Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice

Abstract

The antidiabetic adiponectin receptor agonist AdipoRon has been shown to suppress the tumour growth of human pancreatic cancer cells. Because obesity and diabetes affect pancreatic cancer progression and chemoresistance, we investigated the effect of AdipoRon on orthotopic tumour growth of Panc02 pancreatic cancer cells in DIO (diet-induced obese) prediabetic mice. Administration of AdipoRon into DIO mice fed high-fat diets, in which prediabetic conditions were alleviated to some extent, did not reduce either body weight or tumour growth. However, when the DIO mice were fed low-fat diets, body weight and the blood leptin level gradually decreased, and importantly, AdipoRon became effective in suppressing tumour growth, which was accompanied by increases in necrotic areas and decreases in Ki67-positive cells and tumour microvessels. AdipoRon inhibited cell growth and induced necrotic cell death of Panc02 cells and suppressed angiogenesis of endothelial MSS31 cells. Insulin and IGF-1 only slightly reversed the AdipoRon-induced suppression of Panc02 cell survival but had no effect on the AdipoRon-induced suppression of MSS31 cell angiogenesis. Leptin significantly ameliorated AdipoRon-induced suppression of angiogenesis through inhibition of ERK1/2 activation. These results suggest that obesity-associated factors weaken the anticancer effect of AdipoRon, which indicates the importance of weight loss in combating pancreatic cancer.

Obesity and Pancreatic Cancer: Insight into Mechanisms

“…Conversely, deficiency or knockdown of adiponectin receptors markedly promoted PDAC xenograft growth [118,119]. Interestingly, a recent xenograft study showed that AdipoRon failed to suppress PDAC growth in mice with DIO, while it suppressed tumor growth in lean mice [120]. Taken together, a link between adiponectin and PDAC risk is not conclusively demonstrated by available epidemiologic studies.…”

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

“…IR-A/B and IGF-1R mediate their effects through: Ras/mitogen activated protein kinase (MAPK)/extracellular signal-related kinase 1/2 (ERK-1/2) pathway; phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O (FoxO) pathway; PI3K/Akt/mammalian target of rapamycin (mTOR) pathway; and PI3K/Akt-induced accumulation of the proto-oncogene β-catenin, via inactivation of its inhibitor glycogen synthase kinase 3β (GSK3β) ( 5 , 14 , 20 ) ( Figure 2 ).…”

“…In addition, obesity could be associated with cancer drug resistance. Obesity reduced the anti-cancer effects of the antidiabetic adiponectin receptor agonist AdipoRon in diet-induced obese mice with orthotopic pancreatic cancer through a mechanism involving IGF-1, IGF-1R, and ERK1/2 signaling ( 5 ), indicating the importance of weight loss in combating pancreatic cancer in obese patients.…”

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

“…Standing out as the topscored 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] . Independent research groups have provided convincing evidence supporting the antiproliferative role played by AdipoRon in both in vitro and in vivo PDAC models [61,[68][69][70][71] . Unsurprisingly, querying the main scientific databases for AdipoRon, PDAC represents the most mentioned among the tumor models examined thus far.…”