Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition

Hartmann, Jörg T.; Kanz, Lothar

doi:10.1001/archderm.144.11.1525

Cited by 74 publications

(37 citation statements)

References 6 publications

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“…Sunitinib is an inhibitor of non-RAF kinases that are also inhibited by sorafenib, 20 including vascular epidermal growth factor receptors, platelet-derived growth factor receptors, Flt3 and c-Kit, but it does not target RAF. 21 As a positive control, the activity of sunitinib in CLL cells was demonstrated by its capacity to block CXCL12-induced activation of cAMP response element-binding in the same experiment (data not shown). Thus, these shared kinase targets are not involved in the activation of MEK after treatment with CXCL12.…”

Section: Cxcl12-mediated Mek Activation In Zap-70 ؉ Cll Cells Is Raf mentioning

confidence: 87%

“…Although originally developed as a RAF inhibitor, sorafenib was subsequently found to inhibit other tyrosine kinases, including vascular epidermal growth factor receptor 2 and 3, platelet derived growth factor receptor-␤, Flt3, and c-Kit. 19 That these kinases do not play a role in the MEK signaling induced by CXCL12 is indicated by the lack of activity on the MEK/ERK pathways of another drug, sunitinib, which inhibits these other kinases, 21 but not RAF. Two other RAF inhibitors also blocked CXCL12-induced activation of MEK/ERK in CLL cells, providing additional support for this model.…”

Section: Discussionmentioning

confidence: 99%

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Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Messmer¹,

Fecteau²,

O’Hayre

et al. 2011

Blood

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The chemokine CXCL12, via its receptor CXCR4, promotes increased survival of chronic lymphocytic leukemia (CLL) B cells that express high levels of -chainassociated protein (ZAP-70), a receptor tyrosine kinase associated with aggressive disease. In this study, we investigated the underlying molecular mechanisms governing this effect. Although significant differences in the expression or turnover of CXCR4 were not observed between ZAP-70 ؉ and ZAP-70 ؊ cell samples, CXCL12 induced greater intracellular Ca 2؉ IntroductionChronic lymphocytic leukemia (CLL) is a disease characterized by the accumulation of mature monoclonal B cells in the blood, secondary lymphoid tissue, and marrow. 1,2 Regardless of their apparent longevity in vivo, CLL B cells undergo apoptosis in vitro unless rescued by monocyte-derived nurse-like cells (NLCs) or marrow stromal cells. [3][4][5][6] In line with this hypothesis, the marrow is invariably infiltrated with CLL cells in patients, and the extent of infiltration correlates with clinical stage and prognosis. 5,7 These accessory cells also protect CLL cells from drug-induced apoptosis in vitro. 8 Thus, it has been postulated that CLL cells receive survival signals from these accessory cells, which constitute part of the CLL B-cell microenvironment in secondary lymphoid tissue and marrow. 6 Such niches could protect leukemia cells from spontaneous or drug-induced apoptosis in vivo, motivating the current study to better understand the survival pathways triggered by the microenvironment.Accessory cells such as NLCs protect CLL cells from apoptosis in vitro in part through the secretion of the stromal cell-derived factor-1␣ (renamed as CXCL12). 9,10 CXCL12 is a highly conserved chemokine that signals through the chemokine receptor CXCR4, which is expressed at high levels by CLL cells. 3,10,11 Although most noted for its role in directing cell migration, CXCL12 also provides survival stimuli to CLL cells and partially protects them from spontaneous or drug-induced apoptosis or both in vitro. 3,9 Further, the enhanced viability of these cells in the presence of CXCL12 can be blocked by antibodies to CXCL12 3 or peptide inhibitors of CXCR4. 8 In prior studies, it was found that treatment of CLL cells with CXCL12 induced activation of extracellular signal-regulated kinase (ERK). 8,12 In this study, we further examined the survival and signaling responses of CLL cells to CXCL12 to characterize the mechanism for the survival benefit. In addition, we compared the CXCL12-induced responses of CLL cells from 2 subgroups of patients, with high or low expression levels of -chain-associated protein of 70 kDa (ZAP-70), a tyrosine kinase whose high-level expression is correlated with increased risk of early disease progression and relatively short survival 12,13 . Methods Preparation of CXCL12CXCL12 was prepared as previously described. 14 Briefly, CXCL12 was expressed as a His-tag fusion protein and purified from inclusion bodies in BL21 Escherichia coli. Bacterial pellets were resuspended in 10mM Tris...

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Section: Cxcl12-mediated Mek Activation In Zap-70 ؉ Cll Cells Is Raf mentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Messmer¹,

Fecteau²,

O’Hayre

et al. 2011

Blood

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“…Bunlar tümör anjiyogenez ve tümör proliferasyonunda rol alan tüm paletlerden türetilmiş büyüme faktörleri, plateletderived growth factor (PDGF-Rs) ve vasküler endotel büyüme faktör reseptörlerini, vascular endothelial growth factor receptors (VEGFRs) kapsamaktadır. Sunitinib, ayrıca, RTK olan CD-117'yi (c-KIT) inhibe eder ki, CD-117 uygun olmayan mutasyon ile aktifleştirildiğinde gastrointestinal stromal hücre tümörlerini aktive eder (13). Öte taraftan sunitinib böbrek kanseri için ilk basamak tedavidir.…”

Section: şEkil-4 Ssea-1 Istatistiksel Analiziunclassified

Deneysel diabet modeli oluşturulan farelerde tirozin kinaz inhibitör uygulanımının testis dokusu üzerine olan etkilerinin pluripotensi kapasitesi ve hücre adezyonu özelinde araştırılması

Özdedeli¹,

Aktuğ²,

Oltulu³

et al. 2017

Ege Tıp Dergisi

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Amaç: Tirozin kinaz inhibisyonunun diyabet etkisi altındaki testis dokusu üzerine göstereceği etkileri araştırmaktır. Gereç ve Yöntem:Çalışmamızda 31 adet CD1 türü erkek fare kullanıldı ve dört gruba ayrıldı: Grup 1'de (kontrol grubu) 7, Grup 2'de tirozin kinaz inhibitörü uygulanan 7, Grup 3'te diyabetik ve SF uygulanan 8, Grup 4'te diyabet + tirozin kinaz inhibitörü uygulanan 9 denek hayvanı yer aldı. Grup 1'de herhangi bir uygulama yapılmadı. Grup 2'deki farelere 3 hafta boyunca tirozin kinaz inhibitörü verildi. Diyabet oluşturulması için 0.1mol/L tek doz streptozotosinin intraperitoneal olarak verildi. 250 mg/dL ve üzeri kan glikoz seviyesi diyabetik olarak kabul edildi. Deneysel diyabet modeli oluşturulan farelere 1 hafta beklendikten sonra, Grup 3'e SF, Grup 4'e 3 hafta boyunca tirozin kinaz inhibitörü verildi. Sonunda tüm denek hayvanları anestezi altında sakrifiye edilerek histopatolojik inceleme için testis dokuları alındı. İstatistiksel analiz için tek yönlü varyans analizi (ANOVA) testi yapıldı, 0.05'ten küçük p değerleri, istatistiksel olarak anlamlı kabul edildi. Bulgular:Testis dokusu histopatolojik olarak incelendiğinde deneysel diyabete bağlı olarak seminifer tübülün germ hücre serilerinde kayıp, hücre bütünlüklerinde ise bozulma saptandı.Sonuç: Bu çalışma, diyabetin testiste germ hücre serilerinde sayısal olarak azalmaya ve hücre adezyon mekanizmasında bozulmaya yol açtığını göstermektedir. Tirozin kinaz inhibitörü uygulamasının, bu hasarlanmada tamir edici etkisinin olduğu düşünülmektedir. Bu hasarın tedavisinin derecesi, uygulanan tirozin kinaz inhibitörünün dozu ve süresine bağlı olarak farklılık gösterebilmektedir. Ancak, klinik diyabet uygulamalarında tirozin kinaz inhibitörü kullanılabilmesi için bu konuda moleküler çalışma sayılarının artışına ihtiyaç vardır.

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“…Previously indole-hydrazide-hydrazone derivatives shows antimicrobial [11][12][13][14][15][16][17], antifungal [18], anticonvulsant [19], anti-inflammatory, antiplatelet [20][21][22][23][24] and antituberculosis activities [25][26][27][28]. But these series of indole fused aryl aldehydes analogues shows potent antitumor [29][30][31][32][33] activity on anticancer [34][35][36] human cell lines.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Novel 5-Bromo Indole-Aryl Keto Hydrazide-Hydrazone Analogues

Rudavath¹,

Sreenivasulu²,

Pinapati³

et al. 2018

Asian J. Chem.

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A wide variety of indole, substituted benzaldehyde linked keto hydrazide-hydrazone analogues were designed, synthesized and evaluated for their cytotoxicity against eight human cancer cell lines HeLa, A549, MCF-7, K562, HEK293, HT29, SF295 and HL60. All these synthesized compounds showed potent antitumor activities on the above eight human cancer cell lines. Among them, 6a and 6h compounds exhibited potent antitumor activity on HL 60 and A549 cancer cell lines with IC50 value of 3.913 and 4.838 µM than the standard drug cisplatin with IC50 values of 27 and 36 µM, respectively.

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Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition

Cited by 74 publications

References 6 publications

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Deneysel diabet modeli oluşturulan farelerde tirozin kinaz inhibitör uygulanımının testis dokusu üzerine olan etkilerinin pluripotensi kapasitesi ve hücre adezyonu özelinde araştırılması

Synthesis and Antitumor Evaluation of Novel 5-Bromo Indole-Aryl Keto Hydrazide-Hydrazone Analogues

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