Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Kryštof, Vladimír; Baumli, Sonja; Fürst, Robert

doi:10.2174/138161212800672750

Cited by 104 publications

(82 citation statements)

References 82 publications

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“…These findings indicate that CDK9 has a central role in signaling pathways which determine malignant characteristics of cancer cells such as the ability to invade surrounding tissue, uncontrolled proliferation, and spread to other sites. 28 Indeed, it has been demonstrated that CDK9 mediates apoptotic resistance, a hallmark of cancer cells, by transcriptionally controlling the overexpression of anti-apoptotic proteins in cancer cells such as Mcl-1. 26 Furthermore, we demonstrate that CDK9 serves as a negative prognostic marker in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

et al. 2017

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Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

et al. 2017

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“…4). The role of CDK9 in regulation of these TFs has been reviewed (Kryštof et al 2012, Schmitz & Kracht 2016: Myc and NF-κB are overexpressed in CRPC and their simultaneous overexpression is a signature in the progression of PCa (Hawksworth et al 2010, Jin et al 2014. Moreover, in relapsed PCa that occurs via bypass pathway the underlying molecular defects are characterized by the upregulation of anti-apoptotic proteins like BCL-2, MCL-1 and XIAP (Krajewska et al 1996, Chaudhary et al 1999, Devi 2004.…”

Section: Targeting Cdk9 In Crpcmentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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“…Flavopiridol was found to have potent antiproliferative action on 60 human cancer cell lines in the US National Cancer Institute screen panel and was the first CDK inhibitor to be submitted to clinical trials (36). Flavopiridol suppressed inflammatory processes such as inhibtion of murine collagen-induced arthritis in a dose-dependent manner (37). Additionally, it effectively limited murine hepatitis induced by concanavalin A (ConA), which triggers a strong and rapid leukocyte-dependent inflammatory liver injury (38).…”

Section: Cdk9 With T Cells and Monocytesmentioning

confidence: 99%

Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

et al. 2014

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Abstract. Inflammation is a key component of athero sclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered good candidates for estimating the risk of developing atherosclerosis. Cyclin-dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P-TEFb), is crucial in the cell cycle and apoptosis. Previous studies have focused on its inhibition of immune cells for the resolution of inflammation. Considering the effects of inflammation in the pathogenicity of atherosclerosis, decreasing inflammation through the inhibition of CDK9 may be useful for the prognosis of atherosclerosis. The aim of this review was to examine whether inhibition of the CDK9 monocyte may affect the process of inflammation by acting on the cytokine secretion and interacting with endothelial cells (ECs). Thus, CDK9 may be a novel target for the diagnosis and therapy of atherosclerosis. Contents1. Introduction 2. CDK9 and P-TEFb 3. CDK9 with T cells and monocytes 4. CDK9 and endothelium 5. CDK9 and inflammatory cytokines IntroductionAtherosclerosis is a complex vascular disease that usually begins in the first decade of life and is now recognized mainly as an inflammatory illness (1). It is a process characterized by the accumulation of lipids, mononuclear cells, fibrous components and calcium in the arteries (2). Vascular injury, recruitment of monocyte cells and infiltration of foam cells in combination with T lymphocytes, promotes lesion formation (2,3).Atherogenesis was traditionally considered a metabolic disease demonstrating arterial obstruction by fatty deposits in its wall (4). The current view is that atherogenesis involves highly specific biochemical and molecular responses with continuous interactions between different cellular players. Despite the presence of inflammatory reaction in each individual step of atherosclerosis from its beginning to a terminal manifestation, the cause-effect relationship of the two processes remains to be elucidated (4).Inflammation is crucial in the pathogenesis of atherosclerosis. Genes coding for inflammatory or anti-inflammatory molecules are considered potentially ideal candidates for estimating the risk of developing atherosclerosis (5-7). Accordingly, the production of high inflammatory molecules has been associated with atherosclerosis (8-11). Positive control of inflammation may play a protective role against atherosclerosis and is a potential therapeutic candidate for the prevention of atheroma formation.Cyclin-dependent kinases (CDKs) play an important role in the cell cycle and apoptosis. An increasing number of agents have been identified to interfere with the pathogenicity of atherosclerosis by targeting CDKS. Of these, CDK9 has been shown to exhibit marked characteristics in controlling inflammation (12). In a previous study (unpublished data), results of the 2-D proteomics analysis revealed that CDK9 was highly expressed in the serum of patients with atherosclerosis. The aim of the study was to analyze those results and identify t...

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Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Cited by 104 publications

References 82 publications

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Cyclin-dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

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