| Reference | 1. Mol Cell Biochem. 2013 Oct;382(1-2):217-24.
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MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes
TRAIL-mediated cell death.
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Jiao P, Zhou YS, Yang JX, Zhao YL, Liu QQ, Yuan C, Wang FZ.
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It has become evident that AKT inhibitors have great potential in cancer
treatment. In this study, we investigate the anticancer activity of MK-2206, a
novel AKT inhibitor, on HepG2 hepatocellular carcinoma cell, and to show whether
MK-2206 enhances the apoptosis-inducing potential of tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL). The cell growth inhibition was
evaluated by MTT assay and colony formation assay. Cell cycle distribution was
assessed by propidium iodide flow cytometry. Apoptosis was determined by
AnnexinV-FITC/PI double staining assay and caspase-9, casapse-7, caspase-3, and
PARP cleavage. The results of present study showed that MK-2206-induced G1-phase
arrest was associated with a marked decrease in the protein expression of cyclin
D1 with concomitant induction of p21 and p27. MK-2206-induced apoptosis was
characterized by cleavage of a pro-caspase in a concentration-dependent manner.
Moreover, the MAP family kinases p38 kinase and JNK were activated by exposure to
MK-2206. SB203580, an p38-specific inhibitor, partially blocked MK-2206-induced
death of HepG2 cells and caspase activation. A combination of MK-2206 with TRAIL
significantly inhibited growth of TRAIL resistant HepG2 cells. Taken together,
our findings provide a new insight to better understand anticancer mechanisms of
MK-2206, at least in HepG2 cell. Using of MK-2206 as a potent sensitizer to
TRAIL-induced apoptotic cell death offers a promising means of enhancing the
efficacy of TRAIL-based HCC treatments.
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2. Biochem J. 2012 Oct 1;447(1):137-47. doi: 10.1042/BJ20120772.
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A novel PKB/Akt inhibitor, MK-2206, effectively inhibits insulin-stimulated
glucose metabolism and protein synthesis in isolated rat skeletal muscle.
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Lai YC(1), Liu Y, Jacobs R, Rider MH.
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Author information: <br>
(1)Université catholique de Louvain and de Duve Institute, Avenue Hippocrate 75,
B-1200 Brussels, Belgium.
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PKB (protein kinase B), also known as Akt, is a key component of insulin
signalling. Defects in PKB activation lead to insulin resistance and metabolic
disorders, whereas PKB overactivation has been linked to tumour growth.
Small-molecule PKB inhibitors have thus been developed for cancer treatment, but
also represent useful tools to probe the roles of PKB in insulin action. In the
present study, we examined the acute effects of two allosteric PKB inhibitors,
MK-2206 and Akti 1/2 (Akti) on PKB signalling in incubated rat soleus muscles. We
also assessed the effects of the compounds on insulin-stimulated glucose uptake,
glycogen and protein synthesis. MK-2206 dose-dependently inhibited
insulin-stimulated PKB phosphorylation, PKBβ activity and phosphorylation of PKB
downstream targets (including glycogen synthase kinase-3α/β, proline-rich Akt
substrate of 40 kDa and Akt substrate of 160 kDa). Insulin-stimulated glucose
uptake, glycogen synthesis and glycogen synthase activity were also decreased by
MK-2206 in a dose-dependent manner. Incubation with high doses of MK-2206 (10 μM)
inhibited insulin-induced p70 ribosomal protein S6 kinase and 4E-BP1 (eukaryotic
initiation factor 4E-binding protein-1) phosphorylation associated with increased
eEF2 (eukaryotic elongation factor 2) phosphorylation. In contrast, Akti only
modestly inhibited insulin-induced PKB and mTOR (mammalian target of rapamycin)
signalling, with little or no effect on glucose uptake and protein synthesis.
MK-2206, rather than Akti, would thus be the tool of choice for studying the role
of PKB in insulin action in skeletal muscle. The results point to a key role for
PKB in mediating insulin-stimulated glucose uptake, glycogen synthesis and
protein synthesis in skeletal muscle.
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3. Mol Cancer Ther. 2010 Jul;9(7):1956-67. doi: 10.1158/1535-7163.MCT-09-1012. Epub
2010 Jun 22.
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MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard
chemotherapeutic agents or molecular targeted drugs in vitro and in vivo.
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Hirai H(1), Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y,
Hatch H, Majumder PK, Pan BS, Kotani H.
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Author information: <br>
(1)Department of Oncology, Banyu Tsukuba Research Institute, Merck Research
Laboratories, Tsukuba, Ibaraki 300-2611, Japan. [email protected]
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The serine/threonine kinase Akt lies at a critical signaling node downstream of
phosphatidylinositol-3-kinase and is important in promoting cell survival and
inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in
which increased Akt signaling is associated with reduced sensitivity to cytotoxic
agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel
allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents.
In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer
cell lines in combination with molecular targeted agents such as erlotinib (an
epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth
factor receptor/human epidermal growth factor receptor 2 inhibitor).
Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206
was one mechanism of synergism, and a synergistic effect was found even in
erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in
combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin,
camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule
agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or
ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment
sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206
suppressed the Akt phosphorylation that is induced by carboplatin and
gemcitabine. In vivo, MK-2206 in combination with these agents exerted
significantly more potent tumor inhibitory activities than each agent in the
monotherapy setting. These findings suggest that Akt inhibition may augment the
efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to
treat cancer patients who receive these cytotoxic and/or molecular targeted
agents.
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