Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines

Cheng, Jidong; Imanishi, Hiroyasu; Liu, Weidong; Nakamura, Hitomi; Morisaki, Takayuki; Higashino, Kazuya; Hada, Toshikazu

doi:10.1111/j.1349-7006.2004.tb03327.x

Cited by 31 publications

(41 citation statements)

References 34 publications

(43 reference statements)

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“…We found that treatment with NS398 alone decreased cyclin E expression in a concentration-dependent manner. This effect of NS398 may not be common to all COX-2 inhibitors, as Cheng et al reported that treatment with the selective COX-2 inhibitor etodolac did not alter cyclin E expression (62). We also observed that the effects of the combination on cyclin E levels were similar to the effects of the single agents.…”

Section: Mol Cancer Res 2006;4(6) June 2006supporting

confidence: 60%

Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

Ralstin¹,

Gage²,

Yip-Schneider

et al. 2006

Molecular Cancer Research

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Chemotherapy to date has not been effective in the treatment of human hepatocellular carcinoma. More effective treatment strategies may involve combinations of agents with activity against hepatocellular carcinoma. Parthenolide, a nuclear factor-KB (NF-KB) inhibitor, and NS398, a cyclooxygenase (COX)-2 inhibitor, have been shown to individually suppress the growth of hepatocellular carcinoma cells in vitro. To investigate their effects in combination, three human hepatocellular carcinoma lines (Hep3B, HepG2, and PLC) were treated with parthenolide and/or NS398. Parthenolide (0.1-10 Mmol/L) and NS398 (1-100 Mmol/L) each caused concentration-dependent growth inhibition in all cell lines. The addition of parthenolide to NS398 reduced the concentration of NS398 required to inhibit hepatocellular carcinoma growth. Because parthenolide and COX-2 inhibitors have been reported to influence NF-KB activity, the effects on this pathway were investigated. The combination of parthenolide/NS398 inhibited phosphorylation of the NF-KB-inhibitory protein IKBA and increased total IKBA levels. NF-KB DNA-binding and transcriptional activities were inhibited more by the combination than the single agents in Hep3B and HepG2 cells but not in PLC cells. The response of PLC cells to NS398 was augmented by p65 small interfering RNA to inhibit NF-KB p65 protein expression. The combination of parthenolide/NS398 increased apoptosis only in PLC cells, suggesting that the combination may decrease the apoptotic threshold in these cells. In Hep3B and HepG2 cells, combination treatment with NS398/parthenolide altered the cell cycle distribution resulting in more G 0 -G 1 accumulation. Cyclin D1 levels were further decreased by combination treatment in all cell lines, correlating with the cell cycle alterations. Our results suggest that parthenolide may be effective in combination with COX-2 inhibitors for the treatment of hepatocellular carcinoma. (Mol Cancer Res 2006;4(6):387 -400)

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Section: Mol Cancer Res 2006;4(6) June 2006supporting

confidence: 60%

Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

Ralstin¹,

Gage²,

Yip-Schneider

et al. 2006

Molecular Cancer Research

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“…Although the mechanism by which inhibition of cyclins A and B and, therefore, G 2 arrest by OSU-03012 remains uncertain, this may be related to a possible effect on the MAPK signaling pathway evidenced by the down-regulation of p-MEK1/2 and MEK1/2. In this respect, the selective COX-2 inhibitor, etodolac, was recently reported to induce G 2 arrest in human hepatocellular carcinoma cell lines through the inhibition of expression of cyclins A and B due to an effect on the MAPK signaling pathway, without inhibition of the PDK-1/Akt pathway (45). Of note, however, although cyclin D1 was significantly down-regulated, no significant G 1 -S phase arrest was observed.…”

Section: Discussionmentioning

confidence: 76%

OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms

Zhang¹,

Suvannasankha²,

Crean³

et al. 2007

Clinical Cancer Research

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Purpose: OSU-03012 is a novel celecoxib derivative, without cyclooxygenase-2 inhibitory activity, capable of inducing apoptosis in various cancer cells types, and is being developed as an anticancer drug. We investigated the in vitro activity of OSU-03012 in multiple myeloma (MM) cells. Experimental Design: U266, ARH-77, IM-9, and RPMI-8226, and primary myeloma cells were exposed to OSU-03012 for 6, 24, or 72 h. Cytotoxicity, caspase activation, apoptosis, and effects on intracellular signaling pathways were assessed. Results: OSU-03012 was cytotoxic to MM cells with mean LC 50 3.69 F 0.23 and 6.25 F 0.86 Amol/L and at 24 h for primary MM cells and cell lines, respectively. As a known PDK-1 inhibitor, OSU-03012 inhibited the PI3K/Akt pathway with downstream effects on BAD, GSK-3h, FoxO1a, p70S6K, and MDM-2. However, transfection of MM cells with constitutively active Akt failed to protect against cell death, indicating activity against other pathways is important.Phospho (p)-signal transducers and activators of transcription 3 and p-MAP/ERK kinase 1/2 were downregulated, suggesting that OSU-03012 also inhibited the Janus-activated kinase 2/signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways. Although expression of Bcl-2 proteins was unchanged, OSU-03012 also down-regulated survivin and X-linked inhibitor of apoptosis (XIAP), and also induced G 2 cell cycle arrest with associated reductions in cyclins A and B. Finally, although OSU-03012 induced cleavage of caspases 3, 8 and 9, caspase inhibition did not prevent cell death. Conclusions: We conclude that OSU-03012 has potent activity against MM cells and acts via different mechanisms in addition to phosphoinositide-3-kinase/Akt pathway inhibition. These studies provide rationale for the clinical investigation of OSU-03012 in MM.

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“…However, the key mechanism by which COX-2 inhibitors affect HCC cell growth remains unclear. Some studies have shown that NSAIDs are able to inhibit HCC cell growth by cell cycle arrest [72,73,75] , induction of apoptosis [44,73,74] or necrosis [72] . Recent evidence indicates that phar macological inhibition of COX-1 activity by selective COX-1 inhibitors also blocks cell growth, promotes apoptosis and inhibits the cell cycle in ovarian [57] , breast [76] , bladder and prostate [77] cancer cells.…”

Section: Cox Inhibitors In Hepatocellular Carcinomamentioning

confidence: 99%

Cyclooxygenases in hepatocellular carcinoma

Cervello¹,

Montalto²

2006

WJG

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M a n y e p i d e m i o l o g i c a l s t u d i e s d e m o n s t r a t e t h a t treatment with non-steroidal anti-inflammatory drugs(NSAIDs) reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase (COX) enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, m a l i g n a n t , a n d m e t a s t a s t i c c a n c e r s , i n c l u d i n g hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated H C C s o r h i s t o l o g i c a l l y n o r m a l l i v e r , s u g g e s t i n g that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC.In tumors, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells.The availability of novel agents that selectively inhibit COX-2 (COXIB), has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood.Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiproliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2-dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear.Here we review the features of COX enzymes, t h e r o l e o f t h e e x p r e s s i o n o f C O X i s o f o r m s i n hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.

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Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines

Cited by 31 publications

References 34 publications

Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

Parthenolide Cooperates with NS398 to Inhibit Growth of Human Hepatocellular Carcinoma Cells through Effects on Apoptosis and G0-G1 Cell Cycle Arrest

OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms

Cyclooxygenases in hepatocellular carcinoma

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