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.
Highlights
According to Global Cancer Statistics 2020, pancreatic cancer (PC) ranks the seventh leading cause of cancer death worldwide, with an estimated 466,003 deaths against 495,773 new cases (Collisson et al, 2019; Sung et al, 2021)
MIA PaCa-2 and PANC-1 human pancreatic ductal adenocarcinoma (PDAC) cell lines were purchased by the American Type Culture Collection (ATCC) and maintained at 37°C in a 5% CO2 humidified atmosphere, using Dulbecco’s Minimum Essential Medium (DMEM) (ECM0728L; Euroclone) supplemented with 10% fetal bovine serum (FBS) (ECS0180L; Euroclone) and 1% penicillin/streptomycin (ECB3001D; Euroclone) as culture medium
The following day, AdipoR and Gem were supplemented to fresh media, either individually or in combination, and PDAC cells were incubated for times and concentrations provided in each experimental condition
Summary
According to Global Cancer Statistics 2020, pancreatic cancer (PC) ranks the seventh leading cause of cancer death worldwide, with an estimated 466,003 deaths against 495,773 new cases (Collisson et al, 2019; Sung et al, 2021). Arising from either ductal or acinar cells of the exocrine portion, pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, while the remainder evolves from Langerhans islets (Gao et al, 2020) While this latter subtype is typically linked to an abnormal hormone secretion even at the early stage, facilitating its detection and diagnosis, PDAC is almost a symptom-free disease until metastases, or rather when the advanced stage leaves no longer chances of recovery (Mpilla et al, 2020). Collecting the existing molecular data, a similar subgroup grading has recently been made even in PDAC (Collisson et al, 2019) Albeit quite promising, this therapeutic approach has not been fully translated in clinical yet; chemotherapy still remains the best option for curing PDAC patients (Qian et al, 2020). Considering the advanced and metastasized stages at diagnosis, the surgical resection rate remains very low in PDAC (Huang et al, 2019)
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