prostaglandin-d2 and Neoplasms

Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are one of the most frequently used classes of drug worldwide and inhibit prostaglandin (PG) production by inhibiting cyclooxygenase activity. Although NSAIDs are broadly used against inflammatory diseases, they have side effects including alimentary canal disorders, kidney damage, infection and cardiovascular disorders. Thus, it is necessary to elucidate the pathophysiological role of each PG in various diseases to develop better therapies with fewer and milder side effects. PGD

Topics: Acute Lung Injury; Animals; Capillary Permeability; Colitis; Dermatitis; Inflammation; Mice; Neoplasms; Neovascularization, Pathologic; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Cell Membrane Permeability; Humans; Inflammation; Neoplasms; Prostaglandin D2

Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients.

Topics: Dinoprost; Dinoprostone; Epigenesis, Genetic; Epoprostenol; Gene Silencing; Humans; Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Signal Transduction; Thromboxane A2

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor, is a ligand-activated transcription factor involved in adipogenesis, glucose homeostasis and lipid metabolism. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenous ligand of PPARgamma, has multifaceted cellular functions. Angiogenesis plays an important role in the pathophysiology of ischemic and neoplastic disorders, especially cancer. 15d-PGJ(2) is involved in regulation of angiogenic mediators including vascular endothelial growth factor and hence participates in the blood vessel formation by means of angiogenesis. However, depending on the experimental conditions, this cyclopentenone prostaglandin can exert opposite effects on angiogenesis. 15d-PGJ(2) inhibits angiogenesis via suppression of pro-inflammatory enzymes and cytokines, while it also stimulates angiogenesis via induction of heme oxygenase-1, endothelial nitric-oxide synthase, and hypoxia inducible factor-1alpha. The aim of this review is to highlight such dual effects of 15d-PGJ(2) on angiogenesis and underlying molecular mechanisms.

Topics: Humans; Ligands; Neoplasms; Neovascularization, Pathologic; PPAR gamma; Prostaglandin D2

Chemoprevention refers to the use of defined nontoxic chemical regimens to inhibit, reverse, or retard the process of multistage carcinogenesis that involves multiple signal transduction events. Identification of signaling molecules associated with carcinogenesis as prime targets of chemopreventive agents has become an area of great interest. Recent studies have implicated cysteine thiols present in various transcription factors, such as NF-kappaB, AP-1, and p53 as redox sensors in transcriptional regulation of many genes essential for maintaining cellular homeostasis. Some chemopreventive and cytoprotective agents have been found to target cysteine thiols present in key transcription factors or their regulators, thereby suppressing aberrant over-activation of carcinogenic signal transduction or restoring/normalizing or even potentiating cellular defense signaling. The focus of this review is the oxidation or covalent modification of thiol groups present in key representative redox-sensitive transcription factors and their regulating molecules as a unique strategy for molecular target-based chemoprevention and cytoprotection.

Topics: Cysteine; Humans; Neoplasms; Prostaglandin D2; Signal Transduction; Sulfhydryl Compounds; Transcription Factors; Transcription, Genetic

Prostaglandins are potent lipid molecules that affect key aspects of immunity. The original view of prostaglandins was that they were simply immunoinhibitory. This review focuses on recent findings concerning prostaglandin E2 (PGE2) and the PGD2 metabolite 15-deoxy-Delta(12,14)-PGJ2, and their divergent roles in immune regulation. We will highlight how these two seminal prostaglandins regulate immunity and inflammation, and play an emerging role in cancer progression. Understanding the diverse activities of these prostaglandins is crucial for the development of new therapies aimed at immune modulation.

Topics: Adjuvants, Immunologic; Animals; Dinoprostone; Humans; Inflammation; Models, Immunological; Models, Molecular; Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases

Topics: Apoptosis; Cell Differentiation; Cell Division; Humans; Neoplasms; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.

Topics: Animals; Antineoplastic Agents; Cell Division; Drug Administration Schedule; Drug Carriers; Drug Delivery Systems; Humans; Lipids; Mice; Microspheres; Neoplasms; Prostaglandin D2; Prostaglandins A, Synthetic; Rats; Technology, Pharmaceutical

Molecular cancer epidemiology is a relatively new strategy for malignancies. This strategy has made it possible to diagnose the predisposition to cancer. An individual is said to have a predisposition to cancer when a tumor-suppressor gene is inactivated in germ-line cells. Mainly the inactivation of the tumor-suppressor gene is caused by mutations at the coding region of the gene. However, we clarified that point mutations or hypermethylations of the retinoblastoma tumor-suppressor gene (RB) also cause inactivation of the gene, resulting in retinoblastoma. On the other hand, studies to improve the diagnosed predisposition to cancer have not been performed. We therefore started a basic study for this purpose. As the first example of limiting the predisposition to cancer, the cases with a point mutation at the RB promoter region might be good candidates. In these carriers, only the RB promoter region is inactivated in spite of a lack of abnormalities in the coding region. Therefore, if the RB promoter activity is recovered by drugs, predisposition to retinoblastoma should be limited. As the second example, Li-Fraumeni syndrome in which the p53 gene is hereditarily mutated might be a good candidate. Recently p53 has been reported to stimulate the WAF1 gene, and the WAF1 protein to inhibit cdk activity, which inactivates the RB gene product by phosphorylation. In addition, we found that p53 up-regulates the promoter activity of the RB gene. These findings suggest that p53 directly or indirectly activates RB at the transcriptional or post-transcriptional level. Therefore, reactivation of the WAF1 or RB gene by certain drugs might compensate for the loss of function of p53 in Li-Fraumeni syndrome. We then suggest that it might be possible to prevent cancer by enhancing some intact target genes of the genetically inactivated tumor-suppressor gene. We term this new strategy "gene-regulating chemoprevention." To test this hypothesis it is important to clarify the structure of the RB promoter. In summary we found that RBF-1 and ATF sites are the core promoter regions, that the neighboring E2F site is a silencer site, and that E4TF1 preferentially binds to the RBF-1 site. We then speculate that drugs interfering with the binding of the E2F complex might become good candidates enhancing RB promoter activity. To find drugs regulating the promoters of these genes, it is reasonable to try G1 arresting drugs, because WAF1 and RB are thought to arrest cells at the G1 pha

Topics: Animals; Base Sequence; Flavonoids; Genes, p53; Genes, Retinoblastoma; Genes, Tumor Suppressor; Humans; Methylation; Molecular Epidemiology; Molecular Sequence Data; Mutation; Neoplasms; Promoter Regions, Genetic; Prostaglandin D2

Lung adenocarcinoma (LUADC) belongs to the most prevalent and lethal cancer types. As 15-deoxy-Δ12,14-prostaglandin J

Topics: Adenocarcinoma of Lung; Apoptosis; Cell Proliferation; Cyclooxygenase 2; Humans; Neoplasms; Prostaglandin D2; Prostaglandins; Reactive Oxygen Species; Sirtuin 1

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carbazoles; Cell Line, Tumor; Cyclooxygenase Inhibitors; Dinoprostone; Diphenylamine; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Gene Expression Profiling; Neoplasms; Phenylacetates; Piroxicam; Prostaglandin D2

Prostaglandins (PGs), important modulators in bone biology, may also contribute to tumor formation and progression in human osteosarcoma. 15-Deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), a metabolite of PGD(2) and PPARγ-ligand, exerts a panel of biological activities via receptor-dependent and -independent mechanisms. As inducible cyclooxygenase-2 (Cox-2) is a candidate inflammatory marker in human osteosarcoma and a rate-limiting enzyme in PG biosynthesis, this study aimed at investigating intracellular redox status and signaling cascades leading to Cox-2 induction in human MG-63 osteosarcoma cells. 15d-PGJ(2) induced the accumulation of reactive oxygen species (ROS) that in turn may lead to upregulation of Cox-2 via two different routes in a PPARγ-independent manner. First, phosphorylation of p38 MAPK directly enhances Cox-2 expression by promoting mRNA stability. Second, 15d-PGJ(2) induces activation of epidermal growth factor receptors and downstream activation of Cox-2 via phosphorylation of p42/44 MAPK. Glutathione precursor molecules reversed enhanced ROS levels and Cox-2 expression. Functional activity of Cox-2 expression was tested by measurement of PGE(2) and PGF(2α). The synthetic compound 9,10-dihydro-15d-PGJ(2) lacking the α,β-unsaturated carbonyl group in the cyclopentenone ring did not exhibit the cellular responses observed with 15d-PGJ(2). We conclude that the electrophilic carbon atom of 15d-PGJ(2) is responsible for alterations in intracellular redox status and Cox-2 expression.

Topics: Animals; Cell Line, Tumor; Cyclooxygenase 2; Dinoprost; Dinoprostone; ErbB Receptors; Gene Expression; Glutathione; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; Osteosarcoma; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prostaglandin D2; Reactive Oxygen Species; RNA Stability; Signal Transduction; Up-Regulation

Thiol reactive cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ2), induced a novel, nonapoptotic and microtubule-associated protein 1 light chain 3 (MAP1 LC3) dependent but nonautophagic form of cell death in colon, breast and prostate cancer cell lines, characterized by extensive cytoplasmic vacuolation with dilatation of endoplasmic reticulum (ER). Disruption of sulfhydryl homeostasis, which resulted in ER stress, accumulation of ubiquitinated proteins and subsequent ER dilation, contributed to peroxisome proliferator-activated receptor gamma (PPARgamma)-independent cell death by 15d-PGJ2. Absence of intracellular organelles in these vacuoles, shown by electron microscopy and unique fragmentation of lamin B, suggested this form of cell death to be different from autophagy and apoptosis. Cell death induced by 15d-PGJ2 is prevented by cycloheximide and actinomycin D, suggesting a requirement of new protein synthesis for death with cytoplasmic vacuolation. Here, we report for the first time that upregulation and processing of autophagy marker LC3 is an important event in nonautophagic cytoplasmic vacuolation and cell death. Notably, knockdown of LC3 conferred significant protection against 15d-PGJ2-induced cytoplasmic vacuolation and cell death, suggesting a novel role of LC3 in a death process other than autophagy.

Topics: Adaptor Proteins, Signal Transducing; Antioxidants; Autophagy; Autophagy-Related Protein 8 Family; Cell Death; Cell Line, Tumor; Cytoplasm; Endoplasmic Reticulum; Gene Knockdown Techniques; Humans; Microfilament Proteins; Microtubule-Associated Proteins; Neoplasms; PPAR gamma; Prostaglandin D2; Reactive Oxygen Species; Ubiquitination; Up-Regulation; Vacuoles

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration.. Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators.. The number of PPARgamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPARgamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group.. These results indicate that the PPARgamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Hepatectomy; Hypoglycemic Agents; Liver; Liver Regeneration; Male; Models, Animal; Neoplasms; Pioglitazone; PPAR gamma; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Thiazolidinediones

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ(2) induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Gene Expression; Humans; Jurkat Cells; Membrane Glycoproteins; Neoplasms; Pioglitazone; PPAR gamma; Prostaglandin D2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; RNA Stability; RNA, Messenger; RNA, Small Interfering; Rosiglitazone; Thiazolidinediones; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Cyclopentenone prostaglandins, delta12-PGJ2 and 15d-PGJ2, have potent anti-tumour and anti-inflammatory activities, and have been shown to induce apoptosis in amnion-derived WISH cells. In this study, we have investigated the protective effects of serum and its constituents (growth factors and albumin) on delta12-PGJ2 and 15d-PGJ2-induced apoptosis in WISH cells. Serum (0.5% w/v) was protective against both delta12-PGJ2 and 15d-PGJ2-induced apoptosis. This was not due to the presence of serum-derived growth factors (EGF, IGF-1 and IGF-2), since they had no significant effect on 15d-PGJ2-induced cell death. In contrast, IGF-1 partially inhibited etoposide-induced apoptosis, confirming the presence of a functional IGF-1 receptor signalling system. Albumin was identified as the key survival factor in serum, since albumin and delipidated albumin exhibited the same level of protection from 15d-PGJ2-induced apoptosis as serum itself. The potential for serum albumin to regulate the bioactivity of cyclopentenone PGs may be of considerable importance in pathological conditions where roles for cyclopentenone PGs have been identified.

Topics: Apoptosis; Cell Line; Epithelial Cells; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Neoplasms; Prostaglandin D2; Receptor, IGF Type 1; Serum; Serum Albumin; Signal Transduction

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), 15-deoxy-delta(12,14)-prostaglandin J2, troglitazone, and rosiglitazone increased PPARgamma and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARgamma ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARgamma ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Topics: Angiogenesis Inhibitors; CD36 Antigens; Cells, Cultured; Chromans; Drug Interactions; Endothelium, Vascular; Humans; Ligands; Microcirculation; Neoplasms; Neovascularization, Pathologic; Peptides; PPAR gamma; Prostaglandin D2; Thiazolidinediones; Thrombospondin 1; Troglitazone; Vasodilator Agents

Excessive and prolonged activation of nuclear factor-kappaB (NF-kappaB) has been linked to numerous human diseases, especially cancer, because of the elevated expression of genes encoding antiapoptotic proteins, cytokines, chemokines, cell adhesion molecules, and so on. Eukaryotic cells have developed multiple mechanisms to keep this ubiquitous transcription factor in check. In addition to the inhibitor of kappaB family proteins, a number of endogenous molecules that negatively regulate the activation or activity of NF-kappaB have been identified. These molecules include A20, CYLD, cyPG15-deoxy-Delta(12,14)-prostaglandin J(2), Foxj1, Twist proteins, and beta-arrestins. The extended list of these endogenous inhibitors of NF-kappaB may provide new opportunities for the development of novel strategies for the intervention of malignant transformation. The question to be asked is how NF-kappaB is sustained activated in a number of cancers in which so many antagonists are surrounded.

Topics: Arrestins; beta-Arrestins; Deubiquitinating Enzyme CYLD; DNA-Binding Proteins; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; NF-kappa B; Nuclear Proteins; Prostaglandin D2; Proteins; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Suppressor Proteins

We have been investigating the synergistic cytotoxic interactions between tamoxifen (TAM) and cisplatin (DDP) in human malignant cell lines. Recent data have demonstrated that TAM activates phospholipase D, which can increase the production of prostaglandin D2. Prostaglandin D2 has been shown to have growth inhibitory properties in several malignant cell lines. delta 12-Prostaglandin-J2 (delta 12-PG J2) is a derivative of prostaglandin D2 that has been shown to have similar inhibitory properties. We hypothesized that TAM may increase the production of delta 12-PG J2, which in turn may synergize with DDP. To begin our investigation of this interaction, we sought to determine if delta 12-PG J2 was cytotoxic and synergistic in our melanoma system and then expanded our observations to include a wide range of malignant cells. We have demonstrated that delta 12-PG J2 is cytotoxic to multiple malignant cell lines including melanoma, ovarian, prostate, colon, pancreas, small cell lung cancer, and breast cancer lines. The IC50s ranged from 0.70 microM (small cell lung cancer) to 3.30 microM (DDP-resistant melanoma). Additionally, delta 12-PG J2 exhibited synergistic cytotoxicity with both DDP and ionizing radiation. These data suggest that delta 12-PG J2 should be further evaluated in an in vivo model to confirm activity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Male; Neoplasms; Prostaglandin D2; Tamoxifen; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: Cell Division; G1 Phase; Gene Expression Regulation, Neoplastic; Genes, myc; Heat-Shock Proteins; Humans; Neoplasms; Prostaglandin D2

Prostaglandin(PG)s of the A and J series are categorized as antitumor, antiviral PGs. They have a reactive alpha, beta-unsaturated carbonyl in the cyclopentenone ring, which could be the active moiety. They are actively incorporated into cells and in part transferred to the nuclei, and lead to cell cycle arrest at G1 or cell death depending on the dose.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cell Cycle; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Prostaglandin D2; Prostaglandins A; Transplantation, Heterologous; Viruses

Some PG derivatives have been shown to be inhibitory for tumor cell growth. To elucidate the underlying mechanism(s) for this, we examined various DNA polymerase activities in PG-treated cultured cells. Human KBIII cells were exposed for one day to each of PGJ2, delta 7-PGA1 and delta 12-PGJ2 at a concentration of 5 micrograms/ml. The cells were harvested and homogenized, and the cell-free extracts were analyzed by phosphocellulose column chromatography for separation, identification, and quantification of each of the DNA polymerases. The results obtained were as follows: The activity of DNA polymerase alpha, which is responsible for DNA replication, has remained almost unchanged by any of the PG derivatives tested (77-87%), whereas the activity of DNA polymerase beta (repair enzyme) was found to dramatically decrease to 13 to 20% of that of the nontreated control cells by treatment with any of these PG derivatives. The results indicate that (a) these PG derivatives inhibit, either directly or indirectly, the synthesis of DNA polymerase beta in the KBIII cell, and (b) DNA polymerase beta may also participate in DNA replication other than DNA repair.

Topics: Antineoplastic Agents; Cell Division; Cell Line; Humans; Neoplasms; Nucleic Acid Synthesis Inhibitors; Prostaglandin D2; Prostaglandins A, Synthetic; Prostaglandins D; Prostaglandins, Synthetic

The cytotoxic effect of prostaglandin (PG) D2, PGE1 and PGF2 alpha was examined on human osteosarcoma cells (KSu cell line) in vitro, and PGD2 was most effective. DNA, RNA and protein syntheses of KSu cells were also found to be inhibited by PGD2 at a concentration of 5 micrograms/ml. Furthermore, the proliferation of various human malignant tumor cells was inhibited by PGD2 without exception so far. These results suggest that PGD2 shows an anti-neoplastic effect on a variety of human malignant tumor cells.

Topics: Antineoplastic Agents; Cell Division; Cell Line; Dinoprost; Dinoprostone; Humans; Neoplasm Proteins; Neoplasms; Nucleic Acids; Osteosarcoma; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F