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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes.

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

“…Activation of AMPK and p38 signaling were recognized as survival pathways in this specific experimental design, since their pharmacological inhibition enhanced the AdipoRon cytotoxic effects. The impairment of mitochondrial activity was further confirmed by Manley et al in their latest study [69] . Performing Seahorsebased assays, they noticed that AdipoRon treatments not only decreased basal and maximal mitochondrial respiration but also attenuated proton leak.…”

“…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.…”

“…In accordance with this latter operation, in both oncogene-ablated and gemcitabine-treated PDAC cells, targeting OXPHOS significantly shrank tumor recurrence [31,32,78] . Since an OXPHOS impairment has also been observed in response to AdipoRon administration [68,69] , it is plausible to imagine a link between the damage that occurred at this organelle and the ability to sensitize PDAC resistant cells to gemcitabine. While the aberrant glycolysis usage is considered a metabolic feature of drug resistance in tumor cells [30,79] , after AdipoRon stimulation, this compensatory mechanism could be exploited to completely eradicate the minimal residual disease [Table 1] [69,80,81] .…”

“…Since an OXPHOS impairment has also been observed in response to AdipoRon administration [68,69] , it is plausible to imagine a link between the damage that occurred at this organelle and the ability to sensitize PDAC resistant cells to gemcitabine. While the aberrant glycolysis usage is considered a metabolic feature of drug resistance in tumor cells [30,79] , after AdipoRon stimulation, this compensatory mechanism could be exploited to completely eradicate the minimal residual disease [Table 1] [69,80,81] . Besides the metabolic outlook, another potential mechanistic way to corroborate the AdipoRon-mediated gemcitabine sensitization could be represented by the ABC transporters, which have recently been implicated in chemotherapy resistance, expressly in PDAC [21][22][23] .…”

“…AdipoRon has recently been found to be effective in contrasting PDAC cell growth at preclinical stage [ 61 , 68 , 69 , 71 ] , but, more interestingly, we recently provided evidence of potential cooperating effects between AdipoRon and gemcitabine [ 70 ] . Due to the low rate of radiation and surgery eligibility, gemcitabine-based therapy constitutes the widely used approach in treating PDAC [ 5 ] .…”