Evidence of Insulin-Sensitizing and Mimetic Activity of the Sesquiterpene Quinone Avarone, a Protein Tyrosine Phosphatase 1B and Aldose Reductase Dual Targeting Agent from the Marine Sponge <i>Dysidea avara</i>
Marcello Casertano,
Massimo Genovese,
Alice Santi,
Erica Pranzini,
Francesco Balestri,
Lucia Piazza,
Antonella Del Corso,
Sibel Avunduk,
Concetta Imperatore,
Marialuisa Menna,
Paolo Paoli
Affiliations
Marcello Casertano
Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy
Massimo Genovese
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Alice Santi
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Erica Pranzini
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Francesco Balestri
Biochemistry Unit, Department of Biology, University of Pisa, Via S. Zeno 51, 56123 Pisa, Italy
Lucia Piazza
Biochemistry Unit, Department of Biology, University of Pisa, Via S. Zeno 51, 56123 Pisa, Italy
Antonella Del Corso
Biochemistry Unit, Department of Biology, University of Pisa, Via S. Zeno 51, 56123 Pisa, Italy
Sibel Avunduk
Medical Laboratory Programme, Vocational School of Health Care, Mugla University, Marmaris 48187, Turkey
Concetta Imperatore
Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy
Marialuisa Menna
Department of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy
Paolo Paoli
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.
