AdipoRon and Other Adiponectin Receptor Agonists as Potential Candidates in Cancer Treatments

Abstract

The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as “the real 21st-century disease”. Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

“…Recently, the first synthetic adiponectin receptor agonist is emerging as a promising anticancer compound in several tumors, including myeloma and breast, prostate, and ovarian cancers ( Nigro et al, 2021 ). Convincing evidence is also emerging in PDAC, where AdipoR suppresses tumor growth and induces cell death, mainly through apoptosis and necroptosis induction ( Messaggio et al, 2017 ; Akimoto et al, 2018 ).…”

“…An increasing number of studies have provided consistent evidence supporting the potential anticancer role of AdipoRon (AdipoR) in several preclinical cancer models, including myeloma and breast, prostate, and ovarian cancers ( Nigro et al, 2021 ). More recently, we also described how AdipoR can energetically inhibit cell proliferation in osteosarcoma cells ( Sapio et al, 2020 ).…”

“…More recently, we also described how AdipoR can energetically inhibit cell proliferation in osteosarcoma cells ( Sapio et al, 2020 ). As a synthetic orally active adiponectin receptor agonist, AdipoR exerts comparable pharmacological properties to those of its template, such as anti-obesity, antidiabetic, and anti-ischemic features ( Nigro et al, 2021 ). Antineoplastic effects have been reported even in PDAC where, delaying cell cycle progression in the G0/G1 phase, AdipoR induces both in vitro and in vivo growth arrest ( Messaggio et al, 2017 ; Akimoto et al, 2018 ).…”

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

“…The heavy molecular mass and the reduced half-life/stability of Acrp30 have substantially hampered any clinical application in malignancy as well as in other pathological conditions. Nevertheless, the recent characterization of a plausible Acrp30 active and binding site has broken new ground in the design of derived compounds, thus making different druggable options available [64] .…”

“…In regard to the Acrp30-mediated beneficial properties observed in cell disease models, adiponectin receptor agonists certainly denote the most promising class of compounds having potential therapeutic perspectives. Among the other agonists, AdipoRon is emerging as a fascinating anticancer agent in several malignancies, including osteosarcoma, myeloma, breast and ovarian cancer [ 65 , 66 ] . Standing out as the top-scored in activating AMPK and bonding AdipoR1 and AdipoR2 in murine myeloblast C2C12 cells, AdipoRon is currently recognized as the first orally active adiponectin receptor agonist [ 67 ] .…”