Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Levitzki, Alexander

doi:10.1146/annurev-pharmtox-011112-140341

Cited by 172 publications

(172 citation statements)

References 101 publications

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“…Tyrosine Kinase Inhibitors Block Phosphorylation of PKC␦ at Tyr-64 and Tyr-155-TKIs encompass a large family of drugs that are used clinically for the treatment of neoplastic diseases (27). Our studies suggest that these drugs may also be useful for protection of nontumor tissue in patients undergoing IR treatment.…”

Section: C-abl and C-src Phosphorylate Pkc␦ At Tyr-155 And Tyr-64mentioning

confidence: 81%

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Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Wie

Adwan

DeGregori

et al. 2014

Journal of Biological Chemistry

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Background: Nuclear import of protein kinase C␦ is required for DNA-damage-induced apoptosis. Results: c-Src and c-Abl phosphorylate PKC␦ to regulate nuclear import. Tyrosine kinase inhibitors block nuclear translocation of PKC␦ and suppress apoptosis. Conclusion: Tyrosine kinase inhibitors can regulate the pro-apoptotic function of protein kinase C␦. Significance: Tyrosine kinase inhibitors may improve the quality of life in cancer patients receiving radiation therapy.

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Section: C-abl and C-src Phosphorylate Pkc␦ At Tyr-155 And Tyr-64mentioning

confidence: 81%

“…TKIs have been developed against many kinases required for cancer cell proliferation, including members of the Src family and c-Abl (27). Here we explored the novel use of these inhibitors as prophylactic agents to prevent IR-induced cell death within the salivary gland.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Wie

Adwan

DeGregori

et al. 2014

Journal of Biological Chemistry

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“…Indeed, silencing GSK3b, PDK1, and STAT3 pathways almost completely abrogates the migration of metastatic cancer cells. Hence, by using multi-targeted agents like 6BIO, that combine the advantage of synergistic effects together with the circumvention of potential counter regulation mechanisms, greater efficiency in the treatment of cancer will be achieved (46,47).…”

Section: Discussionmentioning

confidence: 99%

Indirubin Derivative 6BIO Suppresses Metastasis

et al. 2013

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While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of antimetastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3 0 -oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which inhibited adhesion, migration, and invasion of a variety of metastatic cell types in vitro. Mechanistic analyses focused on known targets of 6BIO, which were silenced by this compound. Unexpectedly, RNAi-mediated silencing of glycogen synthase kinase 3b (GSK3b) and phosphoinositide-dependent protein kinase 1 (PDK1), both modulators of cellular metastasis targeted by 6BIO, were not found to affect invasive migration in this study. Instead, the Jak/STAT3 signaling pathway appeared to play a major role through modulation of its downstream migration regulators Cterminal tensin-like protein and matrix metalloproteinase 2. However, PDK1 and GSK3b contributed to the overall response to 6BIO, as silencing of all three pathways resulted in almost complete inhibition of migration, phenocopying the 6BIO response. Taken together, our findings illustrate the antimetastatic activity of 6BIO on the basis of its ability to simultaneously inhibit several kinase cascades involved in metastasis of cancer cells, supporting the concept of "polypharmacology" in developing drugs to attack metastasis, the most deadly aspect of cancer. Cancer Res; 73(19); 6004-12. Ó2013 AACR.

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“…In this respect, the present pharmacology of cancer occupies a special place in the treatment of diseases, since the cytotoxic drugs that constitute its core are not directed towards re-establishing normal physiological control (as is the case for instance with drugs used in cardiology, tending to ensure normal tissue perfusion by our cardiac pump), but are directed towards the elimination of tumor cells, as though these were bacteria or parasites, whereas they are somatic cells endowed with the same basic genome as healthy cells, but in which proliferation control is impaired, usually due to a succession of mutations. Complementary treatments aiming at slowing down the growth of the tumor, either by choking its vascular environment (antiangiogenic agents [65]) or by antagonizing growth factor receptors or blocking elements of intracellular signal transduction cascades downstream of them (monoclonal antibodies [93], tyrosine kinase inhibitors (TKIs) [76], the main weapons for the so-called targeted therapies), may be qualified cytostatic, as they are not used to kill cells (which is what cytotoxics are designed for) but only to slow down entrance or progression in the division cycle. Note however that at high doses cytostatic drugs may become cytotoxic.…”

Section: The Case Of Cancer In Therapeuticsmentioning

confidence: 99%

Deterministic Mathematical Modelling for Cancer Chronotherapeutics: Cell Population Dynamics and Treatment Optimization

Clairambault¹

2014

Mathematical Oncology 2013

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In this short review paper, I will present the mathematical models that have been designed in the frame of continuous deterministic cell population dynamics that aim at optimization of cancer treatments using chronotherapeutics. Many authors have dealt with chronobiology of cancer, less with continuous mathematical models and even less with the declared aim to optimize chronotherapeutics. The biological and theoretical bases for these models are sketched, started from a historical viewpoint, and the main theoretical results are presented, with biological suggestions to account for them. Chronotherapeutics that leads to therapeutic optimization with the constraint of limiting unwanted toxicity of anticancer drugs towards healthy cell populations is put in a medical perspective together with the other main pitfall of cancer therapeutics, for which optimization procedures should have little to do with circadian biology, i.e., emergence of drug resistance in cancer cell populations, which is amenable to the use of other sorts of models, that are briefly mentioned.

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Tyrosine Kinase Inhibitors: Views of Selectivity, Sensitivity, and Clinical Performance

Cited by 172 publications

References 101 publications

Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Indirubin Derivative 6BIO Suppresses Metastasis

Deterministic Mathematical Modelling for Cancer Chronotherapeutics: Cell Population Dynamics and Treatment Optimization

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