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Review
. 2021 Dec;28(12):6730-6747.
doi: 10.1016/j.sjbs.2021.07.046. Epub 2021 Jul 21.

Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects

Kah Min Yap  1 , Mahendran Sekar  1 , Yuan Seng Wu  2 , Siew Hua Gan  3 , Nur Najihah Izzati Mat Rani  4 , Lay Jing Seow  1 , Vetriselvan Subramaniyan  2 , Neeraj Kumar Fuloria  5 , Shivkanya Fuloria  5 , Pei Teng Lum  1
Affiliations
Review

Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects

Kah Min Yap et al. Saudi J Biol Sci. 2021 Dec.

Abstract

Breast cancer (BC) has high incidence and mortality rates, making it a major global health issue. BC treatment has been challenging due to the presence of drug resistance and the limited availability of therapeutic options for triple-negative and metastatic BC, thereby urging the exploration of more effective anti-cancer agents. Hesperidin and its aglycone hesperetin, two flavonoids from citrus species, have been extensively evaluated for their anti-cancer potentials. In this review, available literatures on the chemotherapeutic and chemosensitising activities of hesperidin and hesperetin in preclinical BC models are reported. The safety and bioavailability of hesperidin and hesperetin as well as the strategies to enhance their bioavailability are also discussed. Overall, hesperidin and hesperetin can inhibit cell proliferation, migration and BC stem cells as well as induce apoptosis and cell cycle arrest in vitro. They can also inhibit tumour growth, metastasis and neoplastic changes in tissue architecture in vivo. Moreover, the co-administration of hesperidin or hesperetin with doxorubicin, letrozole or tamoxifen can enhance the efficacies of these clinically available agents. These chemotherapeutic and chemosensitising activities of hesperidin and hesperetin have been linked to several mechanisms, including the modulation of signalling pathways, glucose uptake, enzymes, miRNA expression, oxidative status, cell cycle regulatory proteins, tumour suppressor p53, plasma and liver lipid profiles as well as DNA repair mechanisms. However, poor water solubility, extensive phase II metabolism and apical efflux have posed limitations to the bioavailability of hesperidin and hesperetin. Various strategies for bioavailability enhancement have been studied, including the utilisation of nano-based drug delivery systems and the co-administration of hesperetin with other flavonoids. In particular, nanoformulated hesperidin and hesperetin possess greater chemotherapeutic and chemosensitising activities than free compounds. Despite promising preclinical results, further safety and efficacy evaluation of hesperidin and hesperetin as well as their nanoformulations in clinical trials is required to ascertain their potentials to be developed as clinically useful agents for BC treatment.

Keywords: Bioavailability; Biosafety; Breast cancer; Hesperetin; Hesperidin; Nanoformulation.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Anti-cancer (chemotherapeutic and chemosensitising) activities and associated molecular mechanisms of hesperidin (A) and hesperetin (B) in BC. AKT, Protein kinase B; ASK1/JNK, Apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase; ATPases, adenosine triphosphatases; CDK4, cyclin dependent kinase 4; DMBA, 7,12-dimethylbenz(a)anthracene; DNA, Deoxyribonucleic acid; EGFR/ERK, Epidermal growth factor receptor/extracellular signal-regulated kinase; ERα, Oestrogen receptor-alpha; HER2, Human epidermal growth factor receptor 2; MMP-2 and −9, Matrix metalloproteinase-2 and −9; miRNAs, Micro-ribonucleic acids; NF-κB, Nuclear factor kappa B; Rac1, Ras-related C3 botulinum toxin substrate 1; ROS, Reactive oxygen species.
Fig. 2
Fig. 2
Anti-proliferative activity of hesperidin and hesperetin in BC cells. A) Effects of hesperidin and hesperetin on associated molecular _targets. B) Involvement of AKT and NF-κB signalling pathways in regulation of PD-L1 expression. AKT, Protein kinase B; EMT, Epithelial-mesenchymal transition; GLUT1/4, Glucose transporter type 1/4; GPCRs, G-protein-coupled receptors; HER2, Human epidermal growth factor receptor 2; IKK, IκB kinase; NF-κB, Nuclear factor kappa B; PD-L1, Programmed death-ligand 1; PI3K, Phosphoinositide 3-kinase; RTKs, Receptor tyrosine kinases.
Fig. 3
Fig. 3
Pro-apoptotic and cell cycle arrest-inducing activities of hesperidin and hesperetin in BC cells. A) Effects of hesperidin and hesperetin on associated molecular _targets. B) Cytosolic ROS-mediated activation of ASK1/JNK pathway by hesperetin. ASK1, Apoptosis signal-regulating kinase 1; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; CDK2/4, Cyclin dependent kinase 2/4; HER2, Human epidermal growth factor receptor 2; JNK, c-Jun N-terminal kinase; PARP, Poly (ADP-ribose) polymerase; ROS, Reactive oxygen species.
Fig. 4
Fig. 4
Pharmacokinetics of hesperidin and hesperetin. A) Direct absorption of hesperetin in the small intestine and deglycosylation of hesperidin to hesperetin in the colon. B) Phase II metabolism of hesperetin and subsequent apical ABC transporter-mediated efflux of hesperetin conjugates in enterocytes or colonocytes.
Fig. 5
Fig. 5
Current and proposed future strategies for bioavailability and anti-cancer efficacy enhancement of hesperidin and hesperetin.
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