Review Article Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases Ali Roohbakhsh a , Hamideh Parhiz a,b , Fatemeh Soltani b,c,d , Ramin Rezaee a,d , Mehrdad Iranshahi c, ⁎ a Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran c Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran d Department of molecular sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran abstract article info Article history: Received 12 October 2014 Accepted 31 December 2014 Available online 24 January 2015 Keywords: Flavonoid Anti-cancer Anticoagulant Hesperetin Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have various biological properties, particularly those for the prevention of cancer and cardiovascular diseases. Studies have shown both anti-cancer and cancer chemopreventive effects for Hsd and Hst. Cancer chemopreventive properties of Hsd and Hst are mainly associated with their antioxidant, radical scavenging and anti-inflammatory activities. In addition, Hsd and Hst interfere at different stages of cancer. Unlike conventional anti-cancer drugs, Hsd and Hst inhibit tumor growth by targeting multiple cellular protein targets at the same time, including caspases, Bcl-2 (B-cell lymphoma 2) and Bax (Bcl-2 associated X protein) for the induction of apoptosis, and COX-2 (cyclooxygenase-2), MMP-2 (matrix metalloproteinase-2) and MMP-9 for the inhibition of angiogenesis and metastasis. The results of the recent basic and clinical studies revealed the beneficial effects for Hst, Hsd and their derivatives in the treatment of heart failure and cardiac remodeling, myocardial ischemia and infarction, and hypertension. In addition, the valuable effects of Hst and Hsd in the treatment of diabetes and dyslipidemia with their anti-platelet and anticoagulant effects make them good candidates in the treatment of various cardio- vascular diseases. In this review, new findings regarding the molecular targets of Hsd and Hst, animal studies and clinical trials are discussed. © 2015 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Anticancer and cancer chemopreventive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Alteration of inflammatory responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Evaluation of apoptotic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Effects on the cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 The effects of Hsd/Hst on cardiac functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 The effects of Hsd and Hst on the vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 The effects of Hsd/Hst on coagulant and anticoagulant pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Immobilization of hesperidin on stainless steel surfaces and its blood compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 The effects of Hsd/Hst on metabolic parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Introduction Flavonoids are a large group of phenolic compounds that are widely distributed in plants. To date, a large number of these compounds have Life Sciences 124 (2015) 64–74 ⁎ Corresponding author. Tel.: +98 511 8823255; fax: +98 511 8823251. E-mail address: Iranshahim@mums.ac.ir (M. Iranshahi). http://dx.doi.org/10.1016/j.lfs.2014.12.030 0024-3205/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie