Targeting Multiple Kinase Pathways: A Change In Paradigm

Gossage, Lucy; Eisen, Tim

doi:10.1158/1078-0432.ccr-09-3182

Cited by 100 publications

(68 citation statements)

References 50 publications

(55 reference statements)

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“…1 Despite standard treatments and more recent targeted therapies, 2 CLL is still incurable. Given that in CLL, multiple pathways are dysregulated, 1,3 and considering that targeting one single pathway is often not sufficient to eliminate tumor cells, 4,5 it is necessary to develop novel strategies able to activate multiple apoptotic pathways and, simultaneously inhibit dysregulated survival pathways.…”

Section: Chronic Lymphocytic Leukemia (Cll) Is Characterized By Accummentioning

confidence: 99%

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

Rosati

Sabatini

Falco

et al. 2012

Intl Journal of Cancer

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gamma-Secretase inhibitors (GSIs) have been proposed for combined therapies of malignancies with a dysregulated Notch signaling. GSI I (Z-Leu-Leu-Nle-CHO) induces apoptosis of some tumor cells by inhibiting proteasome and Notch activity. Alterations in these two cell survival regulators contribute to apoptosis resistance of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the mechanisms whereby GSI I increases apoptosis of primary CLL cells. Time-course studies indicate that initial apoptotic events are inhibition of proteasome activity, concomitant with an increased endoplasmic reticulum (ER) stress apoptotic signaling, and a consistent Noxa protein up-regulation. These events precede, and some of them contribute to, mitochondrial alterations, which occur notwithstanding Mcl-1 accumulation induced by GSI I. In CLL cells, GSI I inhibits Notch1 and Notch2 activation only in the late apoptotic phases, suggesting that this event does not initiate CLL cell apoptosis. However, Notch inhibition may contribute to amplify GSI I-induced CLL cell apoptosis, given that Notch activation sustains the survival of these cells, as demonstrated by the evidence that both Notch1 and Notch2 down-regulation by small-interfering RNA accelerates spontaneous CLL cell apoptosis. Overall, our results show that GSI I triggers CLL cell apoptosis by inhibiting proteasome activity and enhancing ER stress, and amplifies it by blocking Notch activation. These findings suggest the potential relevance of simultaneously targeting these three important apoptosis regulators as a novel therapeutic strategy for CLL

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Section: Chronic Lymphocytic Leukemia (Cll) Is Characterized By Accummentioning

confidence: 99%

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

Rosati

Sabatini

Falco

et al. 2012

Intl Journal of Cancer

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“…The partial inhibition of a small number of kinases appears to be a promising strategy to overcome the intrinsic resistance to apoptosis and/or the acquisition of the MDR phenotype by cancer cells (9,(55)(56)(57). As single compounds, some polyphenols such as curcumin, resveratrol and the green tea polyphenol epigallocatechin-3-gallate (EGCG) have the potential to target multiple kinases that have been implicated in cancer cell biology (58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Quercetin inhibits a large panel of kinases implicated in cancer cell biology

Kiss

2011

Int J Oncol

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Abstract. Flavonoids are polyphenolic secondary metabolites from plants that possess a common phenylbenzopyrone structure (C6-C3-C6). Depending upon variations in their heterocyclic C-ring, flavonoids are categorised into one of the following groups: flavones, flavonols, flavanones, flavanols, anthocyanidins, isoflavones or chalcones. Flavonols include, among others, the molecules quercetin, myricetin and kaempferol. The anticancer activity of flavonols was first attributed to their electron-donating ability, which comes from the presence of phenolic hydroxyl groups. However, an emerging view is that flavonoids, including quercetin, may also exert modulatory actions in cells by acting through the protein kinase and lipid kinase signalling pathways. Data from the current study showed that 2 μM quercetin, a low concentration that represents less than 10% of its IC 50 growthinhibitory concentration as calculated from the average of eight distinct cancer cell lines, decreased the activity of 16 kinases by more than 80%, including ABL1, Aurora-A, -B, -C, CLK1, FLT3, JAK3, MET, NEK4, NEK9, PAK3, PIM1, RET, FGF-R2, PDGF-R· and -Rß. Many of these kinases are involved in the control of mitotic processes. Quantitative video microscopy analyses revealed that quercetin displayed strong anti-mitotic activity, leading to cell death. In conclusion, quercetin partly exerts its anticancer activity through the inhibition of the activity of a large set of kinases. Quercetin could be an interesting chemical scaffold from which to generate novel derivatives possessing various types of antikinase activities.

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“…However, several candidates have failed in clinical trials due to the complex nature of the crosstalk and signaling bypasses downstream of the targeted protein tyrosine kinase (PTK). PTK inhibitors with broad-spectrum specificity are increasingly expected to demonstrate a better clinical benefit than selective agents [26] . Some multi-targeted PTK inhibitors approved by the FDA/ EMEA, such as sorafenib [27] and sunitinib [28] , are marked as a new generation of PTK inhibitor drugs.…”

Section: Discussionmentioning

confidence: 99%

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

et al. 2011

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Aim: The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors. Methods: The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system. The screening platform for IGF1R inhibitors was established based on ELISA. The binding profile of IGF1R with the inhibitors was predicted with molecular docking and then subjected to the surface plasmon resonance (SPR) approach. The growth inhibition of cancer cells by the inhibitors was assessed with MTT assay. Apoptosis was analyzed using flow cytometry and Western blotting. Results: A naturally occurring small molecule compound hematoxylin was identified as the most potent inhibitor (IC 50 value=1.8±0.1 μmol/L) within a library of more than 200 compounds tested. Molecular simulation predicted the possible binding mode of hematoxylin with IGF1R. An SPR assay further confirmed that hematoxylin bound directly to IGF1R with high binding affinity (Kd=4.2×10 -6 mol/L). In HL-60 cancer cells, hematoxylin inactivated the phosphorylation of IGF1R and downstream signaling and therefore suppressed cell proliferation. Mechanistic studies revealed that hematoxylin induced apoptosis in HL-60 cells via both extrinsic and intrinsic pathways. Conclusion: A simple, sensitive ELISA-based screening platform for identifying IGF1R inhibitors was established. Hematoxylin was identified as a promising IGF1R inhibitor with effective antitumor activity that deserves further investigation.

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Targeting Multiple Kinase Pathways: A Change In Paradigm

Cited by 100 publications

References 50 publications

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

Quercetin inhibits a large panel of kinases implicated in cancer cell biology

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

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