Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and <scp>l</scp>‐phenylalanine mustard are sensitive to Delta7‐prostaglandin A1 and Delta 12‐prostaglandin J2

Sasaki, Hiroyuki; Takada, Kazuaki; Terashima, Yuya; Ekimoto, Hisao; Takahashi, Kou; Tsuruo, Takashi; Fukushima, Masashi

doi:10.1016/0020-7292(92)90071-p

Cited by 5 publications

(11 citation statements)

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“…Our mechanistic and pharmacophore hypotheses are compatible with the structure-activity relationships reported by Kato et al (1986), Sasaki et al (1991) and Sasaki and Fukushima (1994). Kato et al (1986) reported that ⌬12-PGJ 2 and several related ⌬7-PGA 1 derivatives (all of which are crossconjugated dienones) increased the life span of Ehrlich ascites tumor-bearing mice: i.p.…”

Section: Discussionsupporting

confidence: 90%

“…doses of 20 to 30 mg/kg/day for 5 consecutive days prolonged survival 66 to 111%. In addition, both ⌬12-PGJ 2 and ⌬7-PGA 1 exhibit little cross-resistance with cisplatin and doxorubicin in vivo (Sasaki et al, 1991;Sasaki and Fukushima, 1994). Despite these promising results, ⌬7-PGA 1 is rapidly metabolized to an inactive compound (t 1/2 Ͻ 5 min) in serum (Suzuki et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Mullally

Fitzpatrick

2002

Mol Pharmacol

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The tumor suppressor p53 is mutated in more than 50% of all cancers. Importantly, most clinically useful antineoplastic agents are less potent and efficacious in the context of mutant p53. This situation has prompted a search for agents that cause tumor cell death via molecular mechanisms independent of p53. Our recent investigations with electrophilic prostaglandins enabled us to devise a pharmacophore and mechanism of action hypothesis relevant to this problem: a cross-conjugated ␣,␤-unsaturated dienone with two sterically accessible electrophilic ␤-carbons is a molecular determinant that confers activity among this class of ubiquitin isopeptidases inhibitors, and that inhibitors of ubiquitin isopeptidases cause cell death in vitro independently of p53. Here, we report the use of the National Cancer Institute's Developmental Therapeutics Database to identify compounds to test this hypothesis. Shikoccin (a diterpene), dibenzylideneacetone, and curcumin fit the pharmacophore hypothesis, inhibit cellular isopeptidases, and cause cell death independently of p53 in isogenic pairs of RKO and HCT 116 cells with differential p53 status. The sesquiterpene achillin and 2,6-diphenyl-4H-thiopyran-4-one, which have cross-conjugated dienones with sterically hindered electrophilic ␤-carbons, do not inhibit isopeptidases or cause significant cell death. Furthermore, we show that a catalytic-site proteasome inhibitor causes cell death independently of p53. Combined, these data verify the p53-independence of cell death caused by inhibitors of the proteasome pathway and support the proposition that the ubiquitin-dependent proteasome pathway may contain molecular targets suitable for antineoplastic drug discovery.Ubiquitin isopeptidases (ubiquitin specific proteases) are a family of cysteine proteases that salvage ubiquitin for its reuse by the 26S proteasome system (Hochstrasser, 1996;Hershko and Ciechanover, 1998) and regulate the activity of a variety of substrates by altering their ubiquitination status. The ubiquitin salvage activity of the isopeptidases maintains a cellular pool of monomeric ubiquitin by cleaving the isopeptide bond between the C-terminal carboxyl of ubiquitin and the ⑀-amino group of a lysine residue on an adjacent protein, thereby disassembling ubiquitin oligomers, ubiquitin-protein conjugates, and ubiquitin-peptide conjugates. Few inhibitors of isopeptidases have been identified, other than analogs based on ubiquitin itself. These include nonhydrolyzable ubiquitin dimer analogs (ϳ16 kDa) (Yin et al., 2001) and ubiquitin aldehyde (ϳ8.5 kDa) (Dang et al., 1998), which are suitable for investigating isolated enzymes. Recently, we reported that ⌬12-prostaglandin J 2 (⌬12-PGJ 2 ) is a novel isopeptidase inhibitor with activity in intact cells. Results with cyclopentenone prostaglandins (PG) prompted our hypothesis that isopeptidase inhibition depends on nuances of olefin-ketone conjugation. For example, ⌬12-PGJ 2 , with its cross-conjugated ␣,␤-unsaturated dienone substituent and two sterically access...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Mullally

Fitzpatrick

2002

Mol Pharmacol

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“…Unlike camptothecin, D 12,14 -PGJ2 could not induce the nicked DNA. The results for the 22 4 À100 1 27…”

Section: Stabilization Of Topo I-and Ii-cleavable Complexes By Dmentioning

confidence: 99%

“…They are the most potent antitumor agents among PG compounds and inhibit the growth of some human tumor cells which are resistant to the antitumor agents in clinical use such as doxorubicin and cisplatin. 21,22) These antitumor PGs are actively incorporated into tumor cells and transferred to the nuclei, acting speciˆcally on the cells in the G1 phase and blocking cell cycle progression. 23) Although there are many reports on the actions of antitumor PGs in cells, [24][25][26] the antitumor mechanism and topo inhibition of PGs are not known.…”

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confidence: 99%

Inhibitory Properties of Antitumor Prostaglandins against Topoisomerases

Suzuki

Uyeda

2002

Bioscience, Biotechnology, and Biochemistry

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“…The cyclopentenone prostaglandin A 2 (PGA 2 ) is a potent inhibitor of growth of cultured cells and exhibits antitumor activity in vivo (16,20,28,29,42,51,52). Growth arrest following PGA 2 treatment occurs primarily in the G 1 phase of the cell cycle, but the mechanisms responsible for eliciting this effect are not well understood.…”

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confidence: 99%

Down-Regulation of Cyclin D1 Expression by Prostaglandin A₂ Is Mediated by Enhanced Cyclin D1 mRNA Turnover

Lin

Wang

Wilson

et al. 2000

Molecular and Cellular Biology

126

113

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Prostaglandin A 2 (PGA 2 ), an experimental chemotherapeutic agent, causes growth arrest associated with decreased cyclin D1 expression in several cancer cell lines. Here, using human non-small-cell lung carcinoma H1299 cells, we investigated the mechanisms whereby PGA 2 down-regulates cyclin D1 expression. Transcription rates of the cyclin D1 gene, studied using a cyclin D1 promoter-luciferase construct and nuclear run-on assays, were not affected by PGA 2 treatment. Instead, the cyclin D1 mRNA was rendered unstable after exposure to PGA 2 . Since the stability of labile mRNA is modulated through binding of proteins to specific mRNA sequences, we sought to identify protein(s) recognizing the cyclin D1 mRNA. In electrophoretic mobility-shift assays using radiolabeled RNA probes derived from different regions of cyclin D1 mRNA, we observed that (i) lysates prepared from PGA 2 -treated cells exhibited enhanced protein-cyclin D1 RNA complex formation; (ii) the kinetics of complex formation correlated closely with that of cyclin D1 mRNA loss; and (iii) binding occurred within a 390-base cyclin D1 3 untranslated region (UTR) (K12). This binding activity could be cross-linked, revealing proteins ranging from 30 to 47 kDa. The RNA-binding protein AUF1, previously associated with the degradation of target mRNAs, bound cyclin D1 mRNA, because anti-AUF1 antibodies were capable of supershifting or immunoprecipitating cyclin D1 mRNA-protein complexes. Finally, insertion of K12 in the 3UTR of reporter genes markedly reduced the expression and half-life of the resulting chimeric mRNAs in transfected, PGA 2 -treated cells. Our data demonstrate that PGA 2 down-regulates cyclin D1 expression by decreasing cyclin D1 mRNA stability and implicates a 390-base element in the 3UTR in this regulation.Progression of eucaryotic cells through the division cycle is a highly ordered process involving the sequential activation of cyclin-dependent kinases (cdks) (22,37). This process is regulated in large part through their interaction with specific cyclins, which function during different phases of the cell cycle. D-type cyclins and cyclin D1 in particular play a critical role in regulating G 1 progression (4, 43, 54) as cyclin D1-cdk4 complexes phosphorylate and thereby inactivate the retinoblastoma protein, a critical event required for G 1 -S transition (60). Cyclin D1 is present in low abundance in quiescent cells, but it rapidly accumulates after stimulation with serum or mitogens. Inhibition of cyclin D1 expression prevents transition of cells from G 1 into S phase, while ectopic expression of cyclin D1 shortens the G 1 interval in many cell types (40,43,45,46). Although cyclin D1 levels remain relatively constant in normally growing cells, withdrawal of serum results in the rapid disappearance of the protein as cells enter a state of quiescence (56). In addition to serum withdrawal, treatment of cells with other agents known to induce growth arrest (e.g., retinoic acid) likewise results in reduced cyclin D1 expression (31). Support fo...

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Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and l‐phenylalanine mustard are sensitive to Delta⁷‐prostaglandin A₁ and Delta ¹²‐prostaglandin J₂

Cited by 5 publications

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Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Inhibitory Properties of Antitumor Prostaglandins against Topoisomerases

Down-Regulation of Cyclin D1 Expression by Prostaglandin A₂ Is Mediated by Enhanced Cyclin D1 mRNA Turnover

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Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and l‐phenylalanine mustard are sensitive to Delta7‐prostaglandin A1 and Delta 12‐prostaglandin J2

Cited by 5 publications

References 0 publications

Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death

Inhibitory Properties of Antitumor Prostaglandins against Topoisomerases

Down-Regulation of Cyclin D1 Expression by Prostaglandin A2 Is Mediated by Enhanced Cyclin D1 mRNA Turnover

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Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and l‐phenylalanine mustard are sensitive to Delta⁷‐prostaglandin A₁ and Delta ¹²‐prostaglandin J₂

Down-Regulation of Cyclin D1 Expression by Prostaglandin A₂ Is Mediated by Enhanced Cyclin D1 mRNA Turnover