G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation

Juan, Gloria; Ardelt, Barbara; Li, X; Mikulski, SM; Shogen, Kuslima; Ardelt, Wojciech; Mittelman, Abraham; Darzynkiewicz, Z

doi:10.1038/sj.leu.2401100

Cited by 69 publications

(68 citation statements)

References 39 publications

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“…H-ras oncogenes also impairs growth of human monocytic U937 cells (Maher et al, 1996). However U937, unlike K562, express p16 INK4a (Juan et al, 1998) which may explain the antiproliferative e ect of Ras in U937 through the p16 INK4a /Rb pathway.…”

Section: Discussionmentioning

confidence: 99%

H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism

et al. 2000

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Mutated ras genes are frequently found in human cancer. However, it has been shown that oncogenic ras inhibits growth of primary cells, through pathways involving p53 and the cell cycle inhibitors p16 INK4a and p19 ARF . We have analysed the e ect of the ectopic expression of the three mammalian ras genes on the proliferation of K562 leukemia cells, which are de®cient for p53, p16 INK4a , p15 INK4b and p19 ARF genes. We have found that high expression levels of both wild-type and oncogenic H-, Kand N-ras inhibit the clonogenic growth of K562 cells. Induction of H-rasV12 expression in K562 transfectants retards growth and this e ect is accompanied with an increase of p21 WAF1 mRNA and protein levels. Furthermore, p21 WAF1 promoter is activated potently by oncogenic ras and less pronounced by wild-type ras. This induction is p53-independent since a p21 WAF1 promoter devoid of the p53 responsive elements is still activated by Ras. Finally, inhibition of p21 WAF1 expression by an antisense construct partially overcomes the growth inhibitory action of oncogenic H-ras. Altogether, these results indicate that the antiproliferative e ect of ras in myeloid leukemia cells is associated to the induction of p21 WAF1 expression and suggest the existence of p19 ARF and p16 INK4a -independent pathways for rasmediated growth inhibition. Oncogene (2000) 19, 783 ± 790.

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Section: Discussionmentioning

confidence: 99%

H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism

et al. 2000

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“…A relatively low, cytostatic rather than cytotoxic, concentration of Onc also was used. Specifically, based on our earlier observations 1,22,23,28 and on the data of pilot experiments in the present study 5 μg/ml Onc concentration was chosen to treat the leukemic HL-60, U937 and RPMI-8228 cell lines, which were somewhat more sensitive to Onc, and 10 μg/ml to treat the more resistant prostate cancer lines. At those Onc concentrations the rate of cell growth was distinctly reduced while the frequency of apoptosis was relatively low.…”

Section: Discussionmentioning

confidence: 99%

“…The cytostatic effect of Onc, observed after 24-48 h of the treatment, presents as an arrest in the G 1 phase of the cell cycle. 1,22 The Onc-induced arrest of lymphoma U-937 cells in G 1 was shown to be mediated by downregulation of cyclin D3, upregulation of p27 KIP1 , p16 INK4A and p21 WAF1/CIP1 and hypophosphorylation of pRb. 22 Prolonged exposure of tumor cells to Onc leads to apoptosis, associated with classical changes in morphology, 26 extensive DNA fragmentation, and activation of caspases, serine proteases and transglutaminase.…”

Section: Introductionmentioning

confidence: 99%

“…22 Prolonged exposure of tumor cells to Onc leads to apoptosis, associated with classical changes in morphology, 26 extensive DNA fragmentation, and activation of caspases, serine proteases and transglutaminase. 1,[22][23][24][25] Intriguingly, a strong enhancement in cytotoxicity has been observed when Onc was combined with other antitumor modalities, such as tamoxifen, 10 lovastatin, 10,27 cisplatin, 10 vincristine, 11 tumor necrosis factor a (TNFa), 28 interferons, 29 ionizing radiation, 30 differentiation-inducing agents, 31 or mild hyperthermia. 32 We postulated that Onc enhances cytotoxicity of many antitumor drugs by suppressing translation of the "survival genes" activated by NFκB during drug treatment.…”

Section: Introductionmentioning

confidence: 99%

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Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines

Ita¹,

Halicka²,

Tanaka³

et al. 2008

Cancer Biology & Therapy

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Onconase (Onc), a ribonuclease from oocytes or early embryos of Northern Leopard frog (Rana pipiens), is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and is currently in Phase IIIb clinical trials for malignant mesothelioma where it displays antitumor activity with minor overall toxicity to the patient. One of the characteristic features of Onc is a synergism with a variety of other antitumor modalities. Cepharanthine (Cep), a biscoclaurine alkaloid from Stephania cepharantha Hayata, is widely used in Japan to treat variety of ailments. It also shows low toxicity to patients. The aim of the present study was to assess the interaction of these two drugs on different tumor cell lines. When human promyelocytic leukemia HL-60, histiomonocytic lymphoma U937, multiple myeloma RPMI-8228, prostate carcinoma DU 145 and prostate adenocarcinoma LNCaP cells were exposed to relatively low concentrations of Onc or Cep their growth rates were somewhat suppressed but the cells were still able to proliferate. Cell growth, however, was totally abolished in each of these cell lines when treated with Onc and Cep combined. The frequency of apoptosis was also many-fold higher in cultures treated with a combination of Onc and Cep than in respective cultures treated with Onc or Cep alone. The mechanism of the observed synergism is unclear but it may be associated with the Onc activity in targeting microRNAs and/or NFkappaB and Cep activity also targeting NFkappaB. The data suggest that the combination of these two drugs, that individually express a low toxic profile, may have strong antitumor potential.

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“…61 Treatment of the human histiocytic lymphoma cell line, U937, with onconase (a 12 kDa protein homologous to pancreatic RNase A, isolated from amphibian oocytes) resulted in induction of p16 Ink4a accompanied by G 1 arrest. 62 Onconase shows cytostatic and cytotoxic activity in vitro, inhibits growth of tumors in mice and is currently in phase III clinical trials. [63][64][65] Cell cycle arrest was also observed when p15 Ink4b was induced in mink lung epithelial cells following treatment with TGF␤.…”

Section: G 0 /G 1 To S Phase Transitionmentioning

confidence: 99%

Molecular control of cell cycle progression in primary human hematopoietic stem cells: methods to increase levels of retroviral-mediated transduction

Dao

Nolta

1999

Leukemia

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G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation

Cited by 69 publications

References 39 publications

H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism

H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism

Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines

Molecular control of cell cycle progression in primary human hematopoietic stem cells: methods to increase levels of retroviral-mediated transduction

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