The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma (original) (raw)
Related papers
Cancers
The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance t...
A review on the role of cyclin dependent kinases in cancers
2022
The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.
Journal of Gastrointestinal Surgery, 1998
Pancreatic cancers frequently carry mutations in the K-ras, p53, and p16 genes, which regulate cell proliferation. Transition from G1 to S phase of the cell cycle requires activation of cyclin-dependent kinase 2 (Cdk2), which is inhibited by olomoucine and roscovitine. The purpose of this study was to determine whether olomoucine and roscovitine can block Cdk2 kinase activity and inhibit proliferation of four human pancreatic cancer cell lines with various genetic alterations. Human pancreatic carcinoma cell lines BxPC-3, PANC-1, Capan-2, and CAV were treated with olomoucine or roscovitine. Cdk2 kinase activity was determined using histone H1 as the substrate. Cell cycle distribution was analyzed by DNA flow cytometry. Cell numbers were quantitated by Coulter counter. Olomoucine and roscovitine blocked Cdk2 activity in all four pancreatic cancer cell lines. Both compounds also inhibited cell proliferation in a dose-dependent fashion. Roscovitine was at least threefold more potent than olomoucine for both Cdk2 activity and cell proliferation. We have shown that Cdk inhibitors, olomoucine and roscovitine, block proliferation of human pancreatic cancer cells regardless of their mutations in K-ras, p53, or pl 6 genes.
Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment
Journal of Clinical Oncology, 2006
Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor–dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short h...
Targeting cyclin dependent kinases in management of human cancer
Innovative Publication, 2016
Uncontrolled proliferation is the hall mark of cancer and abnormal cell cycle regulation in cancer. CDK plays very important role in the control of the cell cycle and its proliferation. CDK2 is the " superstar " among the CDK family.CDK2 has cyclin A and cyclin E in its complex which the cyclin A complex require to progress through S phase regulated by phosphorylation and cyclin E require to transition from the G1 to S phase in cell cycle. Also, the mechanism of binding of CDK2 with its inhibitors as well as the changes of binding mechanisms following conformational variation of CDK2 are compared. Considering this fact, inhibition or disruption of the CDK2/cyclin complexes should be possible to suppress the hyper activation of CDK2 and hold back the infinite cell proliferation. There are main four binding site of CDK inhibitors. Competitive binding sites (site 1), Noncompetitive binding sites (site 2 and 3), Allosteric binding site (site 4). CDK inhibitors are mainly used in cancers including leukemia, melanoma, solid tumors and other types are being targeted.
Cyclin-Dependent Kinases as valid targets for cancer treatment
Ineffectiveness of conventional chemotherapeutic drugs and appearance of several side effects such as hair loss and anemia, nausea, vomiting, diarrhea, infections, fatigue and destruction of the immune system, due to inability to discriminate normal cells and cancerous cells, have led to development of new anti proliferative drugs with less side effect and more efficacy .Cell cycle and cell regulation play significant role in drug discovery as they provide new opportunities for discovery of new drug target for treatment of cancers. CDKs are introduced as significant target for anticancer drugs as they are directly and indirectly involved in cell cycle events such as progression, transcription and DNA repair, so development of Cdk inhibitors become goal of many drug discovery companies and researchers, for treatment of cancers. In this paper we focused on Cdks , their regulatory role in cell cycle and their prominent characteristics as valid target for drug discovery . Finally, we have reviewed 14 upcoming anticancer candidates whose target is CDKs .These anticancer drugs are such as Flavopiridol, Roscovitine, Dinaciclib, SNS032, AT7519, PD0332991, RGB-286638, P276-00, BAY-1000394, TG02/SG1317, EM-1421. PHA-848125. LEE-011 and LY2835219 which are currently under investigation for treatment of cancer. We hope this paper gives informative background for understanding importance of Cdks as effective targets for cancer therapy with high effective results and minimum side effect .
Cancer denotes a pathological manifestation that is characterized by hyperproliferation of cells. It has anticipated that a better understanding of disease pathogenesis and the role of cell-cycle regulators may provide an opportunity to develop an effective cancer therapeutic agents. Specifically, the cyclin-dependent kinases (CDKs) which regulate the transition of cell-cycle through different phases; have been identified as fundamental targets for therapeutic advances. It is an evident from experimental studies that several events leading to tumor growth occur by exacerbation of CDK4/CDK6 in G1-phase of cell division cycle. Additionally, the characteristics of Sand G2/M-phase regulated by CDK1/CDK2 are pivotal events that may lead to abrupt the cell division. Although, previously reported CDK inhibitors have shown remarkable results in pre-clinical studies, but have not yielded appreciable clinical results yet. Therefore, the development of clinically potent CDK inhibitors has remained to be a challenging task. However, continuous efforts has led to the development of some novel CDKs inhibitors that have emerged as a potent strategy for the treatment of advanced cancers. In this article, we have summarized the role of CDKs in cell-cycle regulation and tumorigenesis and recent advances in the development of CDKs inhibitors as a promising therapy for the treatment of advanced cancer. In addition, we have also performed a comparison of crystallographic studies to get valuable insight into the interaction mode differences of inhibitors, binding to CDK isoforms with apparently similar binding sites. The knowledge of ligand-specific recognition towards a particular CDK isoform may be applied as a key tool in future for the designing of isoformspecific inhibitors.
Cyclin-Dependent Kinase Inhibitors as Anticancer Drugs
Current Drug Targets, 2010
Poor therapeutic outcomes and serious side effects, together with acquired resistance to multiple drugs, are common problems of current cancer therapies. Therefore, there is an urgent need for new cancer-targeted drugs, which has led (inter alia) to the development of molecules that can specifically inhibit cyclin-dependent kinases (CDKs). In addition to their cell cycle regulatory functions, CDKs, especially CDK7 and CDK9, play important roles in the regulation of RNA polymerase II-mediated transcription. Here, we report on progress in the preclinical development of CDK inhibitors and their anticancer activities. Special attention is paid to the action mechanisms of the pan-specific CDK inhibitors flavopiridol and roscovitine, which have already entered phase II clinical trials as treatments for various tumours. The links between their ability to inhibit transcription and sensitisation of some types of cancer to apoptosis, mechanisms leading to p53 activation, and their synergistic cooperation with common DNA damaging drugs are also discussed. It has been demonstrated that drug-resistant cancer cells can arise during therapeutic application of small molecule protein kinase inhibitors. Clinical resistance to CDK inhibitors has not yet been described, but by comparing CDKs to other kinases, and CDK inhibitors to other clinically used protein kinase inhibitors, we also discuss possible mechanisms that could lead to resistance to CDK inhibitors.