Inhibition of Extracellular-signal Regulated Kinases 1/2 Is Required for Apoptosis of Human Colon Cancer Cells <b>
                     <i>In vitro</i>
                  </b> by Sulindac Metabolites

Rice, Pamela L.; Beard, Keith; Driggers, Linda J.; Ahnen, Dennis J.

doi:10.1158/0008-5472.can-04-1517

Cited by 40 publications

(40 citation statements)

References 18 publications

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“…35,36) In this study, we showed that etodolac inhibits HGF-and 10% FBS-in- duced ERK activity and proliferation of HCC cells. This finding showed that a COX-2 inhibitor might inhibit HCC cell proliferation by interfering with growth signals mediated by growth factors.…”

Section: )mentioning

confidence: 54%

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

et al. 2004

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yclooxygenase 2 (COX-2) is a highly inducible, rate-limiting enzyme involved in the production of prostaglandins (PGs), prostacyclins and thromboxanes. COX-2 is expressed in response to a variety of proinflammatory agents and cytokines.1, 2) Overexpression of COX-2 has been demonstrated in various tumors such as colon cancer, pancreatic cancer and hepatocellular carcinoma (HCC).3-5) Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently being assessed for use in the prevention and treatment of colorectal cancer, based on epidemiologic, preclinical and experimental evidence. 6, 7) Although several studies have shown the up-regulation of COX-2 in cirrhotic tissues adjacent to HCC and well-differentiated HCC, the precise role of COX-2 in hepato-carcinogenesis remains unclear. 5,8) A recent report of ours has also shown that NS-398, a selective COX-2 inhibitor, inhibited growth and induced cell cycle arrest in HCC cell lines. 9) However, the mechanism by which COX-2 inhibitors cause growth inhibition and cell cycle arrest in HCC cells is not known.There is increasing evidence that perturbation of cell cycle regulation is an important contributing factor to cancer, including HCC. 10,11) There are two key checkpoints in the cell cycle, the G1-S and G2-M checkpoints. Cyclins, cyclin-dependent kinases (CDKs) and cyclin/CDK complexes have been found to control the progression of cells through the G0-G1, S and G2-

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Section: )mentioning

confidence: 54%

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

et al. 2004

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“…This was then substantiated by the finding that similar synergistic effects were obtained when the cells were exposed to oxaliplatin followed by C225 (an antibody inhibitor of EGFR) or UO126 (an inhibitor of MEK1). In addition, maintenance of the G 2 -M block and potentiation of apoptosis by the OXA-ZD6474 sequence were completely blocked in HT29-MEK1 (R4F) cells expressing a constitutively active form of MEK (44). Together, these data strongly suggest that the antitumor synergistic interaction between oxaliplatin and ZD6474 depends, in large part, on reversal of ZD6474-mediated antagonism of the activation of the EGFR prosurvival pathway by oxaliplatin.…”

Section: Discussionmentioning

confidence: 79%

“…8). Second, we made use of HT29 cells (R4F) that stably expressing a constitutively active form of MEK1 (44). The R4F cells when treated with the OXA-ZD6474 sequence both failed to undergo apoptosis (Fig.…”

Section: Oxaliplatin and Zd6 474 Interaction Is Egfr Dependentmentioning

confidence: 99%

Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases

Troiani

Lockerbie

Morrow

et al. 2006

Molecular Cancer Therapeutics

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To date, clinical studies combining the new generation of targeted therapies and chemotherapy have had mixed results. Preclinical studies can be used to identify potential antagonism/synergy between certain agents, with the potential to predict the most efficacious combinations for further investigation in the clinical setting. In this study, we investigated the sequence-dependent interactions of ZD6474 with oxaliplatin in two human colon cell lines in vitro. We evaluated the in vitro antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and RET tyrosine kinase activity, and oxaliplatin using three combination schedules: ZD6474 before oxaliplatin, oxaliplatin before ZD6474, and concurrent exposure. Cell proliferation studies showed that treatment with oxaliplatin followed by ZD6474 was highly synergistic, whereas the reverse sequence was clearly antagonistic as was concurrent exposure. Oxaliplatin induced a G 2 -M arrest, which was antagonized if the cells were previously or concurrently treated with ZD6474. ZD6474 enhanced oxaliplatin-induced apoptosis but only when added after oxaliplatin. The sequence-dependent antitumor effects appeared, in part, to be based on modulation of compensatory prosurvival pathways. Thus, expression of total and active phosphorylated EGFR, as well as AKT and extracellular signal-regulated kinase, was markedly increased by oxaliplatin. This increase was blocked by subsequent treatment with ZD6474. Furthermore, the synergistic sequence resulted in reduced expression of insulin-like growth factor-I receptor and a marked reduction in secretion of vascular endothelial growth factor protein. ZD6474 in combination with oxaliplatin has synergistic antiproliferative properties in human colorectal cancer cell lines in vitro when oxaliplatin is administered before ZD6474.

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“…Moreover, restoration of intracellular polyamine concentrations prevented sulindac-induced cell death in those tumors (37). Also, inhibition of extracellular signalregulated kinase 1/2 is absolutely required for the apoptotic effect of exisulind (38,39). Hence, signaling mechanisms other than those dependent on cGMP mediate the antineoplastic effects of exisulind in colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells

Pitari

Baksh

2006

Molecular Cancer Therapeutics

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The nonsteroidal anti-inflammatory drug sulindac is metabolized to sulindac sulfone (exisulind), an antineoplastic agent that inhibits growth and induces apoptosis in solid tumors. In colon cancer cells, the antineoplastic effects of exisulind have been attributed, in part, to induction of cyclic guanosine 3 ¶,5 ¶-monophosphate (cGMP) signaling through inhibition of cGMP-specific phosphodiesterases, which elevates intracellular cGMP, and novel expression of cGMP-dependent protein kinase (PKG) IB, the presumed downstream effector mediating apoptosis. Here, inhibition of proliferation and induction of cell death by exisulind was dissociated from cGMP signaling in human colon cancer cells. Accumulation of intracellular cGMP produced by an exogenous cell-permeant analogue of cGMP or a potent agonist of guanylyl cyclase C yielded cytostasis without cell death. Surprisingly, the antiproliferative effects of induced cGMP accumulation were paradoxically less than additive, rather than synergistic, when combined with exisulind. Further, although exisulind induced expression of PKG IB, it did not elevate intracellular cGMP and its efficacy was not altered by inhibition or activation of PKG I. Rather, PKG I induced by exisulind may mediate desensitization of cytostasis induced by cGMP. Thus, cytotoxic effects of exisulind are independent of cGMP signaling in human colon cancer cells. Moreover, combination therapies, including exisulind and agents that induce cGMP signaling, may require careful evaluation in patients with colon cancer.

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Inhibition of Extracellular-signal Regulated Kinases 1/2 Is Required for Apoptosis of Human Colon Cancer Cells In vitro by Sulindac Metabolites

Cited by 40 publications

References 18 publications

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

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

Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases

Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells

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