Evidence for cAMP-independent inhibition of S-phase DNA synthesis by prostaglandins.

Wiley, Millie Hughes; Feingold, Kenneth R.; Grünfeld, Carl; Quesney-Huneeus, V; Wu, Jianmin

doi:10.1016/s0021-9258(18)33282-4

Cited by 48 publications

(2 citation statements)

References 22 publications

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“…Recently, intense attention has been focused on the antineoplastic and antiviral properties of prostaglandins (PGs) and related compounds. , Certain cyclopentenone prostaglandins are known to be involved in the regulation of the cell cycles 3 and cellular defenses against viral infection . PGs express their activities slowly after dosing, resulting in cell cycle arrest at the G1 phase, and effect inhibition of viral replication at noncytotoxic doses, providing possible new therapeutic strategies. , Some PGs of the A and J series indeed show potent antitumor effects not only in vitro but also in vivo is now under preclinical study for the treatment of chemotherapeutically resistant ovarian cancer by intraperitoneal administration .…”

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confidence: 99%

“…Particularly, Δ 7 -PGA 1 methyl ester ( 1 ), an unnatural dienone PG easily prepared by the three-component synthesis, is now under preclinical study for the treatment of chemotherapeutically resistant ovarian cancer by intraperitoneal administration . Since the activities do not affect intracellular cAMP levels, these PGs differ from the PGs known as local hormones. , This paper discloses the correlation of the fascinating cellular behavior and chemical properties of antitumor PGs …”

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Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

et al. 1997

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Prostaglandins (PGs) such as Δ12-PGJ2 and Δ7-PGA1 methyl ester that possess a cross-conjugated dienone unit exhibit unique antitumor and antiviral activities independent of intracellular cAMP levels. These compounds are transported reversibly into cultured cells and accumulate in nuclei via covalent interaction, eliciting growth inhibition. PGA1 methyl ester, a simple cyclopentenone analog, is less potent. The unique cellular behavior of the dienone PGs correlates well with their chemical properties. The PGs react specifically with thiol nucleophiles such as glutathione. Michael addition of thiols to Δ7-PGA1 methyl ester, an alkylidenecyclopentenone derivative, occurs facilely at the endocyclic C(11) position rather than at the C(7) position. This process is reversible, and in solution phase, the adducts are in equilibrium with considerable amounts of free PG and thiols. However, the reaction of this PG with Sepharose-bound thiols, regarded to be plausible mimics of protein thiols, is irreversible, and the resulting adducts are dissociated only by alkali treatment. On the other hand, PGA1 methyl ester reacts with soluble or polymer-anchored thiols at lower rates than Δ7-PGAl methyl ester, but the resulting thiol adducts are substantially more stable than those of the dienone PGs. This tendency of the PGA1 methyl ester causes its equilibrium to shift to the adduct formation. The reversibility of the Michael reaction of PGs with thiols is consistent with their intracellular behavior and biological activities. Since glutathione adducts of PGs have no antiproliferative activities for cancer cells, the intracellular free PGs are presumed to interact with target molecules to cause cell growth inhibition. The involvement of the ATP-dependent glutathione S-conjugate export pump (GS-X pump) in the efflux of PGs is discussed. Thus, the marked difference in potency of the dienone and enone PGs is explained by considering the combined kinetic and thermodynamic properties and the action of the GS-X pump.

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Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

et al. 1997

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Prostaglandins and Other Metabolites of Arachidonic Acid: An Overview for the Otolaryngologist

Poole¹,

Pillsbury²

1985

Archives of Otolaryngology - Head and Neck Surgery

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\s=b\Metabolites of arachidonic acid have important regulatory functions within several areas of concern to the otolaryngologist. Prostaglandins, composing one group, are involved in smooth-muscle contraction, regulation of renal glomerular blood flow, and in the modulation of immune and allergic responses, inflammation, fever, pain, and tumor growth. A second group, the leukotrienes, may be even more important than prostaglandins in allergy and inflammation. The elusive slow-reacting substance of anaphylaxis belongs in this group. Two other metabolites, thromboxane and prostacyclin, seem to be critical in hemostasis and the metastatic spread of tumors. (Arch Otolaryngol 1985;111:317-321) During the past ten years, research concerning prostaglandins and related substances has proceeded at a faster rate than any other branch of medical investigation. New com¬ pounds have been discovered, charac¬ terized, and pharmacologically ma¬ nipulated. The acquired information has rapidly moved from basic research into clinical usefulness.Since this new and complex area has profound relevance for virtually every area of medicine and surgery, we have conducted a brief review, focusing on the aspects that have particular appli¬ cation in our specialty. METABOLISM AND PHYSIOLOGYThe family of prostaglandinlike compounds might be more correctly referred to as metabolites of arachi¬ donic acid, with true prostaglandins making up only one subset. The prostaglandins are manufactured in all cells, with the exception of those cells lacking microsomes (eg, mature red blood cells). Different cell types, how¬ ever, show marked variation in the amounts and ratios of the different arachidonic acid products. In general, they function as locally active hor¬ mones, with rapid hepatic and pulmo¬ nary catabolism resulting in very short systemic half-lives.1The major metabolic pathways from arachidonic acid are depicted in the Figure. For simplicity, some of the intermediates and less well-known products have been omitted. Arachi¬ donic acid is formed through the action of phospholipases on mem¬ brane phospholipids, which are derived from polyunsaturated longchain fatty acids. In particular, linoleic acid is an essential fatty acid alleg¬ edly because of its role as an arachi¬ donic acid precursor.2 Once in the microsomes, arachidonic acid metabo¬ lism proceeds either along the cyclo-oxygenase pathway or along the lipoxygenase pathway.In the first pathway, cyclo-oxyge¬ nase catalyzes two consecutive steps that lead to the formation of true prostaglandins (PGs). The classes of the prostaglandins are designated by letter suffixes, ie, PGE, PGD, PGF. The degree of unsaturation in a given PG is then depicted by a numerical subscript, as in PGE^PGE2, and PGF2. The important cyclo-oxygenase activity first converts arachidonic acid and molecular oxygen to the cyclic endoperoxide PGG2 and subse¬ quently to PGH2 by hydroperoxidation.3 Then PGH2 can be metabolized to any of the more stable prostaglan¬ dins (PGE2, PGD2, or PGF2), thromboxane, or to prost...

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Cell cycle arrest by prostaglandin A₁ at the G₁/S phase interface with up‐regulation of oncogenes in S‐49 cyc⁻ cells

Hughes‐Fulford

1994

J of Cellular Biochemistry

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Our previous studies have implied that prostaglandins inhibit cell growth independent of cAMP. Recent reports, however, have suggested that prostaglandin arrest of the cell cycle may be mediated through protein kinase A. In this report, in order to eliminate the role of c-AMP in prostaglandin mediated cell cycle arrest, we use the -49 lymphoma variant (cyc-) cells that lack adenylate cyclase activity. We demonstrate that dimethyl prostaglandin A1 (dmPGA1) inhibits DNA synthesis and cell growth in cyc- cells. DNA synthesis is inhibited 42% by dmPGA1 (50 microM) despite the fact that this cell line lacks cellular components needed for cAMP generation. The ability to decrease DNA synthesis depends upon the specific prostaglandin structure with the most effective form possessing the alpha, beta unsaturated ketone ring. Dimethyl PGA1 is most effective in inhibiting DNA synthesis in cyc- cells, with prostaglandins PGE1 and PGB1 being less potent inhibitors of DNA synthesis. DmPGE2 caused a significant stimulation of DNA synthesis. S-49 cyc- variant cells exposed to (30-50 microns) dmPGA1, arrested in the G1 phase of the cell cycle within 24 h. This growth arrest was reversed when the prostaglandin was removed from the cultured cells; growth resumed within hours showing that this treatment is not toxic. The S-49 cyc- cells were chosen not only for their lack of adenylate cyclase activity, but also because their cell cycle has been extensively studied and time requirements for G1, S, G2, and M phases are known. Within hours after prostaglandin removal the cells resume active DNA synthesis, and cell number doubles within 15 h suggesting rapid entry into S-phase DNA synthesis from the G1 cell cycle block.(ABSTRACT TRUNCATED AT 250 WORDS)

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Evidence for cAMP-independent inhibition of S-phase DNA synthesis by prostaglandins.

Cited by 48 publications

References 22 publications

Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

Prostaglandins and Other Metabolites of Arachidonic Acid: An Overview for the Otolaryngologist

Cell cycle arrest by prostaglandin A₁ at the G₁/S phase interface with up‐regulation of oncogenes in S‐49 cyc⁻ cells

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Evidence for cAMP-independent inhibition of S-phase DNA synthesis by prostaglandins.

Cited by 48 publications

References 22 publications

Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ7-Prostaglandin A1 and Prostaglandin A1 Methyl Esters with Thiols

Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ7-Prostaglandin A1 and Prostaglandin A1 Methyl Esters with Thiols

Prostaglandins and Other Metabolites of Arachidonic Acid: An Overview for the Otolaryngologist

Cell cycle arrest by prostaglandin A1 at the G1/S phase interface with up‐regulation of oncogenes in S‐49 cyc− cells

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Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

Chemical Implications for Antitumor and Antiviral Prostaglandins: Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

Cell cycle arrest by prostaglandin A₁ at the G₁/S phase interface with up‐regulation of oncogenes in S‐49 cyc⁻ cells