benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Pancreatic-Neoplasms

Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2'3'-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2'3'-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2'3'-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Cell Line, Tumor; Gene Expression Regulation; Humans; Immunomodulation; Interferon Regulatory Factor-1; Interferon-beta; Membrane Proteins; Necroptosis; NF-kappa B; Nucleotides, Cyclic; Oligopeptides; Pancreatic Neoplasms; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Heterocyclic organobismuth compounds, such as N-tert-butyl-bi-chlorodibenzo[c,f][1,5]azabismocine (compound 1) and bi-chlorodibenzo[c,f ][1,5]thiabismocine (compound 3), exert potent antiproliferative activities in vitro in human cancer cell lines. We showed that compound 3 induced both apoptotic and nonapoptotic cell death via reactive oxygen species production and mitotic arrest in a dose-dependent manner. The mechanisms underlying the dose-dependent effect of these organobismuth compounds were not clear. In the present study, we examined the dose-dependent mechanism underlying cell death induced by compound 1 in a human pancreatic cancer cell line, SUIT-2, and a human colorectal cancer cell line, DLD-1. Compound 1 inhibited cell growth in a dose-dependent manner and induced cell death. Treatment with the pan-caspase inhibitor zVAD-fmk reduced cell death induced by compound 1, whereas the inhibitory effect of zVAD-fmk was limited. Moreover, compound 1 significantly induced lipid peroxidation with concomitant induction of caspase-independent cell death. Our results suggested that eight-membered ring organobismuth compounds induce nonapoptotic cell death via lipid peroxidation.

Topics: alpha-Tocopherol; Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Bismuth; Caspase Inhibitors; Cell Death; Cell Line, Tumor; Cell Membrane; Colorectal Neoplasms; Dose-Response Relationship, Drug; HeLa Cells; Humans; Isoquinolines; Lipid Peroxidation; Organometallic Compounds; Pancreatic Neoplasms; Reactive Oxygen Species

Necroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer.. We used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells.. RIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis.. These findings indicate that necroptosis at the pancreatic cancer invasion front can promote cancer cell migration and invasion via the CXCL5-CXCR2 axis.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Chloromethyl Ketones; Cell Line, Tumor; Cell Movement; Chemokine CXCL5; Culture Media, Conditioned; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Necroptosis; Neoplasm Invasiveness; Oligopeptides; Pancreatic Neoplasms; Phenylurea Compounds; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Interleukin-8B; RNA, Small Interfering; Tumor Necrosis Factor-alpha; Up-Regulation

Pancreatic cancer is one of the most lethal types of cancer with a mortality rate of almost 95%. Treatment with current chemotherapeutic drugs has limited success due to poor responses. Therefore, the development of novel drugs or effective combination therapies is urgently required. Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels. In the present study, we demonstrated that PL induced cancer cell death through, at least in part, the induction of ferroptosis, as the cancer cell-killing activity was inhibited by the antioxidant, N‑acetylcysteine, ferroptosis inhibitors (ferrostatin‑1 and liproxstatin‑1) and the iron chelator, deferoxamine (DFO), but not by the apoptosis inhibitor, Z-VAD-FMK, or the necrosis inhibitor, necrostatin‑1. Cotylenin A (CN‑A; a plant growth regulator) exhibits potent antitumor activities in several cancer cell lines, including pancreatic cancer cell lines. We found that CN‑A and PL synergistically induced the death of pancreatic cancer MIAPaCa‑2 and PANC‑1 cells for 16 h. CN‑A enhanced the induction of ROS by PL for 4 h. The synergistic induction of cell death was also abrogated by the ferroptosis inhibitors and DFO. The present results revealed that clinically approved sulfasalazine (SSZ), a ferroptosis inducer, enhanced the death of pancreatic cancer cells induced by PL and the combined effects were abrogated by the ferroptosis inhibitors and DFO. SSZ further enhanced the cancer cell-killing activities induced by combined treatment with PL plus CN‑A. On the other hand, the synergistic induction of cell death by PL and CN‑A was not observed in mouse embryonic fibroblasts (MEFs), and SSZ did not enhance the death of MEFs induced by PL plus CN‑A. These results suggest that the triple combined treatment with PL, CN‑A and SSZ is highly effective against pancreatic cancer.

Topics: Acetylcysteine; Amino Acid Chloromethyl Ketones; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Line, Tumor; Cyclohexylamines; Deferoxamine; Dioxolanes; Diterpenes; Drug Synergism; Fibroblasts; Humans; Iron; Mice; Pancreatic Neoplasms; Phenylenediamines; Quinoxalines; Reactive Oxygen Species; Spiro Compounds; Sulfasalazine

Evasion of apoptosis represents a key mechanism of treatment resistance of pancreatic cancer (PC) and contributes to the poor prognosis of this cancer type. Here, we report that induction of necroptosis is an alternative strategy to trigger programmed cell death in apoptosis-resistant PC cells. We show that the second mitochondrial activator of caspases (Smac) mimetic BV6 that antagonizes inhibitor of apoptosis (IAP) proteins induces necroptosis in PC cells in which apoptosis is blocked by the caspase inhibitor zVAD.fmk. Intriguingly, BV6 switches autocrine/paracrine production of tumor necrosis factor (TNF)α by PC cells into a death signal and also acts in concert with exogenously supplied TNFα to trigger necroptosis, when caspase activation is simultaneously blocked. BV6 stimulates TNFα production and formation of the receptor-interacting protein (RIP)1/RIP3-containing necrosome complex in PC cells. Knockdown of TNF receptor 1 (TNFR1) protects PC cells from BV6- or BV6/TNFα-mediated cell death, demonstrating that TNFα autocrine/paracrine signaling by PC cells contributes to BV6-induced necroptosis. Importantly, genetic silencing of receptor interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) significantly rescues PC cells from BV6- or BV6/TNFα-induced cell death. Similarly, pharmacological inhibition of RIP1, RIP3 or MLKL significantly reduces BV6- or BV6/TNFα-stimulated cell death. By demonstrating that Smac mimetics can bypass resistance to apoptosis by triggering necroptosis as an alternative form of programmed cell death, our findings have important implications for the design of new treatment concepts for PC.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autocrine Communication; Biological Mimicry; Caspase Inhibitors; Caspases; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Jurkat Cells; MAP Kinase Kinase Kinases; Mitochondrial Proteins; Necrosis; Nuclear Pore Complex Proteins; Oligopeptides; Pancreatic Neoplasms; Paracrine Communication; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor, Type I; RNA Interference; RNA-Binding Proteins; Signal Transduction; Time Factors; Transfection; Tumor Necrosis Factor-alpha

The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and the necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer.

Topics: Acetylcysteine; Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclohexylamines; Diterpenes; Glycosides; Humans; Isothiocyanates; Pancreatic Neoplasms; Phenylenediamines; Quinolines; Reactive Oxygen Species

Pancreatic ductal adenocarcinomas are an extremely aggressive and devastating type of cancer with high mortality. Given the dense stroma and poor vascularization, accessibility to nutrients is limited in the tumor microenvironment. Here, we aimed to elucidate the role of autophagy in promoting the survival of human pancreatic cancer PANC-1 cells exposed to nutrient-deprived media (NDM) lacking glucose, amino acids, and serum. NDM inhibited Akt activity and phosphorylation of p70 S6K, and induced AMPK activation and mitochondrial depolarization. NDM also time-dependently increased LC3-II accumulation, number of GFP-LC3 puncta, and colocalization between GFP-LC3 and lysosomes. These results suggested that autophagy was progressively activated through Akt- and AMPK-mTOR pathway in nutrient-deficient PANC-1 cells. Autophagy inhibitors (chloroquine and wortmannin) or silencing of Atg5 augmented PANC-1 cell death in NDM. In cells exposed to NDM, chloroquine and wortmannin induced apoptosis and Z-VAD-fmk inhibited cytotoxicity of these inhibitors. These data demonstrate that autophagy is anti-apoptotic and sustains the survival of PANC-1 cells following extreme nutrient deprivation. Autophagy modulation may be a viable therapeutic option for cancer cells located in the core of solid tumors with a nutrient-deficient microenvironment.

Topics: Amino Acid Chloromethyl Ketones; Amino Acids; AMP-Activated Protein Kinases; Androstadienes; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Chloroquine; Glucose; Humans; Pancreas; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Wortmannin

The Akt signaling pathway mediates a potent anti-apoptotic signal in pancreatic cancer and inhibition of this pathway has become an attractive mechanism to increase the efficacy of traditional chemotherapies. Autophagy is a lysosomal catabolic pathway by which eukaryotic cells recycle macromolecules and organelles. Although autophagy may function as a survival mechanism under metabolic stress conditions, it also serves as an alternate route to programmed cell death distinct from apoptosis. In the present study, we examined the role of autophagy in Akt-mediated regulation of cell death in pancreatic cancer.. Mia-PaCa-2 and PANC-1 human pancreatic cancer cell lines were used in our experiments. The small-molecule inhibitor A-443654 was used to inhibit Akt, and rapamycin was used to inhibit mTOR. Autophagy was inhibited with Chloroquine and 3-methyladenine. Autophagy was assessed by immunoblotting for light chain-3 (LC-3) processing as well as fluorescence microscopy for autophagosome formation following transfection with a LC-3/GFP construct. Cell death was determined by fluorescence-activated cell sorting (FACS) with quantitation of the sub-G0 content.. Inhibition of either Akt or mTOR induced autophagy; inhibition of Akt but not of mTOR led to traditional caspase-mediated apoptosis. When autophagy was inhibited, cell death was abrogated following Akt, but not mTOR, inhibition.. The Akt signaling pathway regulates both autophagy and apoptosis through divergent pathways; mTOR mediates autophagy signaling but appears to be un-involved in cell death. Autophagy appears to play a role in the regulation of cell survival by Akt, but only when proximal signaling pathways not involving mTOR are simultaneously activated.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Autophagy; Caspases; Cell Line, Tumor; Enzyme Activation; Humans; Indazoles; Indoles; Microscopy, Fluorescence; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Cationic lytic-type peptides have been studied for clinical application in various infections and cancers, but their functional cellular mechanisms remain unclear. We generated anti-cancer epithelial growth factor receptor (EGFR)-lytic hybrid peptide, a 32-amino-acid peptide composed of an EGFR-binding sequence and lytic sequence. In this study, we investigated the distribution of EGFR-lytic hybrid peptide in BxPC-3 human pancreatic cancer cells by an immunocytochemical (ICC) method. Distribution of EGFR protein expression was unchanged after treatment with EGFR-lytic peptide compared with non-treated cells. In confocal laser scanning microscopy, immunostaining of EGFR-lytic peptide was observed in the cytoplasm, mostly in the form of granules. Some staining was also localized on the mitochondrial membrane. At the ultrastructure level, cells treated with EGFR-lytic peptide had a low electron density, disappearance of microvilli, and swollen mitochondria. Fragments of cell membrane were also observed in the proximity of the membrane. In immunoelectron microscopy, EGFR-lytic peptide was observed in the cell membrane and cytoplasm. A number of granules were considered swollen mitochondria. Activation of the caspase pathway as a result of mitochondrial dysfunction was also examined to determine the cytotoxic activity of EGFR-lytic peptide; however, no effect on cell death after EGFR-lytic treatment was observed, and moreover, apoptosis was not found to play a critical role in the cell death mechanism. These results suggest that EGFR-lytic peptide is localized on cell and mitochondrial membranes, with disintegration of the cell membrane contributing mainly to cell death.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Caspase Inhibitors; Cell Line, Tumor; Cell Survival; Doxorubicin; ErbB Receptors; Humans; Immunohistochemistry; Microscopy, Confocal; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling; Pancreatic Neoplasms; Protein Transport; Reactive Oxygen Species; Recombinant Fusion Proteins

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth leading cause of cancer death in the western world, with a 5-year survival rate below 5%. Murine double minute 2 (Mdm2) is an important negative regulator of the tumor suppressor p53. Reactivation of wild-type p53 is a promising treatment strategy, and inhibitors of Mdm2 have already entered clinical trials. To investigate the effects of Mdm2 inhibitors in PDAC, we used a murine cell line platform with a genetically defined status of p53. Here, we describe that Mdm2 inhibitors can act on a subset of murine PDAC cell lines p53 independently. Furthermore, we observed that Mdm2 inhibitors increase the sensitivity of murine PDAC cell lines toward topoisomerase II inhibitors by inducing effector caspase-independent cell death. The combination of Mdm2 inhibitors with topoisomerase II inhibitors acts independent of the survival factor NFκB/RelA. Mechanistically, Mdm2 inhibitors increase topoisomerase II inhibitor-induced DNA double-strand breaks. We show that Mdm2 binds to Nbs1 of the Mre11-Rad50-Nijmegen breakage syndrome (Nbs) 1 DNA repair complex. In addition, we provide evidence that Mdm2 inhibitors delay DNA repair. These findings may help to design novel therapeutic strategies to overcome therapeutic resistance of PDAC.

Topics: Amino Acid Chloromethyl Ketones; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; DNA Damage; Doxorubicin; Drug Synergism; Etoposide; Gemcitabine; Imidazoles; Immunohistochemistry; Immunoprecipitation; Indoles; Mice; Pancreatic Neoplasms; Piperazines; Proto-Oncogene Proteins c-mdm2; Pyrrolidinones; Topoisomerase II Inhibitors

The CD95 and TRAIL death receptors can potently stimulate proinflammatory signalling, especially in apoptosis resistant cells. Here, we show that caspases are of cell type-specific relevance for non-apoptotic death receptor signalling in pancreatic tumour cells. Inhibition of caspases by zVAD-fmk strongly enhanced the proinflammatory response in PancTuI, BxPc3 and Panc89 cells, but inhibited this response in Colo357 cells as well as in apoptosis-resistant Colo357-BclxL cells overexpressing BclxL. To characterize the role of caspases in non-apoptotic death receptor signalling, we analysed CD95L- and TRAIL-induced signalling pathways in Colo357-BclxL cells in comparison with PancTuI cells. Both death ligands induced NFkappaB, ERKs, JNK and p38 in Colo357-BclxL cells and except for ERKs also in PancTuI cells. However, inhibition of caspases with zVAD-fmk resulted in strong inhibition of all these signalling pathways in Colo357-BclxL, but enhanced NFkappaB and JNK signalling in PancTuI cells. Caspase-mediated activation of NFkappaB and ERKs were involved in CD95L- and TRAIL-induced up-regulation of proinflammatory genes in Colo357-BclxL cells. At the level of the DISC we did not observe any significant differences in recruitment or processing of FADD, caspase-8, FLIP, TRAF2 and RIP between PancTuI and Colo357-BclxL cells. Consequently, an NFkappaB and ERK stimulating, caspase-dependent factor must operate downstream of the DISC in Colo357-BclxL cells.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; bcl-X Protein; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Caspases; Cell Line, Tumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fas Ligand Protein; Humans; Inflammation Mediators; NF-kappa B; Pancreatic Neoplasms; Signal Transduction; TNF Receptor-Associated Factor 2; TNF-Related Apoptosis-Inducing Ligand

Apoptosis induced by DNA-damaging agents or radiation mainly proceeds through death receptor-independent caspase activation. The release of mitochondrial apoptogenic proteins, such as cytochrome c, into the cytoplasm leading to Apaf1-dependent activation of caspase-9 is a key event in this pathway. The permeability of the mitochondrial outer membrane is regulated by the various pro- and antiapoptotic Bcl-2 family proteins, and it is thought that DNA damage triggers apoptosis through the downregulation of antiapoptotic Bcl-2. Using murine embryonic fibroblasts (MEF) deficient and proficient in Apaf1, we show that DNA-damaging agents and radiation lead to a decline in Bcl-2 protein only in wt MEF, but not in apaf1(-/-) MEF, which are defective in the activation of effector caspases and apoptosis. In contrast, the induction of proapoptotic Noxa, the activation of Bax, the cytoplasmic release of cytochrome c, as well as a drop of the mitochondrial transmembrane potential Deltapsim are equally observed in wt and apaf1(-/-) MEF following DNA damage. Moreover, the loss of Bcl-2 protein occurring in wt MEF can be prevented by caspase inhibition. Hence, the activation of proapoptotic Bcl-2 family proteins rather than the downregulation of antiapoptotic Bcl-2 mediates the primary signal in the DNA damage-induced release of mitochondrial apoptogenic proteins in MEF.

Topics: Adenocarcinoma; Adenoviridae; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase Inhibitors; Caspases; Cell Transplantation; Dactinomycin; DNA Damage; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Enzyme Activation; Enzyme Inhibitors; Etoposide; Fibroblasts; Gene Deletion; Humans; Mice; Mice, SCID; Pancreatic Neoplasms; Proteins; Proto-Oncogene Proteins c-bcl-2; Transplantation, Heterologous; Tumor Cells, Cultured; Ultraviolet Rays

All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

Topics: Adenocarcinoma; Alitretinoin; Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Aspartic Acid; bcl-2-Associated X Protein; Cysteine Proteinase Inhibitors; DNA Fragmentation; Drug Resistance; Fatty Acids, Unsaturated; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Mice; Mitochondria; Neoplasm Proteins; Pancreatic Neoplasms; Protein Isoforms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured