scholarly journals CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy

2021 ◽  
Vol 22 (16) ◽  
pp. 8391
Author(s):  
Valerio Nardone ◽  
Marcella Barbarino ◽  
Antonio Angrisani ◽  
Pierpaolo Correale ◽  
Pierpaolo Pastina ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Anticancer Agents ◽  
Recent Literature ◽  
Cancer Control ◽  
Phase Cell ◽  
Therapeutic Approaches ◽  
Combination Strategy ◽  
Rational Combination ◽  
Cell Cycle Transition ◽  
Other Neoplasms

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.

Anticancer Agents Based on Vulnerable Components in a Signalling Pathway

2020 ◽  
Vol 20 (10) ◽  
pp. 886-907 ◽  
Author(s):  
Ankur Vaidya ◽  
Shweta Jain ◽  
Sanjeev Sahu ◽  
Pankaj Kumar Jain ◽  
Kamla Pathak ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Dna Methyltransferase ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Sphingosine Kinase 2 ◽  
Family Protein ◽  
Rational Combination ◽  
Protein Kinase Akt ◽  
Parp 1

Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

scholarly journals Rational combination therapy in resistant arterial hypertension

2011 ◽  
Vol 17 (4) ◽  
pp. 384-390
Author(s):  
I. V. Emelianov ◽  
A. O. Konradi
Keyword(s):  
Combination Therapy ◽  
Arterial Hypertension ◽  
Resistant Hypertension ◽  
Drug Resistant ◽  
Therapeutic Approaches ◽  
Rational Combination ◽  
Resistant Arterial Hypertension

The article reviews therapy in drug-resistant hypertension. Current therapeutic approaches to treatment and rational combination therapy are discussed.

scholarly journals Neuroinflammatory Nexus of Pediatric Epilepsy

2018 ◽  
Vol 07 (02) ◽  
pp. 032-039
Author(s):  
Shruti Bagla ◽  
Alan Dombkowski
Keyword(s):  
Inflammatory Mediators ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Recent Literature ◽  
Refractory Epilepsy ◽  
Genetic Mutation ◽  
Pediatric Epilepsy ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches

AbstractA rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

An architectural perspective of cell-cycle control at the G1/S phase cell-cycle transition

2006 ◽  
Vol 209 (3) ◽  
pp. 706-710 ◽  
Author(s):  
Gary S. Stein ◽  
André J. van Wijnen ◽  
Janet L. Stein ◽  
Jane B. Lian ◽  
Martin Montecino ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
S Phase ◽  
Phase Cell ◽  
Cell Cycle Transition ◽  
Architectural Perspective

Evaluation of antiproliferative and apoptotic effects of the rational combination of the MEK1/2 inhibitor selumetinib (AZD6244) and inhibitors of the hedgehog pathway in colorectal cancer (CRC) cell lines.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 422-422
Author(s):  
A. Spreafico ◽  
J. J. Tentler ◽  
A. Tan ◽  
T. M. Pitts ◽  
M. I. Kachaeva ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mapk Pathway ◽  
Mutant Cell ◽  
Gene Array ◽  
Combination Strategy ◽  
Cell Viability Assay ◽  
Inhibition Of Proliferation ◽  
Antiproliferative Effects ◽  
Rational Combination

422 Background: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. Hyperactivation of this pathway due to mutations in KRAS have been reported in up to 50% of CRC cases. Clinical trials have shown that KRAS patients do not benefit from therapies targeting EGFR, highlighting the need for new therapeutic options. Utilizing differential gene array analyses, we have identified the hedgehog (HH) signaling pathway as a potential mediator of resistance to AZD6244. Based on these results, we tested the rational combination of selumetinib and the HH inhibitor, cyclopamine against human CRC cell lines. Methods: CRC cell lines were exposed to varying concentrations of selumetinib and cyclopamine. For AZD6244, cell lines with IC50≤ 0.1 μM were considered extremely sensitive (ES) and those with IC50≥ 1μM were deemed extremely resistant (ER). Four KRAS mutant cell lines (2ES, 2ER) were selected for combination studies. The antiproliferative effects were assessed using the sulforhodamine B (SRB) cell viability assay, and potential synergy was evaluated using the Chou and Talalay method. Apoptosis was analyzed using bioluminescent caspase 3/7 detection. Results: In all four cell lines tested, synergistic antiproliferative effects of selumetinib and cyclopamine were observed, including resistant lines to selumetinib. We observed significant induction of apoptosis when cell lines were exposed to the combination treatment, independent of their responsiveness to selumetinib in the SRB assay. Conclusions: Treatment of KRAS mutant CRC cell lines with selumetinib and cyclopamine resulted in synergistic inhibition of proliferation, regardless of sensitivity to selumetinib. Interestingly, a significant increase in apoptosis was observed in response to the combination, which may explain the synergy observed by the combination index (CI). In vivo analyses of this combination in cell lines and human CRC explants are ongoing to further validate these results. These preclinical data may suggest a rational combination strategy for patients with KRAS mutant CRC. No significant financial relationships to disclose.

scholarly journals Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1.

1996 ◽  
Vol 7 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R M Böhmer ◽  
E Scharf ◽  
R K Assoian
Keyword(s):  
Cell Cycle ◽  
Cell Adhesion ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Human Fibroblasts ◽  
Cytochalasin D ◽  
Phase Cell ◽  
Dependent Part ◽  
Molecular Events ◽  
Normal Human

The proliferation of many nontransformed cells depends on cell adhesion. We report here that disrupting the cytoskeleton in normal human fibroblasts causes the same cell cycle phenotype that is observed after blocking cell adhesion: suspended cells and cytochalasin D-treated monolayers fail to progress through G1 despite normal mitogen-induced expression of c-myc mRNA. Midway between G0 and the beginning of S-phase, cell cycle progression becomes independent of adhesion and the cytoskeleton. At this stage, the cells are also mitogen independent. Molecular analyses showed that Rb hyperphosphorylation and the induction of cyclin D1 occur slightly earlier than the transition to cytoskeleton independence. Moreover, these molecular events are blocked by cytochalasin D. Overall, our data indicate the following: 1) anchorage and cytoskeletal integrity are required throughout the mitogen-dependent part of G1; 2) mitogens and the cytoskeleton jointly regulate the phosphorylation of Rb; and 3) this interdependence is manifest in the regulation of cyclin D1.

scholarly journals Legionella pneumophila translocated translation inhibitors are required for bacterial-induced host cell cycle arrest

2019 ◽  
Vol 116 (8) ◽  
pp. 3221-3228 ◽  
Author(s):  
Asaf Sol ◽  
Erion Lipo ◽  
Dennise A. de Jesús-Díaz ◽  
Connor Murphy ◽  
Mildred Devereux ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Bacterial Replication ◽  
Cell Cycle Machinery

The cell cycle machinery controls diverse cellular pathways and is tightly regulated. Misregulation of cell division plays a central role in the pathogenesis of many disease processes. Various microbial pathogens interfere with the cell cycle machinery to promote host cell colonization. Although cell cycle modulation is a common theme among pathogens, the role this interference plays in promoting diseases is unclear. Previously, we demonstrated that the G1 and G2/M phases of the host cell cycle are permissive for Legionella pneumophila replication, whereas S phase provides a toxic environment for bacterial replication. In this study, we show that L. pneumophila avoids host S phase by blocking host DNA synthesis and preventing cell cycle progression into S phase. Cell cycle arrest upon Legionella contact is dependent on the Icm/Dot secretion system. In particular, we found that cell cycle arrest is dependent on the intact enzymatic activity of translocated substrates that inhibits host translation. Moreover, we show that, early in infection, the presence of these translation inhibitors is crucial to induce the degradation of the master regulator cyclin D1. Our results demonstrate that the bacterial effectors that inhibit translation are associated with preventing entry of host cells into a phase associated with restriction of L. pneumophila. Furthermore, control of cyclin D1 may be a common strategy used by intracellular pathogens to manipulate the host cell cycle and promote bacterial replication.

scholarly journals The RASSF1A Tumor Suppressor Restrains Anaphase-Promoting Complex/Cyclosome Activity during the G1/S Phase Transition To Promote Cell Cycle Progression in Human Epithelial Cells

2008 ◽  
Vol 28 (10) ◽  
pp. 3190-3197 ◽  
Author(s):  
Angelique W. Whitehurst ◽  
Rosalyn Ram ◽  
Latha Shivakumar ◽  
Boning Gao ◽  
John D. Minna ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Anaphase Promoting Complex ◽  
Cycle Progression

ABSTRACT Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

Sign in / Sign up

Export Citation Format

Share Document