Role of a small molecular weight phosphoprotein in the mechanism of action of CI‐994 (N‐acetyldinaline)

Rummel, Sue A.; Kraker, Alan J.; Steinkampf, Randall W.; Hook, Kenneth E.; Klohs, Wayne D.

doi:10.1002/ijc.2910620524

Cited by 11 publications

(5 citation statements)

References 8 publications

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“…Although the specific mechanism of action of this compound is unclear, it was recently demonstrated that it inhibits HDAC [45]. In addition, it has been shown that CI‐994 has a predominantly cytostatic effect because of its ability to arrest the cell cycle in G1 [46]. Antiproliferative effects are observed at rather high concentrations with an IC 50 of ∼4 μM [47,48].…”

Section: Discussionmentioning

confidence: 99%

“…Antiproliferative effects are observed at rather high concentrations with an IC 50 of ∼4 μM [47,48]. The lack of the mitochondrial‐dependent apoptotic cell death effect [46], together with the low efficacy on growth inhibition, may explain in part the disappointing clinical results with CI‐994 (see 44). However, TSA has a mechanism of action different from CI‐994 in that it arrests cellular growth in G2 and induces apoptosis, effects that are seen at much lower concentrations than those observed with CI‐994.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

Donadelli

Costamagna

Faggioli

et al. 2003

Molecular Carcinogenesis

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In cells with an altered p53 gene, the expression of p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53-independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as trichostatin A (TSA) have potential utility in pancreatic cancer, as most of these tumors possess mutations in p53, which in fact is the main cause of chemoresistance to 5-fluorouracil. We have analyzed the effect of TSA on the proliferation of nine pancreatic adenocarcinoma cell lines, all containing a mutated p53 gene. TSA strongly inhibited the cellular growth of all these cell lines at submicromolar concentrations. The cellular mechanisms underlying this effect consisted of cell cycle arrest at the G2 phase and apoptotic cell death. The expression of p21(WAF1/CIP1) normally induced at the transcriptional level by p53 was also strongly activated by TSA. These findings suggest that inhibitors of HDAC may represent a novel therapeutic strategy for treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

Donadelli

Costamagna

Faggioli

et al. 2003

Molecular Carcinogenesis

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“…The mechanism of apoptosis was not investigated in this study but previous reports suggest that it may be initiated by either inhibition of a 16 kDa nuclear phosphoprotein or an increase in histone acetylation [8, 9]. In both studies, these targets were modulated within 2 hours of exposure and thus represent the earliest effects detected following CI-994 treatment in vitro .…”

Section: Discussionmentioning

confidence: 84%

“…CI-994 is not an antimetabolite, does not covalently bind to or intercalate DNA, and does not affect microtubule synthesis [7]. Studies have shown that CI-994 can inhibit a 16 kDa nuclear phosphoprotein and increase histone acetylation [8, 9]. Currently, CI-994 is in phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Graziano

Spoon

Cockrell

et al. 2001

BioMed Research International

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CI-994 (acetyldinaline) is an investigational anticancer drug currently in clinical trials. In preclinical safety studies in rats and dogs, CI-994 resulted in significant toxicity to bone marrow and lymphoid tissue. To determine if apoptosis was involved in CI-994 toxicity, peripheral blood lymphocytes were isolated from untreated male Wistar rats and exposed to CI-994 (1, 3, 10, or 30 μM) in vitro for up to 24 hours. Morphological and biochemical features of apoptosis were evaluated using several techniques, and lactate dehydrogenase (LDH) release was measured as an indicator of cell necrosis. No evidence of apoptosis or necrosis was detected in lymphocytes exposed to CI-994 for 4 hours. After 24 hours, concentration-dependent increases in apoptosis characterized by DNA condensation, DNA fragmentation, and/or externalization of phosphatidyl serine were seen at CI-994 concentrations as low as 1 μM and were statistically significant beginning at 10 μM. Ultrastructural analysis confirmed the presence of DNA condensation, DNA fragmentation, cell shrinkage, and membrane blebbing in cells exposed to 30 μM CI-994. After 24 hours, the percent of maximum LDH release from lymphocytes treated with 10 and 30 μM CI-994 was 7% and 15%, respectively, compared with 0% in the controls. In comparison, morphological changes of apoptosis detected by fluorescent microscopy were observed in 79% of the lymphocytes at these two concentrations. Additionally, apoptosis was seen in more than 24% of lymphocytes exposed to 1 and 3 μM CI-994, whereas maximum LDH release was less than or equal to 1% at these concentrations. These results show that apoptosis is the primary mode of cell death in rat lymphocytes exposed to CI-994 in vitro.

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“…CI-994 also had the advantage of non-linear pharmacokinetics. Finally, both dinaline and CI-994 appear to share a novel mechanism of action, possibly involving the modulation of the expression of specific histones [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Preclinical antitumor activity of CI-994

et al. 1996

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CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma #03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (> 50 days) was tolerated with no gross toxicity. Doses > or = 90 mg/kg/injection caused lethality after 4-5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.

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Role of a small molecular weight phosphoprotein in the mechanism of action of CI‐994 (N‐acetyldinaline)

Cited by 11 publications

References 8 publications

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI‐994 (Acetyldinaline)

Preclinical antitumor activity of CI-994

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