| Reference | 1. Biofactors. 2017 Nov;43(6):812-820. doi: 10.1002/biof.1380. Epub 2017 Aug 17. <br />
The combination of digoxin and GSK2606414 exerts synergistic anticancer activity
against leukemia in vitro and in vivo. <br />
Zhang XH(1)(2), Wang XY(2)(3), Zhou ZW(4), Bai H(1), Shi L(1), Yang YX(5), Zhou
SF(2), Zhang XC(1). <br />
Author information: <br />
(1)Department of Pediatrics, General Hospital, Ningxia Medical University,
Yinchuan, People/’s Republic of China.
(2)Department of Pharmaceutical Sciences, College of Pharmacy, University of
South Florida, Tampa, FL, USA.
(3)Department of Pharmacy and Institute of Clinical Pharmacology, General
Hospital, Ningxia Medical University, Yinchuan, People/’s Republic of China.
(4)Department of Radiation Oncology, University of Texas Southwestern Medical
Center, Dallas, TX, USA.
(5)Department of Colorectal Surgery, General Hospital, Ningxia Medical
University, Yinchuan, People/’s Republic of China. <br />
Digoxin is a member of cardiac glycosides and recent studies show that digoxin
plays anticancer role in several types of cancer. However, the anticancer effects
and mechanism of digoxin in leukemia is largely unknown. Her, our data show that
digoxin treatment significantly inhibits leukemia cell viability. In addition,
digoxin treatment significantly induced apoptosis and G2/M cell cycle arrest in
leukemia cells. Furthermore, we demonstrated that digoxin treatment inactivate
that oncogenic pathway Akt/mTOR signaling in leukemia cells. In addition, our
data show that digoxin treatment induces activation of unfolded protein response
(UPR) signaling in leukemia cells. Interestingly, our in vitro and in vivo
experiments show that combination treatment of digoxin and UPR inhibitor can
synergistically suppress leukemia growth and induces apoptosis and cell cycle
arrest compared to single drug treatment. In summary, our findings indicate that
digoxin has potential anticancer effects on leukemia. The combination of digoxin
and UPR signaling inhibitor can exerts synergistic anticancer activity against
leukemia. © 2017 BioFactors, 43(6):812-820, 2017. <br />
2. Cell Death Differ. 2017 Jun;24(6):1100-1110. doi: 10.1038/cdd.2017.58. Epub 2017
Apr 28. <br />
When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues
on the specificity and use of GSK2606414 and GSK2656157. <br />
Rojas-Rivera D(1)(2), Delvaeye T(1)(2)(3), Roelandt R(1)(2), Nerinckx W(4)(5),
Augustyns K(6), Vandenabeele P(1)(2), Bertrand MJM(1)(2). <br />
Author information: <br />
(1)Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052,
Belgium.
(2)Department of Biomedical Molecular Biology, Ghent University, Technologiepark
927, Zwijnaarde-Ghent 9052, Belgium.
(3)Physiology Group, Department of Basic Medical Sciences, Ghent University,
Ghent 9000, Belgium.
(4)Unit for Medical Biotechnology, Medical Biotechnology Center, VIB,
Technologiepark 927, Ghent 9052, Belgium.
(5)Laboratory for Protein Biochemistry and Biomolecular Engineering, Department
of Biochemistry and Microbiology, Ghent University, K.L.-Ledeganckstraat 35,
Ghent 9000, Belgium.
(6)Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein
1, Antwerp B-2610, Belgium. <br />
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes a
state of cellular stress known as ER stress. The cells respond to ER stress by
activating the unfolded protein response (UPR), a signaling network emerging from
the ER-anchored receptors IRE1α, PERK and ATF6. The UPR aims at restoring ER
protein-folding homeostasis, but turns into a toxic signal when the stress is too
severe or prolonged. Recent studies have demonstrated links between the UPR and
inflammation. Consequently, small molecule inhibitors of IRE1α and PERK have
become attractive tools for the potential therapeutic manipulation of the UPR in
inflammatory conditions. TNF is a master pro-inflammatory cytokine that drives
inflammation either directly by promoting gene activation, or indirectly by
inducing RIPK1 kinase-dependent cell death, in the form of apoptosis or
necroptosis. To evaluate the potential contribution of the UPR to TNF-induced
cell death, we tested the effects of two commonly used PERK inhibitors,
GSK2606414 and GSK2656157. Surprisingly, we observed that both compounds
completely repressed TNF-mediated RIPK1 kinase-dependent death, but found that
this effect was independent of PERK inactivation. Indeed, these two compounds
turned out to be direct RIPK1 inhibitors, with comparable potency to the recently
developed RIPK1 inhibitor GSK/’963 (about 100 times more potent than NEC-1s).
Importantly, these compounds completely inhibited TNF-mediated RIPK1-dependent
cell death at a concentration that did not affect PERK activity in cells. In
vivo, GSK2656157 administration protected mice from lethal doses of TNF
independently of PERK inhibition and as efficiently as GSK/’963. Together, our
results not only report on new and very potent RIPK1 inhibitors but also
highlight the risk of misinterpretation when using these two PERK inhibitors in
the context of ER stress, cell death and inflammation. <br />
3. Mol Med Rep. 2017 May;15(5):3105-3110. doi: 10.3892/mmr.2017.6418. Epub 2017 Mar
30. <br />
Effects of GSK2606414 on cell proliferation and endoplasmic reticulum
stress‑associated gene expression in retinal pigment epithelial cells. <br />
Jiang X(1), Wei Y(1), Zhang T(1), Zhang Z(1), Qiu S(1), Zhou X(1), Zhang S(1). <br />
Author information: <br />
(1)State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun
Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China. <br />
GSK2606414 is a novel, highly selective inhibitor of protein kinase R‑like
endoplasmic reticulum kinase (PERK). GSK2606414 and its analogues have recently
been demonstrated to delay tumor growth and prevent neurodegeneration. The
present study investigated the effects of GSK2606414 on proliferation, apoptosis,
and the expression of activating transcription factor 4 (ATF4),
CCAAT/enhancer‑binding protein homologous protein (CHOP) and vascular endothelial
growth factor (VEGF) in human retinal pigment epithelial (RPE) cells under
endoplasmic reticulum (ER) stress. ARPE‑19 human RPE cells were treated with
0.01‑50 μM GSK2606414, and ER stress was induced by thapsigargin (TG) treatment.
Cell proliferation was assessed using the Cell Counting kit‑8 cell viability
assay. Apoptosis was detected by Annexin‑V/propidium iodide double staining using
flow cytometry. Western blot analysis was used to measure eukaryotic initiation
factor 2α (eIF2α) phosphorylation levels. ATF4, CHOP and VEGF mRNA expression
levels were assessed using reverse transcription‑quantitative polymerase chain
reaction. GSK2606414 treatment inhibited RPE cell proliferation in a
dose‑dependent manner, however it did not induce apoptosis. In addition,
GSK2606414 treatment inhibited eIF2α phosphorylation and reduced CHOP and VEGF
mRNA expression levels in RPE cells under TG‑induced ER stress. To the best of
our knowledge, the present study is the first to demonstrate that GSK2606414 has
a potential antiproliferative effect in RPE cells in vitro. This effect appeared
to be achieved via inhibition of the PERK/ATF4/CHOP signaling pathway and
suppression of VEGF expression levels. <br />
4. J Med Chem. 2012 Aug 23;55(16):7193-207. doi: 10.1021/jm300713s. Epub 2012 Aug 8. <br />
Discovery of
7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p
yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective
first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum
kinase (PERK). <br />
Axten JM(1), Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA,
Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A,
Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk
LM, Gampe RT. <br />
Author information: <br />
(1)Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and
Development, Collegeville, Pennsylvania 19426, United States.
[email protected] <br />
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in
response to a variety of endoplasmic reticulum stresses implicated in numerous
disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell
survival stimulated our search for small molecule inhibitors. Through screening
and lead optimization using the human PERK crystal structure, we discovered
compound 38 (GSK2606414), an orally available, potent, and selective PERK
inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth
of a human tumor xenograft in mice. <br />
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