Introduction: Checkpoint kinase 1 (CHK1) inhibitors have been in development for two decades. The initial CHK1 inhibitor staurosporine analog, UCN01, entered clinical trials whilst it was still ...considered to act via PKC inhibition; only later were trials performed in a more focused fashion to determine whether CHK1 inhibition could dysregulate cell cycle checkpoints. Many of the subsequently synthesized more specific CHK1 inhibitors have failed because of poor PK/PD or cumulative normal tissue toxicities in patients. CHK1 inhibitor monotherapy often demonstrates limited efficacy and in general, must be combined with other agents. The combination of CHK1 inhibitors with modern signaling regulators may be a better therapeutic strategy.
Areas covered: This review discusses the history of, and translational use of CHK1 inhibitors; the latest generation of CHK1 inhibitors to enter clinic development are also examined.
Expert opinion: Some CHK1 inhibitors can be administered safely, but that when they are combined with traditional cytotoxic DNA damaging agents, the normal tissue toxicities outweigh the very modest gains in therapeutic efficacy. Researchers need to think outside of the box and consider how CHK1 inhibitors can be combined with other signal transduction modulators such as MEK1/2 and PARP1 inhibitors to kill tumor cells.
The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) ...inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737+/-roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737-induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737+roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia.
Bile acids as regulatory molecules Hylemon, Phillip B.; Zhou, Huiping; Pandak, William M. ...
Journal of lipid research,
08/2009, Letnik:
50, Številka:
8
Journal Article
Recenzirano
Odprti dostop
In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of cholesterol in the gallbladder ...and for stimulating the absorption of cholesterol, fat-soluble vitamins, and lipids from the intestines. However, during the last two decades, it has been discovered that bile acids are regulatory molecules. Bile acids have been discovered to activate specific nuclear receptors (farnesoid X receptor, preganane X receptor, and vitamin D receptor), G protein coupled receptor TGR5 (TGR5), and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT, and ERK 1/2) in cells in the liver and gastrointestinal tract. Activation of nuclear receptors and cell signaling pathways alter the expression of numerous genes encoding enzyme/proteins involved in the regulation of bile acid, glucose, fatty acid, lipoprotein synthesis, metabolism, transport, and energy metabolism. They also play a role in the regulation of serum triglyceride levels in humans and rodents. Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning from the intestines to the liver following a meal. In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways.—Hylemon, P. B., H. Zhou, W. M. Pandak, S. Ren, G. Gil, and P. Dent. Bile acids as regulatory molecules.
Bile acids have been shown to be important regulatory molecules for cells in the liver and gastrointestinal tract. They can activate various cell signaling pathways including extracellular regulated ...kinase (ERK)1/2 and protein kinase B (AKT) as well as the G‐protein–coupled receptor (GPCR) membrane‐type bile acid receptor (TGR5/M‐BAR). Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids has been reported to be sensitive to pertussis toxin (PTX) and dominant‐negative Gαi in primary rodent hepatocytes. However, the GPCRs responsible for activation of these pathways have not been identified. Screening GPCRs in the lipid‐activated phylogenetic family (expressed in HEK293 cells) identified sphingosine‐1‐phosphate receptor 2 (S1P2) as being activated by taurocholate (TCA). TCA, taurodeoxycholic acid (TDCA), tauroursodeoxycholic acid (TUDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and S1P‐induced activation of ERK1/2 and AKT were significantly inhibited by JTE‐013, a S1P2 antagonist, in primary rat hepatocytes. JTE‐013 significantly inhibited hepatic ERK1/2 and AKT activation as well as short heterodimeric partner (SHP) mRNA induction by TCA in the chronic bile fistula rat. Knockdown of the expression of S1P2 by a recombinant lentivirus encoding S1P2 shRNA markedly inhibited the activation of ERK1/2 and AKT by TCA and S1P in rat primary hepatocytes. Primary hepatocytes prepared from S1P2 knock out (S1P2−/−) mice were significantly blunted in the activation of the ERK1/2 and AKT pathways by TCA. Structural modeling of the S1P receptors indicated that only S1P2 can accommodate TCA binding. In summary, all these data support the hypothesis that conjugated bile acids activate the ERK1/2 and AKT signaling pathways primarily through S1P2 in primary rodent hepatocytes. (HEPATOLOGY 2012)
Targeting the Bcl-2 family for cancer therapy Thomas, Shibu; Quinn, Bridget A; Das, Swadesh K ...
Expert opinion on therapeutic targets,
01/2013, Letnik:
17, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Introduction:
Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well ...documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation.
Areas covered:
This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 family proteins, recent approaches use small molecule inhibitors (SMIs) and peptides. Structural similarity of the Bcl-2 family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics.
Expert opinion:
Strategies to specifically identify and inhibit critical determinants that promote therapy resistance and tumor progression represent viable approaches for developing effective cancer therapies. From a clinical perspective, pretreatment with novel, potent Bcl-2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. Identifying SMIs with broader and higher affinities for inhibiting all of the Bcl-2 pro-survival proteins will facilitate development of superior cancer therapies.
Background Range of motion (ROM) is a critical component of a physician's evaluation for many consultations. The purpose of this study was to evaluate if teleconference goniometry could be as ...accurate as clinical goniometry. Methods Forty-eight volunteers participated in the study. There was a sample size of 52 elbows. Each measurement was recorded consecutively in person, through teleconference, and still-shot photography by two researchers trained in goniometry. Measurements of maximum elbow flexion and extension were taken and recorded. Results Teleconference goniometry had a high agreement with clinical goniometry (Pearson coefficient: flexion: 0.93, Extension: 0.87). Limits of agreement found from the Bland-Altman test were 7⁰ and -3⁰ for flexion and 10.4⁰ and -7.4⁰ for extension. A t-test revealed a P-value of less than 0.001 between teleconference and clinical measurements, proving the data are significant. Conclusions ROM measurements through a teleconferencing medium are comparable to clinical ROM measurements. This would allow for interactive elbow ROM assessment with the orthopedist without having to incorporate travel time and expenses.
It is historically well known that signaling by the PI3K-AKT and MEK1/2-ERK1/2 pathways in a cell type-dependent fashion can collaborate to maintain cell viability.
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Signaling pathways can also ...crosstalk with each other wherein one pathway can signal to either enhance or suppress signaling by another.
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Signaling by the ERK1/2 pathway can also stimulate release of growth factors which can feed back onto tumor cells to re-energize signaling pathways.
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The studies described by Toulany et al. add to this knowledge base by examining the relationship between PI3K-AKT and MEK1/2-ERK1/2 pathway signaling, EGF receptor signaling, K-RAS function, and tumor cell survival.
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Summary
Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI‐32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large‐B cell lymphoma (DLBCL) and mantle cell ...lymphoma (MCL) cells, including those highly resistant to bortezomib. Co‐administration of PCI‐32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre‐ or activated B‐cell‐like‐DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)‐κB (NFKB1) inactivation, down‐regulation of Mcl‐1 (MCL1), Bcl‐xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib‐resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI‐32765/bortezomib regimens displayed minimal toxicity toward normal CD34+ bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF‐κB “super‐repressor” (IκBαser34/36) increased both PCI‐32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant‐negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI‐32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI‐32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.
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