YKL-5-124 is a potent and selective covalent inhibitor of CDK7 that induces cell cycle arrest at the G1/S transition. It inhibits E2F-driven gene expression on-target through covalent bonding with CDK7. Unlike THZ1, another CDK7 inhibitor, YKL-5-124 does not change RNA polymerase II phosphorylation but inhibition can be achieved by combining it with THZ531, a CDK12/13 inhibitor, revealing potential redundancies between CDKs. Artesunate arrests the cell cycle in G2/M phase and induces senescence and autophagy in colorectal cancer cells by promoting mitochondrial reactive oxygen species generation. It increases intracellular
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNT) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
This study investigated the mechanisms by which the HDAC inhibitor vorinostat induces apoptosis in acute myeloid leukemia (AML) cells. The results showed that vorinostat causes early DNA damage and activation of p38 MAPK in AML cell lines. Activation of p38 was required for vorinostat-induced G2/M cell cycle arrest and apoptosis. However, the role of p38 activation varied among different HDAC inhibitors, being pro-apoptotic for vorinostat but not necessary for apoptosis induced by other inhibitors. This highlights the importance of understanding specific mechanisms of individual HDAC inhibitors.
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a type of
cancer that starts in the blood-forming cells of the bone marrow and invades the blood.
Each human cell contains 23 pairs of chromosomes. Most cases of CML start when a "swapping"
of chromosomal material (DNA) occurs between chromosomes 9 and 22 during cell division due
to attack of DNA by radiation or other damage. Part of chromosome 9 goes to 22 and part of 22
goes to 9. This is known as a translocation and gives rise to a chromosome 22 that is shorter than
normal. This new abnormal chromosome is known as the Philadelphia chromosome.
This document summarizes research on the disruption of the cyclin D/CDK/INK4/Rb regulatory pathway in human neuroblastoma cell lines. The researchers found that 17 neuroblastoma cell lines highly expressed the CDK inhibitors p16INK4a and p18INK4c, but CDK6 kinase activity and phosphorylated Rb were still detected. One cell line was found to have a mutation in CDK6 that disrupts p16INK4a binding and prevents its inhibition of CDK6, bypassing the cell cycle block. The mechanisms allowing CDK6 activity in the other 16 cell lines despite high p16INK4a levels is unknown.
Molecular mechanisms of action and potential biomarkers of growth inhibition ...Enrique Moreno Gonzalez
Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.
1) GRK5 regulates prostate cancer cell migration and invasion in vitro and tumor growth and metastasis in vivo.
2) GRK5 phosphorylates the cytoskeletal protein moesin, regulating its subcellular distribution and localization to the cell periphery.
3) Phosphorylation of moesin at threonine 66 by GRK5 is important for cell spreading, and mutation of this site reduces cell spreading.
Effectiveness of Resveratrol on Metastasis: A Reviewiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kd...Mark Lipstein
This document summarizes a study examining the combination of a novel PI3Kδ inhibitor, TGR-1202, with the proteasome inhibitor carfilzomib for treating hematological malignancies. The study found that TGR-1202 synergizes strongly with carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary cells by silencing c-Myc translation. This synergistic effect is driven by TGR-1202's unexpected additional activity of inhibiting CK1ε, which contributes to repressing phosphorylation of 4E-BP1 and lowering c-Myc protein levels. The results suggest that TGR-1202, as a dual PI3Kδ/CK1ε inhibitor, may have
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNT) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
This study investigated the mechanisms by which the HDAC inhibitor vorinostat induces apoptosis in acute myeloid leukemia (AML) cells. The results showed that vorinostat causes early DNA damage and activation of p38 MAPK in AML cell lines. Activation of p38 was required for vorinostat-induced G2/M cell cycle arrest and apoptosis. However, the role of p38 activation varied among different HDAC inhibitors, being pro-apoptotic for vorinostat but not necessary for apoptosis induced by other inhibitors. This highlights the importance of understanding specific mechanisms of individual HDAC inhibitors.
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a type of
cancer that starts in the blood-forming cells of the bone marrow and invades the blood.
Each human cell contains 23 pairs of chromosomes. Most cases of CML start when a "swapping"
of chromosomal material (DNA) occurs between chromosomes 9 and 22 during cell division due
to attack of DNA by radiation or other damage. Part of chromosome 9 goes to 22 and part of 22
goes to 9. This is known as a translocation and gives rise to a chromosome 22 that is shorter than
normal. This new abnormal chromosome is known as the Philadelphia chromosome.
This document summarizes research on the disruption of the cyclin D/CDK/INK4/Rb regulatory pathway in human neuroblastoma cell lines. The researchers found that 17 neuroblastoma cell lines highly expressed the CDK inhibitors p16INK4a and p18INK4c, but CDK6 kinase activity and phosphorylated Rb were still detected. One cell line was found to have a mutation in CDK6 that disrupts p16INK4a binding and prevents its inhibition of CDK6, bypassing the cell cycle block. The mechanisms allowing CDK6 activity in the other 16 cell lines despite high p16INK4a levels is unknown.
Molecular mechanisms of action and potential biomarkers of growth inhibition ...Enrique Moreno Gonzalez
Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.
1) GRK5 regulates prostate cancer cell migration and invasion in vitro and tumor growth and metastasis in vivo.
2) GRK5 phosphorylates the cytoskeletal protein moesin, regulating its subcellular distribution and localization to the cell periphery.
3) Phosphorylation of moesin at threonine 66 by GRK5 is important for cell spreading, and mutation of this site reduces cell spreading.
Effectiveness of Resveratrol on Metastasis: A Reviewiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kd...Mark Lipstein
This document summarizes a study examining the combination of a novel PI3Kδ inhibitor, TGR-1202, with the proteasome inhibitor carfilzomib for treating hematological malignancies. The study found that TGR-1202 synergizes strongly with carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary cells by silencing c-Myc translation. This synergistic effect is driven by TGR-1202's unexpected additional activity of inhibiting CK1ε, which contributes to repressing phosphorylation of 4E-BP1 and lowering c-Myc protein levels. The results suggest that TGR-1202, as a dual PI3Kδ/CK1ε inhibitor, may have
Annals of Mutagenesis is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Mutagenesis.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Mutagenesis. Annals of Mutagenesis accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of mutagenesis.
Annals of Mutagenesis strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Apoptosis, or programmed cell death, is an internally controlled suicide program where cells are removed with minimal disruption of surrounding tissue. It plays important roles in development, tissue homeostasis, and defense against infection and cancer. There are two main apoptotic pathways - the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Both pathways activate caspases, cysteine proteases that cleave proteins to execute the cell death program through processes like DNA fragmentation and formation of apoptotic bodies. Deregulation of apoptosis contributes to cancer development by allowing damaged or unnecessary cells to survive. Targeting the apoptotic pathway is a strategy for cancer treatment.
By using flow cytometry, staining dyes are needed. Creative Bioarray can choose different dyes to perform the assays, including propidium iodide (PI), BrdU, 7-amino actinomycin-D (7-AAD), Hoechst 33342 and 33258, and 4’6’-diamidino-2-phenylindole (DAPI), based on the customer’s applications or requirements.
https://www.creative-bioarray.com/cell-cycle-assays.htm
Cell cycle refers to the set of events through which a cell grows, replicates its genome, and ultimately divides into two daughter cells through the process of mitosis.
https://www.creative-bioarray.com/cell-cycle-assays.htm
Cell cycle regulation is controlled by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Cyclins bind to and activate CDKs to promote cell cycle progression. CDK inhibitors like p16 and p21 inhibit CDK activity to induce cell cycle arrest. Checkpoints like the DNA damage checkpoint ensure DNA integrity before replication or division. Dysregulation of these regulators can lead to uncontrolled cell growth and cancer.
This research article investigates the effects of the natural flavonoid luteolin on colon cancer cells. The researchers found that physiological concentrations of luteolin induce apoptosis in colon cancer cells by increasing levels of the sphingolipid ceramide. Luteolin inhibits the conversion of ceramide to more complex sphingolipids and disrupts the transport of ceramide between organelles. These effects are mediated by luteolin's ability to inhibit the enzymes sphingosine kinase 2 and Akt, thereby reducing levels of the molecule sphingosine-1-phosphate which normally promotes cell survival. Overall, the study reveals that luteolin exerts anticancer effects by targeting the balance between ceramide and sphingosine-1-
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...eshaasini
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 Induced PI3K/Akt/mTor Pathway in the Regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive
cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC
directly related to the disease agressivity. Télomérase, is expressed
by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by
IL-6 is activated in the HCC. Our aim is to investigate the effect
of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/
PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...eshaasini
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
The document summarizes research on developing glycopeptide analogues of PSGL-1 that inhibit P-selectin. Key findings include:
1) Researchers developed an efficient multi-step synthesis of a C2 O-glycan building block, overcoming prior limitations.
2) Using the building block, they synthesized glycopeptide mimics of PSGL-1's N-terminus via solid phase peptide synthesis, replacing acid-labile tyrosine sulfates with stable sulfonates.
3) Screening identified a compound, GSnP-6, with nanomolar affinity for P-selectin that potently blocks P-selectin/PSGL-1 interactions in vitro and
The Notch signaling pathway regulates cell proliferation, stem cell maintenance, differentiation, and homeostasis. Mammals have four Notch receptors that are single-pass transmembrane proteins composed of extracellular and intracellular portions. Notch signaling is initiated by ligand binding and proteolytic cleavage of the receptor. The cleaved intracellular domain then translocates to the nucleus to regulate transcription of target genes. Crosstalk between signaling pathways like Notch and YAP/TAZ can impact processes like stem cell self-renewal and differentiation. Notch signaling can be inhibited by blocking receptor cleavage with γ-secretase inhibitors or interfering with ligand-receptor interaction using monoclonal antibodies.
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new
agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to
alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer
chemotherapeutic agents either because they are directly involved in their metabolism or help
eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid
peroxides). Furthermore, this cellular stress activates the nuclear factor-erythroid 2 p45-related
factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are
upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance
drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines,
mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this
mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the
elimination of progestogens and are involved in hormonal-dependent malignancies. They are
upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance.
Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug
resistance and/or synergize the effects of existing drugs.
Human aldo-keto reductases (AKR) of the 1A, 1B, 1C and 1D subfamilies are involved in the pre-receptor regulation of nuclear (steroid hormone and orphan) receptors by regulating the local concentrations of their lipophilic ligands. AKR1C3 is one of the most interesting isoforms. It was cloned from human prostate and the recombinant protein was found to function as a 3-, 17- and 20-ketosteroid reductase with a preference for the conversion of Δ4-androstene-3,17- dione to testosterone implicating this enzyme in the local production of active androgens within the prostate. Using a validated isoform specific real-time RT-PCR procedure the AKR1C3 transcript was shown to be more abundant in primary cultures of epithelial cells than stromal cells, and its expression in stromal cells increased with benign and malignant disease. Using a validated isoform specific monoclonal Ab, AKR1C3 protein expression was also detected in prostate epithelial cells by immunoblot analysis.
Immunohistochemical staining of prostate tissue showed that AKR1C3 was expressed in adenocarcinoma and surprisingly high expression was observed in the endothelial cells. These cells are a rich source of prostaglandin G/H synthase 2 (COX-2) and
vasoactive prostaglandins (PG) and thus the ability of recombinant AKR1C enzymes to act as PGF synthases was compared. AKR1C3 had the highest catalytic efficiency (kcat/Km) for the 11-ketoreduction of PGD2 to yield 9α,11β-PGF2 raising the prospect that AKR1C3 may govern ligand access to peroxisome proliferator activated receptor (PPARγ). Activation of PPARγ is often a pro-apoptotic signal and/or leads to terminal differentiation, while 9α,11β- PGF2 is a pro-proliferative signal. AKR1C3 is potently inhibited by non-steroidal anti- inflammatory drugs suggesting that the cancer chemopreventive properties of these agents may be mediated either by inhibition of AKR1C3 or COX. To discriminate between these effects we developed potent AKR1C inhibitors based on N-phenylanthranilic acids that do not inhibit COX-1 or COX-2. These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9α,11β-PGF2.
Anindya seminar 1 growth factors and cell cycle signalling in pathogenesis of...Kazi Manir
The document discusses several key concepts regarding the molecular basis of cancer including:
1. Cancer is caused by mutations in proto-oncogenes, tumor suppressor genes, DNA repair genes, and apoptotic genes.
2. Self-sufficiency in growth signals is achieved through mutations in proto-oncogenes encoding growth factors, growth factor receptors, signal transducing proteins, and cell cycle regulators.
3. Examples of targeted cancer therapies include monoclonal antibodies, tyrosine kinase inhibitors, hormones, and hormonal agents.
This document discusses a study that investigated how inhibiting the epidermal growth factor receptor (EGFR) signaling pathway with the anti-EGFR monoclonal antibody IMC-C225 affects nuclear factor-kappa B (NF-κB) activation and regulation of apoptosis genes in human pancreatic cancer cells. The study found that IMC-C225 treatment blocked EGFR activation in pancreatic cancer cells, leading to decreased NF-κB DNA binding activity. This downregulation of NF-κB by IMC-C225 resulted in decreased expression of the anti-apoptotic genes bcl-xl and bfl-1. Therefore, targeting the NF-κB pathway with an anti-EGFR antibody may help restore apoptosis in pancreatic cancer cells and
This document summarizes a study examining the pharmacological effects of asiatic acid (AA), a compound extracted from Centella asiatica, on glioblastoma cells under normoxic and hypoxic conditions. Key findings include:
1) AA reduced glioblastoma cell viability in a time- and concentration-dependent manner, with lower EC50 values than cisplatin after short treatment times.
2) Under normoxia, AA treatment did not significantly affect cell proliferation or cell cycle progression at the EC25 concentration.
3) Under hypoxia, AA treatment resulted in significantly more apoptosis in glioblastoma cells compared to cisplatin treatment.
4) AA treatment reduced glioblastoma
Annals of Mutagenesis is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Mutagenesis.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Mutagenesis. Annals of Mutagenesis accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of mutagenesis.
Annals of Mutagenesis strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Apoptosis, or programmed cell death, is an internally controlled suicide program where cells are removed with minimal disruption of surrounding tissue. It plays important roles in development, tissue homeostasis, and defense against infection and cancer. There are two main apoptotic pathways - the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Both pathways activate caspases, cysteine proteases that cleave proteins to execute the cell death program through processes like DNA fragmentation and formation of apoptotic bodies. Deregulation of apoptosis contributes to cancer development by allowing damaged or unnecessary cells to survive. Targeting the apoptotic pathway is a strategy for cancer treatment.
By using flow cytometry, staining dyes are needed. Creative Bioarray can choose different dyes to perform the assays, including propidium iodide (PI), BrdU, 7-amino actinomycin-D (7-AAD), Hoechst 33342 and 33258, and 4’6’-diamidino-2-phenylindole (DAPI), based on the customer’s applications or requirements.
https://www.creative-bioarray.com/cell-cycle-assays.htm
Cell cycle refers to the set of events through which a cell grows, replicates its genome, and ultimately divides into two daughter cells through the process of mitosis.
https://www.creative-bioarray.com/cell-cycle-assays.htm
Cell cycle regulation is controlled by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Cyclins bind to and activate CDKs to promote cell cycle progression. CDK inhibitors like p16 and p21 inhibit CDK activity to induce cell cycle arrest. Checkpoints like the DNA damage checkpoint ensure DNA integrity before replication or division. Dysregulation of these regulators can lead to uncontrolled cell growth and cancer.
This research article investigates the effects of the natural flavonoid luteolin on colon cancer cells. The researchers found that physiological concentrations of luteolin induce apoptosis in colon cancer cells by increasing levels of the sphingolipid ceramide. Luteolin inhibits the conversion of ceramide to more complex sphingolipids and disrupts the transport of ceramide between organelles. These effects are mediated by luteolin's ability to inhibit the enzymes sphingosine kinase 2 and Akt, thereby reducing levels of the molecule sphingosine-1-phosphate which normally promotes cell survival. Overall, the study reveals that luteolin exerts anticancer effects by targeting the balance between ceramide and sphingosine-1-
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...eshaasini
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 Induced PI3K/Akt/mTor Pathway in the Regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive
cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC
directly related to the disease agressivity. Télomérase, is expressed
by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by
IL-6 is activated in the HCC. Our aim is to investigate the effect
of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/
PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...eshaasini
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
Involvement of Interleukin-6 induced PI3K/Akt/mTor pathway in the regulation ...semualkaira
Hepatocellular Carcinoma (HCC) is an invasive cancer. Alphafoetoprotein (AFP) is a diagnostic marker for HCC directly related to the disease agressivity. Telomerase, is expressed by 90% of HCC. PI3K/Akt/mTOR pathway wich is regulated by IL-6 is activated in the HCC. Our aim is to investigate the effect of IL-6 on AFP and telomerase secretion in HepG2/C3A and PLC/ PRF/5 cell lines.
The document summarizes research on developing glycopeptide analogues of PSGL-1 that inhibit P-selectin. Key findings include:
1) Researchers developed an efficient multi-step synthesis of a C2 O-glycan building block, overcoming prior limitations.
2) Using the building block, they synthesized glycopeptide mimics of PSGL-1's N-terminus via solid phase peptide synthesis, replacing acid-labile tyrosine sulfates with stable sulfonates.
3) Screening identified a compound, GSnP-6, with nanomolar affinity for P-selectin that potently blocks P-selectin/PSGL-1 interactions in vitro and
The Notch signaling pathway regulates cell proliferation, stem cell maintenance, differentiation, and homeostasis. Mammals have four Notch receptors that are single-pass transmembrane proteins composed of extracellular and intracellular portions. Notch signaling is initiated by ligand binding and proteolytic cleavage of the receptor. The cleaved intracellular domain then translocates to the nucleus to regulate transcription of target genes. Crosstalk between signaling pathways like Notch and YAP/TAZ can impact processes like stem cell self-renewal and differentiation. Notch signaling can be inhibited by blocking receptor cleavage with γ-secretase inhibitors or interfering with ligand-receptor interaction using monoclonal antibodies.
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new
agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to
alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer
chemotherapeutic agents either because they are directly involved in their metabolism or help
eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid
peroxides). Furthermore, this cellular stress activates the nuclear factor-erythroid 2 p45-related
factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are
upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance
drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines,
mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this
mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the
elimination of progestogens and are involved in hormonal-dependent malignancies. They are
upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance.
Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug
resistance and/or synergize the effects of existing drugs.
Human aldo-keto reductases (AKR) of the 1A, 1B, 1C and 1D subfamilies are involved in the pre-receptor regulation of nuclear (steroid hormone and orphan) receptors by regulating the local concentrations of their lipophilic ligands. AKR1C3 is one of the most interesting isoforms. It was cloned from human prostate and the recombinant protein was found to function as a 3-, 17- and 20-ketosteroid reductase with a preference for the conversion of Δ4-androstene-3,17- dione to testosterone implicating this enzyme in the local production of active androgens within the prostate. Using a validated isoform specific real-time RT-PCR procedure the AKR1C3 transcript was shown to be more abundant in primary cultures of epithelial cells than stromal cells, and its expression in stromal cells increased with benign and malignant disease. Using a validated isoform specific monoclonal Ab, AKR1C3 protein expression was also detected in prostate epithelial cells by immunoblot analysis.
Immunohistochemical staining of prostate tissue showed that AKR1C3 was expressed in adenocarcinoma and surprisingly high expression was observed in the endothelial cells. These cells are a rich source of prostaglandin G/H synthase 2 (COX-2) and
vasoactive prostaglandins (PG) and thus the ability of recombinant AKR1C enzymes to act as PGF synthases was compared. AKR1C3 had the highest catalytic efficiency (kcat/Km) for the 11-ketoreduction of PGD2 to yield 9α,11β-PGF2 raising the prospect that AKR1C3 may govern ligand access to peroxisome proliferator activated receptor (PPARγ). Activation of PPARγ is often a pro-apoptotic signal and/or leads to terminal differentiation, while 9α,11β- PGF2 is a pro-proliferative signal. AKR1C3 is potently inhibited by non-steroidal anti- inflammatory drugs suggesting that the cancer chemopreventive properties of these agents may be mediated either by inhibition of AKR1C3 or COX. To discriminate between these effects we developed potent AKR1C inhibitors based on N-phenylanthranilic acids that do not inhibit COX-1 or COX-2. These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9α,11β-PGF2.
Anindya seminar 1 growth factors and cell cycle signalling in pathogenesis of...Kazi Manir
The document discusses several key concepts regarding the molecular basis of cancer including:
1. Cancer is caused by mutations in proto-oncogenes, tumor suppressor genes, DNA repair genes, and apoptotic genes.
2. Self-sufficiency in growth signals is achieved through mutations in proto-oncogenes encoding growth factors, growth factor receptors, signal transducing proteins, and cell cycle regulators.
3. Examples of targeted cancer therapies include monoclonal antibodies, tyrosine kinase inhibitors, hormones, and hormonal agents.
This document discusses a study that investigated how inhibiting the epidermal growth factor receptor (EGFR) signaling pathway with the anti-EGFR monoclonal antibody IMC-C225 affects nuclear factor-kappa B (NF-κB) activation and regulation of apoptosis genes in human pancreatic cancer cells. The study found that IMC-C225 treatment blocked EGFR activation in pancreatic cancer cells, leading to decreased NF-κB DNA binding activity. This downregulation of NF-κB by IMC-C225 resulted in decreased expression of the anti-apoptotic genes bcl-xl and bfl-1. Therefore, targeting the NF-κB pathway with an anti-EGFR antibody may help restore apoptosis in pancreatic cancer cells and
This document summarizes a study examining the pharmacological effects of asiatic acid (AA), a compound extracted from Centella asiatica, on glioblastoma cells under normoxic and hypoxic conditions. Key findings include:
1) AA reduced glioblastoma cell viability in a time- and concentration-dependent manner, with lower EC50 values than cisplatin after short treatment times.
2) Under normoxia, AA treatment did not significantly affect cell proliferation or cell cycle progression at the EC25 concentration.
3) Under hypoxia, AA treatment resulted in significantly more apoptosis in glioblastoma cells compared to cisplatin treatment.
4) AA treatment reduced glioblastoma
Executive Directors Chat Leveraging AI for Diversity, Equity, and InclusionTechSoup
Let’s explore the intersection of technology and equity in the final session of our DEI series. Discover how AI tools, like ChatGPT, can be used to support and enhance your nonprofit's DEI initiatives. Participants will gain insights into practical AI applications and get tips for leveraging technology to advance their DEI goals.
How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
This presentation was provided by Steph Pollock of The American Psychological Association’s Journals Program, and Damita Snow, of The American Society of Civil Engineers (ASCE), for the initial session of NISO's 2024 Training Series "DEIA in the Scholarly Landscape." Session One: 'Setting Expectations: a DEIA Primer,' was held June 6, 2024.
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
ISO/IEC 27001, ISO/IEC 42001, and GDPR: Best Practices for Implementation and...PECB
Denis is a dynamic and results-driven Chief Information Officer (CIO) with a distinguished career spanning information systems analysis and technical project management. With a proven track record of spearheading the design and delivery of cutting-edge Information Management solutions, he has consistently elevated business operations, streamlined reporting functions, and maximized process efficiency.
Certified as an ISO/IEC 27001: Information Security Management Systems (ISMS) Lead Implementer, Data Protection Officer, and Cyber Risks Analyst, Denis brings a heightened focus on data security, privacy, and cyber resilience to every endeavor.
His expertise extends across a diverse spectrum of reporting, database, and web development applications, underpinned by an exceptional grasp of data storage and virtualization technologies. His proficiency in application testing, database administration, and data cleansing ensures seamless execution of complex projects.
What sets Denis apart is his comprehensive understanding of Business and Systems Analysis technologies, honed through involvement in all phases of the Software Development Lifecycle (SDLC). From meticulous requirements gathering to precise analysis, innovative design, rigorous development, thorough testing, and successful implementation, he has consistently delivered exceptional results.
Throughout his career, he has taken on multifaceted roles, from leading technical project management teams to owning solutions that drive operational excellence. His conscientious and proactive approach is unwavering, whether he is working independently or collaboratively within a team. His ability to connect with colleagues on a personal level underscores his commitment to fostering a harmonious and productive workplace environment.
Date: May 29, 2024
Tags: Information Security, ISO/IEC 27001, ISO/IEC 42001, Artificial Intelligence, GDPR
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2. Itraconazole
Inhibits cell cycle at G1 phase; also SMO antagonist
Itraconazole inhibits the Hedgehog signaling pathway
thereby inducing autophagy-mediated apoptosis of colon
cancer cells.
Itraconazole is an antifungal drug of the triazole class, with a high
bioavailability, broad spectrum and few side effects. It is widely used
for the prevention and treatment of systemic fungal infections5,6.
Recent studies have shown that itraconazole can induce autophagy
thereby inhibiting glioblastoma growth via downregulation of steroid
carrier protein 2 expression and redistribution of intracellular
cholesterol.
Mechanism: Itraconazole acts by inhibiting the fungal cytochrome P-450 dependent enzyme
lanosterol 14-α-demethylase. When this enzyme is inhibited it blocks the conversion of
lanosterol to ergosterol, which disrupts fungal cell membrane synthesis. Itraconazole exhibits
fungistatic (slows the growth) activity against yeast-like fungi and fungicidal (kills the fungus)
activity against Aspergillus spp.
In adult tissue, abnormal activation of the Hedgehog signaling
pathway is associated with the development of several cancer types
including breast, gastric, pancreatic and ovarian cancers as well as
hepatocellular carcinoma15–18. Binding of Sonic Hedgehog (shh) to the
Hedgehog receptor protein patched homolog 1 (PTCH1) initiates
activation of the Hedgehog pathway via reduction of smoothened
(SMO) repression, which in turn leads to the zinc-finger transcription
factor Gli family enabled transcription of downstream target genes19. It
3. is known that GANT61, a small molecule inhibitor of Gli1 and Gli2,
induces autophagy of human hepatocellular carcinomas20. Another
Hedgehog pathway inhibitor vismodegib, which is an antagonist of
SMO, induces autophagy of chronic myeloid leukemia cells, thereby
promoting apoptosis and decreased drug resistance21. Studies have
shown that itraconazole is not only effective for the treatment of
fungal infections, but also can inhibit cancer cell growth by
inactivating the Hedgehog pathway22. In the present study, the role of
itraconazole on Hedgehog pathway related autophagy has been
evaluated.
Cyclin-dependent kinase 7 (CDK7) regulates both cell cycle and transcription, but its precise role
remains elusive. We previously described THZ1, a CDK7 inhibitor, which dramatically inhibits
superenhancer-associated gene expression. However, potent CDK12/13 off-target activity obscured
CDK7s contribution to this phenotype. Here, we describe the discovery of a highly selective covalent
CDK7 inhibitor. YKL-5- 124 causes arrest at the G1/S transition and inhibition of E2F-driven gene
expression; these effects are rescued by a CDK7 mutant unable to covalently engage YKL-5-124,
demonstrating on-target specificity. Unlike THZ1, treatment with YKL-5-124 resulted in no change to
RNA polymerase II C-terminal domain phosphorylation; however, inhibition could be reconstituted
by combining YKL-5-124 and THZ531, a selective CDK12/13 inhibitor, revealing potential
redundancies in CDK control of gene transcription. These findings highlight the importance of
CDK7/12/13 polypharmacology for anti-cancer activity of THZ1 and posit that selective inhibition of
CDK7 may be useful for treatment of cancers marked by E2F misregulation.
YKL-5-124 Covalently Targets CDK7 Our initial efforts to develop a selective CDK7 inhibitor using
THZ1 (Figure 1A) as a lead compound were not productive. We turned our attention to PF-3758309,
a PAK4 inhibitor (Murray et al., 2010), since molecules from the series of compounds that gave rise
to PF-3758309 are reported to have strong CDK7 inhibitory activity (Rudolph et al., 2015). We
envisioned that the hybridization of the covalent warhead from THZ1 and the pyrrolidinopyrazole
core from PF-3758309 could lead to more selective CDK7 inhibitors. The first compound in the new
series, YKL-1-116 (Figure 1A) (Kalan et al., 2017), showed good selectivity for CDK7 but only
moderate potency, and had minimal anti-proliferative effects on cancer cell lines (Kalan et al., 2017).
Further iterative optimization has focused on tuning the acidity of the aminopyrazole core, gaining
additional hydrophobic interactions with the side-chain residue, and optimizing the length and
trajectory of the covalent warhead that targets C312. This focused medicinal chemistry campaign
yielded YKL-5-124, a potent and selective covalent CDK7 inhibitor, and YKL-5-167, an inactive analog
lacking the acrylamide reactive center and therefore incapable of forming a covalent bond with
CDK7- C312 (Figure 1A). Biochemical evaluation of YKL-5-124 using a fixed time-point, in vitro kinase
assay indicated that YKL-5-124 inhibited CDK7/ Mat1/CycH with an IC50 of 9.7 nM, while the other
CDKs tested biochemically, CDK2 and CDK9, had IC50 values of 1,300 nM and 3,020 nM, respectively.
To more precisely assay the contribution of covalent bond formation to compound inhibitory
activity, we measured kinact/Ki using a kinetic assay that monitors the shift in the electrophoretic
YKL 5-124
Potent and selective CDK7 inhibitor; induces cell cycle arrest at the G1/S transition
4. mobility of a CDK7 peptide substrate following incubation with YKL-5-124 (Blackwell et al., 2009; Tan
et al., 2017). YKL-5-124 and THZ1 displayed similar ki values (1.9 nM and 2.1 nM, respectively)
showing that they achieved nearly equivalent inhibition of CDK7 (Figures 1B, S1A, and S1B).
However, YKL-5-124 exhibited a faster kinact of 103 ms1 nM1 as compared with kinact of 9 ms1 nM1
for of THZ1, demonstrating that YKL-5-124 covalently modifies CDK7 approximately 11-fold faster
than THZ1 (Figures 1B, S1A, and S1B).
10058-F4
Arrests cell cycle at G0/G1
A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and
myeloid differentiation of human acute myeloid leukemia. Exp Hematol.
The protooncogene c-Myc plays an important role in the control of cell proliferation,
apoptosis, and differentiation, and its aberrant expression is frequently seen in multiple
human cancers, including acute myeloid leukemia (AML). As c-Myc heterodimerizes with Max
to transactivate downstream target genes in leukemogenesis. Inhibition of the c-Myc/Max
heterodimerization by the recently identified small-molecule compound, 10058-F4, might be
a novel antileukemic strategy.
10058-F4, a c-Myc inhibitor, markedly increases valproic acid-induced cell death in Jurkat
and CCRF-CEM T-lymphoblastic leukemia cells
ABT 263
Induces G1/G0 phase arrest; Bcl-2 family inhibitor
ABT-263, a new BH3 mimetic, is a potent Bcl-2 family inhibitor that antagonizes Bcl-2
family members (Bcl-2, Bcl-xL and Bcl-w) [9]. It was found safe and effective against
some leukemia, lymphoma, small cell lung cancer, and other malignancies
ABT-263 induces G1/G0-phase arrest, apoptosis and
autophagy in human esophageal cancer cells in vitro
ABT-263 (5–20 μmol/L) dose-dependently induced G1/G0-phase arrest
in the 3 cancer cell lines and induced apoptosis evidenced by
increased the Annexin V-positive cell population and elevated levels of
cleaved caspase 3, cleaved caspase 9 and PARP. We further
demonstrated that ABT-263 treatment markedly increased the
expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and
5. phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780)
proteins that contributed to the G1/G0-phase arrest. Knockdown of
p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover,
ABT-263 treatment enhanced pro-survival autophagy, shown as the
increased LC3-II levels and decreased p62 levels, which counteracted
its anticancer activity. Our results suggest that ABT-263 exerts
cytostatic and cytotoxic effects on human esophageal cancer cells in
vitro and enhances pro-survival autophagy, which counteracts its
anticancer activity.
Artesunate
Arrests cell cycle in G2/M; antimalarial
Artesunate caused excessive mitochondrial ROS to induce cell senescence and inhibit
cell proliferation. (A) Artesunate arrested cell cycle at G0/G1 phase in SW480 and
HCT116.
Although artesunate has been reported to be a promising candidate
for colorectal cancer (CRC) treatment, the underlying mechanisms and
molecular targets of artesunate are yet to be explored. Here, we report
that artesunate acts as a senescence and autophagy inducer to exert
its inhibitory effect on CRC in a reactive oxygen species (ROS)-
dependent manner. In SW480 and HCT116 cells, artesunate treatment
led to mitochondrial dysfunction, drastically promoted mitochondrial
ROS generation, and consequently inhibited cell proliferation by
causing cell cycle arrest at G0/G1 phase as well as subsequent p16-
and p21-mediated cell senescence. Senescent cells underwent
endoplasmic reticulum stress (ERS), and the unfolded protein
response (UPR) was activated via IRE1α signaling, with upregulated
BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further
experiments revealed that autophagy was induced by artesunate
treatment due to oxidative stress and ER stress. In contrast, N-
Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA,
an autophagy inhibitor) restored cell viability and attenuated
autophagy in artesunate-treated cells. Furthermore, cellular free
Ca2+ levels were increased and could be repressed by NAC, 3-MA, and
GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration
reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67
and cyclin D1 expression was downregulated in tumor tissue, while
p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken
6. together, artesunate induces senescence and autophagy to inhibit cell
proliferation in colorectal cancer by promoting excessive ROS
generation.
artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART
arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of
p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II
programmed cell death). In addition, ART stimulated the aggregation of LC3, which is
considered to be a marker of autophagosome formation. We further verified the
transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor,
attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest,
and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by
knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the
chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study
showed that ART induced autophagy in breast cancer cells and indicated that the anticancer
effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast
cancer cells to epirubicin chemotherapy