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Journal of Hematology & Oncology Oct 2022Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly... (Review)
Review
Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through "synthetic lethality" mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.
Topics: Adenosine Diphosphate; Cell Cycle; Cell Cycle Checkpoints; DNA Damage; DNA Repair; Genomic Instability; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Tumor Suppressor Protein p53
PubMed: 36253861
DOI: 10.1186/s13045-022-01360-x -
Philosophical Transactions of the Royal... Dec 2004The release of adenosine diphosphate (ADP) from the actomyosin cross-bridge plays an important role in the adenosine-triphosphate-driven cross-bridge cycle. In fast... (Review)
Review
The release of adenosine diphosphate (ADP) from the actomyosin cross-bridge plays an important role in the adenosine-triphosphate-driven cross-bridge cycle. In fast contracting muscle fibres, the rate at which ADP is released from the cross-bridge correlates with the maximum shortening velocity of the muscle fibre, and in some models the rate of ADP release defines the maximum shortening velocity. In addition, it has long been thought that the rate of ADP release could be sensitive to the load on the cross-bridge and thereby provide a molecular explanation of the Fenn effect. However, direct evidence of a strain-sensitive ADP-release mechanism has been hard to come by for fast muscle myosins. The recently published evidence for a strain-sensing mechanism involving ADP release for slower muscle myosins, and in particular non-muscle myosins, is more compelling and can provide the mechanism of processivity for motors such as myosin V. It is therefore timely to examine the evidence for this strain-sensing mechanism. The evidence presented here will argue that a strain-sensitive mechanism of ADP release is universal for all myosins but the basic mechanism has evolved in different ways for different types of myosin. Furthermore, this strain-sensing mechanism provides a way of coordinating the action of multiple myosin motor domains in a single myosin molecule, or in complex assemblies of myosins over long distances without invoking a classic direct allosteric or cooperative communication between motors.
Topics: Actins; Adenosine Diphosphate; Animals; Models, Biological; Molecular Motor Proteins; Muscle Contraction; Muscle, Skeletal; Myosins
PubMed: 15647162
DOI: 10.1098/rstb.2004.1560 -
Molecular Cell Apr 2015Hsp90 chaperones receive much attention due to their role in cancer and other pathological conditions, and a tremendous effort of many laboratories has contributed in... (Review)
Review
Hsp90 chaperones receive much attention due to their role in cancer and other pathological conditions, and a tremendous effort of many laboratories has contributed in the past decades to considerable progress in the understanding of their functions. Hsp90 chaperones exist as dimers and, with the help of cochaperones, promote the folding of numerous client proteins. Although the original view of these interactions suggested that these dimeric complexes were symmetrical, it is now clear that many features are asymmetrical. In this review we discuss several recent advances that highlight how asymmetric interactions with cochaperones as well as asymmetric posttranslational modifications provide mechanisms to regulate client interactions and the progression through Hsp90's chaperone cycle.
Topics: Acetylation; Adenosine Diphosphate; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Phosphorylation; Protein Binding; Protein Conformation; Protein Folding; Protein Isoforms; Protein Multimerization; Protein Processing, Post-Translational; Signal Transduction; Sumoylation
PubMed: 25839432
DOI: 10.1016/j.molcel.2015.02.022 -
Japanese Journal of Pharmacology Oct 1998In this review, after a summary of the history and current status of the receptors involved in purinergic signalling, we focus on the distribution and physiological... (Review)
Review
In this review, after a summary of the history and current status of the receptors involved in purinergic signalling, we focus on the distribution and physiological roles of purines and pyrimidines in both short-term events such as neurotransmission, exocrine and endocrine secretion and regulation of immune cell function, and long-term events such as cell growth, differentiation and proliferation in development and regeneration. Finally, the protective roles of nucleosides and nucleotides in events such as cancer, ischemia, wound healing, drug toxicity, inflammation and pain are explored and some suggestions made for future developments in this rapidly expanding field, with particular emphasis on the involvement of selective agonists and antagonists for purinergic receptor subtypes in therapeutic strategies.
Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Humans; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction; Synaptic Transmission
PubMed: 9829617
DOI: 10.1254/jjp.78.113 -
Annales de Biologie Clinique Feb 2021During primary hemostasis the platelets aggregate to form the platelet thrombus. ADP and thrombin generated by coagulation are the main agonists in platelet aggregation....
During primary hemostasis the platelets aggregate to form the platelet thrombus. ADP and thrombin generated by coagulation are the main agonists in platelet aggregation. In a previous study we were able to show that patients with lung cancer had hypercoagulability, hyperfibrinogemia (≥ 6.22 g/L) was predictive of thromboembolic disease at the start of diagnosis before any therapy. In this study, we studied platelet aggregation in these patients in order to demonstrate whether they have hyperaggregability associated with the hypercoagulability demonstrated previously, and this by evaluating abnormalities in primary hemostasis (platelet count and platelet aggregation). One hundred and one patients diagnosed before any therapy and 72 blood donors were included. Agonists used for platelet aggregation are collagen and adenosine diphosphate at low concentrations. Hyperaggregability is observed when blood platelets are stimulated by ADP at different concentrations (p ≤ 0.01). This hyperaggregability is influenced by the histological type and not the development of the cancer, the age of the subjects and the platelet count, it is independent of hyperfibrinogemia and the occurrence of thromboembolic disease. However, an increase in the platelet level is found in patients with hyperfibrinogemia. Patients with lung cancer present platelet activation observed by aggregometry in response to ADP; which is not influenced by hyperfibrinogemia during cancer.
Topics: Adenosine Diphosphate; Blood Platelets; Humans; Lung Neoplasms; Platelet Aggregation; Thrombin
PubMed: 33648917
DOI: 10.1684/abc.2021.1623 -
Organic Letters Jul 2023Adenosine diphosphate (ADP) ribosylation is an important post-translational modification (PTM) that plays a role in a wide variety of cellular processes. To study the...
Adenosine diphosphate (ADP) ribosylation is an important post-translational modification (PTM) that plays a role in a wide variety of cellular processes. To study the enzymes responsible for the establishment, recognition, and removal of this PTM, stable analogues are invaluable tools. We describe the design and synthesis of a 4-thioribosyl APRr peptide that has been assembled by solid phase synthesis. The key 4-thioribosyl serine building block was obtained in a stereoselective glycosylation reaction using an alkynylbenzoate 4-thioribosyl donor.
Topics: Adenosine Diphosphate Ribose; ADP-Ribosylation; Protein Processing, Post-Translational; Peptides; Glycosylation; Adenosine Diphosphate
PubMed: 37338412
DOI: 10.1021/acs.orglett.3c01554 -
Current Opinion in Obstetrics &... Feb 2021To highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials. (Review)
Review
PURPOSE OF REVIEW
To highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials.
RECENT FINDINGS
The use of PARP inhibition (PARPi) for frontline maintenance offers substantial clinical benefit in patients with homologous recombination-deficient tumors. However, expanding PARPi from recurrent therapy to frontline maintenance may potentially result in more PARPi resistant tumors earlier in the treatment continuum and data for the use of PARPi after PARPi remain limited. Clinical evidence demonstrates tumors may develop resistance to PARPi through demethylation of the BRCA promoter or BRCA reversion mutations. Multiple clinical trials investigating therapeutic strategies to overcome resistance, such as combinations of PARPi with antiangiogenic drugs, PI3K/AKT/mTOR, or MEK inhibitors have already been reported and more are ongoing. Furthermore, increasing the amount of DNA damage in the tumor using chemotherapy or cell cycle inhibitors such as ATM, ATR/CHK1/WEE1 is also under exploration.
SUMMARY
There is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance. PARPi represent a class of drugs that have significantly impacted the treatment and maintenance of ovarian cancer; as the use of PARPi increases, better understanding of resistance mechanisms is essential.
Topics: Adenosine Diphosphate; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Ribose
PubMed: 33315700
DOI: 10.1097/GCO.0000000000000678 -
Chemical Reviews Dec 2019Inorganic polyphosphates (polyP) consist of linear chains of orthophosphate residues, linked by high-energy phosphoanhydride bonds. They are evolutionarily old... (Review)
Review
Inorganic polyphosphates (polyP) consist of linear chains of orthophosphate residues, linked by high-energy phosphoanhydride bonds. They are evolutionarily old biopolymers that are present from bacteria to man. No other molecule concentrates as much (bio)chemically usable energy as polyP. However, the function and metabolism of this long-neglected polymer are scarcely known, especially in higher eukaryotes. In recent years, interest in polyP experienced a renaissance, beginning with the discovery of polyP as phosphate source in bone mineralization. Later, two discoveries placed polyP into the focus of regenerative medicine applications. First, polyP shows morphogenetic activity, i.e., induces cell differentiation via gene induction, and, second, acts as an energy storage and donor in the extracellular space. Studies on acidocalcisomes and mitochondria provided first insights into the enzymatic basis of eukaryotic polyP formation. In addition, a concerted action of alkaline phosphatase and adenylate kinase proved crucial for ADP/ATP generation from polyP. PolyP added extracellularly to mammalian cells resulted in a 3-fold increase of ATP. The importance and mechanism of this phosphotransfer reaction for energy-consuming processes in the extracellular matrix are discussed. This review aims to give a critical overview about the formation and function of this unique polymer that is capable of storing (bio)chemically useful energy.
Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Energy Metabolism; Extracellular Matrix; Humans; Polyphosphates; Thermodynamics
PubMed: 31738523
DOI: 10.1021/acs.chemrev.9b00460 -
GeroScience Dec 2023Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and...
The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).
Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH (flavin adenine dinucleotide), O (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).
Topics: Mitochondria; Adenosine Triphosphate; Adenosine Diphosphate; Peptides
PubMed: 37462785
DOI: 10.1007/s11357-023-00861-y -
Indian Journal of Cancer Mar 2022Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor... (Review)
Review
Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.
Topics: Adenosine Diphosphate; Adenosine Diphosphate Ribose; Breast Neoplasms; Female; Humans; Receptor, ErbB-2; Ribose
PubMed: 35343197
DOI: 10.4103/ijc.IJC_30_21