Pancreatic cancer ranks fourth among
cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage
tumors. Moreover,
pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid
disease progression, resistance and
metastasis. The main goal of this study was to define the mechanisms by which
calix[6]arene, but not other
calixarenes, efficiently decreases the aggressiveness of a
drug resistant human pancreas
carcinoma cell line (Panc-1).
Calix[6]arene was more potent in reducing Panc-1 cell viability than
gemcitabine and
5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and
retinoblastoma proteins. Importantly,
calix[6]arene abolished signal transduction of Mer and AXL
tyrosine kinase receptors, both of which are usually overexpressed in
pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these
proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308,
calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of
calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight
calix[6]arene as a potential candidate for overcoming
pancreatic cancer aggressiveness. Importantly, we provide evidence that
calix[6]arene affects a broad array of key targets that are usually dysfunctional in
pancreatic cancer, a highly desirable characteristic for chemotherapeutics.