been found to be associated with altered ratios of pro-/antiapoptotic proteins, caspase activation, c-Jun N-terminal kinase (JNK) pathway activation and caspase-independent pathways. CONCLUSION: Available scientific literature data indicate complex effects, dependent on cell lines and exposure conditions, suggesting that HSD and HST doses need to be optimized according to the cellular and organismal context. The establishment of the main antiproliferative mechanisms is of utmost importance for a possible therapeutic benefit of citrus flavanones in the context of cancer.
BACKGROUND: The ability of cancer cells to divide without restriction and to escape programmed cell death is a feature of the proliferative state. Citrus flavanones are flavonoids with potential multiple anticancer actions, from antioxidant and chemopreventive, to anti-inflammatory, anti-angiogenic, cytostatic and cytotoxic in different cancer models. PURPOSE: This review aims to summarize the current knowledge on the antiproliferative actions of the citrus flavanoneshesperidin (HSD) and hesperetin (HST), with emphasis on cell cycle arrest and apoptosis. METHODS: Cochrane Library, Scopus, Pubmed and Web of Science collection databases were queried for publications reporting antiproliferative effects of HSD and HST in cancer models. RESULTS:HSD and HST have been proven to delay cell proliferation in several cancer models. Depending on the compound, dose and cell line studied, different effects have been reported. Cell cycle arrest associated with cytostatic effects has been reported in cells with increased levels of p53 and also cyclin-dependent kinase inhibitors, as well as decreased levels of specific cyclins and cyclin-dependent kinases. Moreover, apoptotic effects have been found to be associated with altered ratios of pro-/antiapoptotic proteins, caspase activation, c-Jun N-terminal kinase (JNK) pathway activation and caspase-independent pathways. CONCLUSION: Available scientific literature data indicate complex effects, dependent on cell lines and exposure conditions, suggesting that HSD and HST doses need to be optimized according to the cellular and organismal context. The establishment of the main antiproliferative mechanisms is of utmost importance for a possible therapeutic benefit of citrus flavanones in the context of cancer.