ABSTRACT
OBJECTIVES: To investigate the effects and mechanism of Frondanol-A5P, a polar extract from Cucumaria frondosa, on growth inhibition and apoptosis in S2013 and AsPC-1 human pancreatic cancer cells. METHODS: The effects of Frondanol-A5P on proliferation, cell cycle, expression of cell cycle proteins and p21, phosphorylation of MAP kinases, annexin V binding, and caspase-3 activation were examined. RESULTS: Frondanol-A5P inhibited proliferation and induced G2/M phase cell cycle arrest in both cell lines with decreased expression of cyclin A, cyclin B, and cdc25c. Frondanol-A5P induced phosphorylation of stress-activated protein kinase and Janus kinase (SAPK/JAK) and p38 mitogen-activated protein kinase (MAP) within 5 minutes. Frondanol-A5P markedly increased expression of p21 messenger RNA and protein at 3 hours in both cell lines. This effect was reduced by the p38 kinase inhibitor, SB203580. Frondanol-A5P markedly increased annexin V binding and activated caspase-3. CONCLUSIONS: Frondanol-A5 causes cell cycle arrest and apoptosis in human pancreatic cancer cells. These changes are associated with decreased expression of cyclin A, cyclin B, and cdc25c and increased expression of p21 that, at least in part, is mediated by a p38 kinase-dependent mechanism. Because Frondanol-A5P is derived from an edible, nontoxic, sea cucumber, it may be valuable for nutritional therapy or prevention of pancreatic cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Complex Mixtures/pharmacology , Cucumaria , Pancreatic Neoplasms/metabolism , Animals , Annexins/metabolism , Apoptosis/drug effects , Caspase 3/metabolism , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Humans , Phosphorylation , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND: Retinoids are potent growth inhibitory and differentiating agents in a variety of cancer cell types. We have shown that retinoids induce growth arrest in all pancreatic cancer cell lines studied, regardless of their p53 and differentiation status. However, the mechanism of growth inhibition is not known. Since TGF-beta2 is markedly induced by retinoids in other cancers and mediates MUC4 expression in pancreatic cancer cells, we investigated the role of TGF-beta in retinoic acid-mediated growth inhibition in pancreatic cancer cells. RESULTS: Retinoic acid markedly inhibited proliferation of two cell lines (Capan-2 and Hs766T) in a concentration and time-dependent manner. Retinoic acid increased TGF-beta2 mRNA content and secretion of the active and latent forms of TGF-beta2 (measured by ELISA and bioassay). The concentrations of active and TGF-beta2 secreted in response to 0.1 - 10 muM retinoic acid were between 1-5 pM. TGF-beta2 concentrations within this range also inhibited proliferation. A TGF-beta neutralizing antibody blocked the growth inhibitory effects of retinoic acid in Capan-2 cells and partially inhibitory the effects in Hs766T cells. CONCLUSION: These findings indicate that TGF-beta can cause growth inhibition of pancreatic cancer cells, in a p53-independent manner. Furthermore, it demonstrates the fundamental role of TGF-beta in growth inhibition in response to retinoic acid treatment is preserved in vitro.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Antineoplastic Agents/pharmacology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Transforming Growth Factor beta2/physiology , Tretinoin/pharmacology , Antibodies/immunology , Antibodies/pharmacology , Antibody Specificity , Cell Growth Processes/drug effects , Cell Growth Processes/physiology , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Humans , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Transforming Growth Factor beta2/biosynthesis , Transforming Growth Factor beta2/genetics , Transforming Growth Factor beta2/immunology , Transforming Growth Factor beta2/pharmacologyABSTRACT
Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer.
Subject(s)
Cell Cycle/drug effects , Cell Proliferation/drug effects , Depsipeptides/administration & dosage , Pancreatic Neoplasms/pathology , Antineoplastic Agents/administration & dosage , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , HumansABSTRACT
Pancreatic cancer is a disease carrying a dismal prognosis, with overall 5-year survival at around 4%. Recent clinical trials of adjuvant therapies have not found a dramatic increase in median survival. In the current review, we examine the available literature on flavonoids, a group of naturally occurring substances, for their effects on cancer cells and potential for therapy of pancreatic cancer in the future. With the available in vitro and in vivo data, it is likely that flavonoids will move into the clinical arena as therapeutic or preventive tools for cancer.
