Pancreatic Cancer Cell Death Research Articles

Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand induced inhibition of pancreatic cancer cell growth COX-2 gene induction

BACKGROUND. Pancreatic cancer is the fifth leading cause of cancer deaths; current treatment options have been ineffective in prolonging survival. Peroxisome proliferator-activated receptor-~, (PPAR-~/) is a nuclear receptor that is expressed in certain human cancers; ligandinduced PPAR-',/activation can result in growth inhibition and differentiation in these cells. Increased cyclooxygenase-2 (COX-2) expression has been shown to enhance malignant potential in certain cells; PPAR-'y ligands can indirectly suppress COX-2 expression by interfering with the NF-KB signaling pathway or, conversely, directly activate COX-2 transcription. The purpose of this study was to assess the effect of PPAR-~/activation on cellular growth and the expression of COX-2 in human pancreatic cancer cell lines. METHODS. The effect of the PPAR--~ selective ligands, 15-deoxy-A~2'~'-proetaglandin J2 (15d-PGJ2) and ciglltazone, on pancreatic cancer cell growth was assessed by cell counting over a time course using three human pancreatic cancer cell lines (Mia PaCa-2, BxPC-3 and L3.6). In addition, expression of PPAR-x and COX-2 was evaluated by Western blots. RESULTS. Both 15d-PGJ2 (25/LM) and ciglitazone (35 ~M) inhibited the growth of the three pancreatic cancer cell lines in a temporal-dependent fashion. In addition, both 15d-PGJ2 and ciglitazone increased COX-2 protein and PPAR-~/expression at 4-6 h after treatment in BxPC-3 and L3.6 cells. CONCLUSIONS. Ligand-induced PPAR-~ activation significantly inhibited the growth of human pancreatic cancer cells in vitro', this inhibition of cell growth was associated with induction of COX2 expression suggesting that the mechanisms for PPAR--y-induced pancreatic cancer cell death is independent of COX-2 suppression. Therapeutic agents which activate PPAR-.,/may provide novel strategies for the adjuvant treatment of pancreatic cancers in which no effective therapy exists.

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism

Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism.

Polyunsaturated fatty acids (PUFAs), reported to be cytotoxic at micromolar concentrations for cancer cells in vitro and in vivo, are currently being tested in clinical trials as anti-cancer agents. This study has shown that seven PUFAs all inhibited the growth in vitro of three pancreatic cancer cell lines and the HL-60 leukaemic cell line. Five PUFAs induced cell death within 20-30 h, but two less potent PUFAs induced death between 50 and 75 h. Apoptosis was demonstrated to be the mode of cell death by light, UV fluorescence, and electron microscopy, together with studies of DNA fragmentation. In a time-course study of PUFA-treated Mia-Pa-Ca-2 cells, apoptosis accounted for an average of 80 per cent of the loss of viability, with 'secondary necrosis', a feature of late apoptosis, apparently accounting for the remainder. Correlations were found between the number of fatty acid double bonds and the proportion of cells undergoing apoptosis induced in both Mia-Pa-Ca-2 cells (R = 0.88, P = 0.0001) and HL-60 cells (R = 0.85, P = 0.0001) and inversely with the micromolar concentrations of PUFAs required for 50 per cent inhibition of growth (IC50) of Mia-Pa-Ca-2 cells (R = -0.73, P = 0.05). Cell death was preceded by progressively increasing lipid peroxidation. The extent of PUFA-induced lipid peroxidation, measured as malondialdehyde (MDA), also correlated with the proportion of apoptosis induced in Mia-Pa-Ca-2 cells (R = 0.69, P = 0.025) or HL-60 cells (R = 0.64, P = 0.043), as well as with the number of fatty acid double bonds (R = 0.82, P = 0.0015). PUFA-induced apoptosis was oxidative, being blocked by both vitamin E acetate and sodium selenite, the latter in a critically time-dependent manner. The cytotoxic effects of exposure to a PUFA and to gamma-irradiation simultaneously with, or prior to, the addition of PUFA.

Combinatorial effect of epigallocatechin-3-gallate and TRAIL on pancreatic cancer cell death

Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, can exert growth suppressive effect on human pancreatic cancer cells by evoking apoptotic response. EGCG-induced apoptosis of pancreatic cancer cells is accompanied by growth arrest at an earlier phase of cell cycle along with depolarization of mitochondrial membrane. In this report, using MIA PaCa-2 cells as in vitro model, we demonstrate EGCG-induced cell death involves activation of caspase-8 and disappearance of intact 21 kDa Bid protein. Furthermore, exogenous expression of dominant negative caspase-8 or dominant negative FADD significantly abrogates apoptosis inducing ability of EGCG in MIA PaCa-2 cells. RNase protection assay revealed upregulation of the members of death receptor family, thus indicating the involvement of transmembrane extrinsic signaling in this polyphenol triggered pancreatic carcinoma cell death. Based on this, we examined the effect of EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) together on pancreatic cancer cells. A synergistic increase in apoptosis and cleavage of procaspase-3 was noted. Furthermore, clonogenic cell survival assay demonstrates the significant diminishment of MIA PaCa-2 cell proliferation in the presence of both EGCG and TRAIL. This combination treatment strategy has potential therapeutic advantage for pancreatic carcinoma.