Methylseleninic Acid Suppresses Pancreatic Cancer Growth Involving Multiple Pathways

Abstract

As a potential novel agent for treating pancreatic cancer, methylseleninic acid (MSeA) was evaluated in cell culture and xenograft models. Results showed that MSeA induced G₁ cell cycle arrest and apoptosis in a majority of human and mouse pancreatic cancer cell lines, but G₂ arrest in human PANC-1 and PANC-28 cell lines. In contrast to our previous finding in human prostate cancer LNCaP cells having a lack of P53 activation by MSeA, induction of G₂ arrest in PANC-1 cells was accompanied by increased mutant P53 Ser15 phosphorylation, upregulation of P53-targets P21Cip1 and GADD45 and G₂ checkpoint kinase (Chk2) activation, suggestive of DNA damage responses. A rapid inhibition of AKT phosphorylation was followed by reduced mTOR signaling and increased autophagy in PANC-1 cells attenuating caspase-mediated apoptosis execution. Furthermore, daily oral treatment with MSeA (3 mg Se/kg body weight) significantly suppressed growth of subcutaneously inoculated PANC-1 xenograft in SCID mice. Immunohistochemical analyses detected increased p-Ser15 P53, P21Cip1, pS139-H2AX (DNA damage responses), and caspase-3 cleavage and decreased pSer473AKT and Ki67 proliferative index and reduced intratumor vascular density in MSeA-treated xenograft. These results provide impetus for further research of MSeA in the therapy and/or chemoprevention of pancreatic cancer.

ACKNOWLEDGMENT

The authors thank Todd Schuster for expert help with flow cytometric analyses.

Hongbo Hu is currently at the College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China. Zhe Wang is currently at the Department of Pathology, Fourth Military Medical University, Xian, China.