Antitumor Effect of CGP41251, a New Selective Protein Kinase C Inhibitor, on Human Non-Small Cell Lung Cancer Cells

Ikegami, Yuri; Yano, Shunsuke; Nakao, Kenzo

doi:10.1254/jjp.70.65

Cited by 30 publications

(19 citation statements)

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“…This drug at 260 nM caused accumulation of A431 cells in Go/,, but at 1.54 ,UM it delayed G2/M progression transiently up to 12 h, followed by a Go/, block (Akinaga et al, 1994). CGP 41251 at concentrations above those employed here has been shown to arrest cell cycle progression in G2/M, at 0.5 and 1 giM in A549 cells and in NCI-H520 squamous carcinoma cells (Ikegami et al, 1996); and at 10 ,uM in ras-transformed rat fibroblasts (Akinaga et al, 1993). The results presented above, together with the relevant literature, are consistent with the notion that accumulation in Go/1 might be important for the cytostasis exerted by the indolocarbazoles, staurosporine and UCN-01, at low concentrations.…”

Section: Discussionmentioning

confidence: 77%

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

Courage

Snowden²,

Gescher³

1996

Br J Cancer

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Summary Staurosporine is a potent but non-specific kinase inhibitor. It has served as synthetic template for a variety of analogues with high specificity for protein kinase C (PKC). Here staurosporine and four PKCselective analogues, the indolocarbazoles, UCN-01 and CGP 41251, and the bisindolylmaleimides, Ro 31-8220 and GF 109203X, were investigated as growth inhibitors of human-derived A549 human lung adenocarcinoma cells. They were compared with respect to (1) effect on the cell cycle, (2) time dependency of growth arrest and (3) cytotoxic potency. Cells were exposed for 1, 2 and 4 days, or for 6, 12 and 24 h in the case of cyclesynchronised cells, to staurosporine analogues at concentrations at which they inhibited growth by 80% after 4 day exposure. Staurosporine and UCN-01 retarded cells in Go/, and CGP 41251 appeared to inhibit cell growth without cell cycle specificity. Ro 31-8220 slowed progression of synchronised cells through the cycle; over a longer time period it induced a weak block in G2/M. GF 109203X induced potent G2/M arrest in synchronised cells. This was not so apparent in asynchronous cells, which by day 4 were slowed in Go/, instead.Growth arrest induced by these inhibitors was more potent after incubation for 4 rather than 2 days. Incubation for 1 day followed by maintenance in drug-free medium for 3 days was sufficient to exert some cytostasis. The differences between cytotoxic and cytostatic concentrations, the former measured by release from cells of lactate dehydrogenase, were 15 000-fold for staurosporine, 300-fold for UCN-01, -400-fold for CGP 41251, 25-fold for Ro 31-8220 and -4-fold for GF 109203X. The results show that PKC-selective staurosporine analogues differ with respect to the mechanisms by which they interfere with the cell cycle. The necessity of long-term exposure for effective growth inhibition and the considerable margin between cytostatic and acute cytotoxic indolocarbazole concentrations are findings which might influence the planning and interpretation of clinical trials of these kinase inhibitors.

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Section: Discussionmentioning

confidence: 77%

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

Courage

Snowden²,

Gescher³

1996

Br J Cancer

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“…PKC412 has been shown to have an antitumor effect on human non-small-cell lung cancer cells 10 and myeloma cells 11,12 and has also been shown to inhibit growth factor-dependent C-FOS mRNA expression. 13 PKC412 has also shown antitumor activity in a murine model of myeloproliferative disease 14 as well as in an FGFR3 TDII-induced murine model of B-cell lymphoma.…”

Section: Introductionmentioning

confidence: 99%

PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells

Sharkey

Khong

Spencer

2006

Blood

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The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 M PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNKdependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFB and increased expression of the heat shock proteins HSP70 and HSP90. IntroductionMultiple myeloma (MM) is a B-cell malignancy, which occurs predominantly at an older age and is still incurable despite progress in treatment. 1 The investigation of novel anticancer drugs for the treatment of this disease is therefore warranted. Protein kinase C (PKC) is a phospholipid-dependent, serine/threonine kinase responsible for signal transduction in response to growth factors, hormones, and neurotransmitters. 2 PKC plays an important role in cell-growth regulation and tumor promotion 3 and has also been implicated in metastasis 4 and chemotherapy-associated multidrug resistance. 5 Total PKC activity has been reported to be elevated in carcinomas of breast 6 and lung. 7 In MM, PKC has been implicated in the shedding of CD138 8 and the IL-6 receptor, 9 both of which are thought to play important roles in tumor progression. Eleven isoforms of PKC have been identified, and these have been separated into 3 subgroups: (1) the conventional calcium-dependent and DAG (diacylglycerol)-dependent PKCs (cPKCs: ␣, ␤ I , ␤ II , ␥), (2) the nonconventional calcium-independent but DAG-dependent PKCs (nPKCs: ␦, ε, , , ), and (3) the atypical calcium-independent and DAGunresponsive PKCs (aPKCs: , ).The PKC inhibitor PKC412 (N-benzylstaurosporine) is a derivative of the naturally occurring alkaloid staurosporine and has been shown to inhibit the conventional isoforms of PKC (␣, ␤ I , ␤ II , ␥). PKC412 has been shown to have an antitumor effect on human non-small-cell lung cancer cells 10 and myeloma cells 11,12 and has also been shown to inhibit growth factor-dependent C-FOS mRNA expression. 13 PKC412 has also shown antitumor activity in a murine model of myeloproliferative disease 14 as well as in an FGFR3 TDII-induced murine model of B-cell lymphoma. 11The AP-1 transcription factor consists of homodimers of Jun proteins or heterodimers of Fos and Jun proteins 15,16 and plays a key role in the regulation of expression of genes involved in DNA repair, cell proliferation, cell-cycle arrest, death by apoptosis, and tissue and extracellular matr...

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“…Interestingly, single treatment of cells with PKC 412 leads to the formation of tetraploid cells, indicating that PKC 412 disturbs mitosis-related signaling. 15 PKC 412 treatment is also associated with a concentration-dependent decrease in the phosphorylation of Akt and of the MEK target, ERK1/2. 14 The staurosporine analog Ro 31-8220 had an opposite effect on cells; exposure to this compound leads to an increase in Akt and ERK phosphorylation, and this compound cannot sensitize cells to DNA damage.…”

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confidence: 95%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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Antitumor Effect of CGP41251, a New Selective Protein Kinase C Inhibitor, on Human Non-Small Cell Lung Cancer Cells

Cited by 30 publications

References 20 publications

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

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