Progress of CDK4/6 Inhibitor Palbociclib in the Treatment of Cancer

2019 ◽  
Vol 18 (9) ◽  
pp. 1241-1251 ◽  
Author(s):  
Fengquan Chen ◽  
Chunxi Liu ◽  
Jian Zhang ◽  
Wenfang Xu ◽  
Yingjie Zhang
Keyword(s):  
Cell Cycle ◽  
Clinical Trials ◽  
Anticancer Agents ◽  
Combined Therapy ◽  
Breast Cancer Treatment ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinases ◽  
Cycle Arrest ◽  
Antitumor Potential ◽  
Excessive Proliferation

The Cyclin-Dependent Kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. These kinases are closely related to oncogenesis and have been proved to be attractive targets for designing novel anticancer agents. The CDK inhibitors can effectively suppress the excessive proliferation of tumor cells by inducing cell cycle arrest. In recent years, a large number of CDK inhibitors have entered pre-clinical and/or clinical trials. Among these compounds, the selective CDK4/6 inhibitor Palbociclib has been approved by FDA for breast cancer treatment. Moreover, Palbociclib demonstrated promising antitumor potential as monotherapy or combined therapy in numerous clinical trials. Herein, we provide a brief review focused on the recent progress of clinical studies about Palbociclib.

A review on plant flavonoids as potential anticancer agents

2020 ◽  
Vol 24 ◽  
Author(s):  
Bhupinder Kapoor ◽  
Monica Gulati ◽  
Reena Gupta ◽  
Sachin Kumar Singh ◽  
Mukta Gupta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Trials ◽  
Multidrug Resistance ◽  
Anticancer Agents ◽  
Fruits And Vegetables ◽  
Polyphenolic Compounds ◽  
Anticancer Effect ◽  
Cycle Arrest ◽  
Inhibition Of Angiogenesis ◽  
Induction Of Apoptosis

Abstract:: Flavonoids are polyphenolic compounds that are mainly derived from fruits and vegetables and constitute an essential part of plant-derived beverages such as green tea, wine and cocoa-based products. They have been shown to possess anticancer effect via different mechanisms such as carcinogen inactivation, antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, anti-oxidation and reversal of multidrug resistance or a combination of any two or more of these mechanisms. The present review summarizes the chemistry, biosynthesis and anticancer evaluation of flavonoids in both animal and human studies. A special emphasis has been placed on the flavonoids that are being screened in different phases of clinical trials for chemoprotective action against various cancers.

scholarly journals Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Viktorija Juric ◽  
Lance Hudson ◽  
Joanna Fay ◽  
Cathy E. Richards ◽  
Hanne Jahns ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cortical Neurons ◽  
Apoptotic Cell ◽  
Cdk Inhibitors ◽  
Induce Cell Death ◽  
Viability Loss ◽  
Cycle Arrest ◽  
Recurrent Gbm

AbstractActivation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

scholarly journals Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1790
Author(s):  
Katarzyna Malarz ◽  
Jacek Mularski ◽  
Michał Kuczak ◽  
Anna Mrozek-Wilczkiewicz ◽  
Robert Musiol
Keyword(s):  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
P53 Protein ◽  
Structural Similarity ◽  
M Cell ◽  
Cycle Arrest ◽  
Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2755-2764 ◽  
Author(s):  
Igor Matushansky ◽  
Farshid Radparvar ◽  
Arthur I. Skoultchi
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Erythroid Cells ◽  
Stable Transfectants ◽  
Cyclin Dependent Kinases ◽  
Erythroleukemia Cells ◽  
Murine Erythroleukemia ◽  
Murine Erythroleukemia Cells

Abstract Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.

scholarly journals Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.

1995 ◽  
Vol 9 (15) ◽  
pp. 1831-1845 ◽  
Author(s):  
I Reynisdottir ◽  
K Polyak ◽  
A Iavarone ◽  
J Massague
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cdk Inhibitors ◽  
Tgf Beta ◽  
Induce Cell Cycle Arrest ◽  
Cycle Arrest

Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2755-2764 ◽  
Author(s):  
Igor Matushansky ◽  
Farshid Radparvar ◽  
Arthur I. Skoultchi
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cdk Inhibitors ◽  
Cyclin D ◽  
Erythroid Cells ◽  
Stable Transfectants ◽  
Cyclin Dependent Kinases ◽  
Erythroleukemia Cells ◽  
Murine Erythroleukemia ◽  
Murine Erythroleukemia Cells

Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.

scholarly journals Inactivation of p21 by E1A Leads to the Induction of Apoptosis in DNA-Damaged Cells

2001 ◽  
Vol 75 (20) ◽  
pp. 9844-9856 ◽  
Author(s):  
Debasis Chattopadhyay ◽  
Mrinal K. Ghosh ◽  
Asoke Mal ◽  
Marian L. Harter
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitor ◽  
Human Colon ◽  
Wild Type ◽  
Human Colon Carcinoma Cell ◽  
Adenovirus E1a ◽  
Cycle Arrest ◽  
Induction Of Apoptosis

ABSTRACT A major impediment to successful chemotherapy is the propensity for some tumor cells to undergo cell cycle arrest rather than apoptosis. It is well established, however, that the adenovirus E1A protein can sensitize these cells to the induction of apoptosis by anticancer agents. To further understand how E1A enhances chemosensitivity, we have made use of a human colon carcinoma cell line (HCT116) which typically undergoes cell cycle arrest in response to chemotherapeutic drugs. As seen by the analysis of E1A mutants, we show here that E1A can induce apoptosis in these cells by neutralizing the activities of the cyclin-dependent kinase inhibitor p21. E1A's ability to interact with p21 and thereby restore Cdk2 activity in DNA-damaged cells correlates with the reversal of G1 arrest, which in turn leads to apoptosis. Analysis of E1A mutants failing to bind p300 (also called CBP) or Rb shows that they are almost identical to wild-type E1A in their ability to initially overcome a G1 arrest in cells after DNA damage, while an E1A mutant failing to bind p21 is not. However, over time, this mutant, which can still target Rb, is far more efficient in accumulating cells with a DNA content greater than 4N but is similar to wild-type E1A and the other E1A mutants in releasing cells from a p53-mediated G2 block following chemotherapeutic treatment. Thus, we suggest that although E1A requires the binding of p21 to create an optimum environment for apoptosis to occur in DNA-damaged cells, E1A's involvement in other pathways may be contributing to this process as well. A model is proposed to explain the implications of these findings.

scholarly journals p21 and p27: roles in carcinogenesis and drug resistance

2008 ◽  
Vol 10 ◽  
Author(s):  
Abde M. Abukhdeir ◽  
Ben Ho Park
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Death ◽  
Cell Growth ◽  
Cdk Inhibitors ◽  
Paradoxical Effect ◽  
Cyclin Dependent Kinases ◽  
Functional Loss ◽  
Growing Body ◽  
Identification Function

Human cancers arise from an imbalance of cell growth and cell death. Key proteins that govern this balance are those that mediate the cell cycle. Several different molecular effectors have been identified that tightly regulate specific phases of the cell cycle, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors. Notably, loss of expression or function of two G1-checkpoint CDK inhibitors – p21 (CDKN1A) and p27 (CDKN1B) – has been implicated in the genesis or progression of many human malignancies. Additionally, there is a growing body of evidence suggesting that functional loss of p21 or p27 can mediate a drug-resistance phenotype. However, reports in the literature have also suggested p21 and p27 can promote tumours, indicating a paradoxical effect. Here, we review historic and recent studies of these two CDK inhibitors, including their identification, function, importance to carcinogenesis and finally their roles in drug resistance.

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