The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck

Mandal, Mahitosh; Younes, Mamoun; Swan, Eric A.; Jasser, Samar A.; Doan, Dao; Yigitbasi, Orhan; McMurphey, Andrea; Ludwick, James; El‐Naggar, Adel K.; Bucana, C. D.; Mills, Gordon B.; Myers, Jeffrey N.

doi:10.1016/j.oraloncology.2005.09.011

Cited by 54 publications

(40 citation statements)

References 20 publications

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“…Indeed, in line with previous work from our laboratory and others (11,12,15), Akt was activated in a high proportion of the tumors examined, as judged by the immunodetection of its Ser 473 and Thr 308 phosphorylated forms. Upon EGFR stimulation, Akt is activated in a multistep process that involves the stimulation of the activity of phosphatidylinositol 3 ¶-OH kinase by EGFR-dependent phosphorylation and recruitment to the membrane of the phosphatidylinositol 3 ¶-OH kinase p85 subunit.…”

Section: Discussionsupporting

confidence: 88%

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Molinolo

Hewitt

Amornphimoltham

et al. 2007

Clinical Cancer Research

229

200

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Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. Conclusions:These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.

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Section: Discussionsupporting

confidence: 88%

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Molinolo

Hewitt

Amornphimoltham

et al. 2007

Clinical Cancer Research

229

200

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“…However, depending upon Akt phosphorylation status, the mode of apoptosis induction is different [144,145] . KP372-1, a triazinones derivative (Figure 3), inhibits proliferation and induces apoptosis in thyroid cancer, glioblastoma, squamous cell cancer, and acute myelogenous leukemia cell lines [146][147][148][149] . It is also a PDK1 and FLT3 inhibitor that causes the inhibition of PKB activation through Ser473 phosphorylation, as well as downstream target phosphorylation, which reflects the non-selective mode of action.…”

Section: Akt Inhibitorsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

Self Cite

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…1A) was provided by Myriad Pharmaceuticals Inc.. Because CTFB at a concentration of 1 Amol/L was sufficient for growth delay in viability assays and showed only weak apoptotic effects in FaDu cells, this dose was used for all further experiments. 7 Pleiman et al, manuscript in preparation. For statistical evaluation, mean values and SD were calculated using three independent experiments; significance was determined by paired Student's t test.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, CTFB showed significant inhibition of the growth of ovarian cancer cells in athymic nude mice xenografts. 7 When CTFB was tested to determine its susceptibility to MDR pumps, its anticancer activity in the MDR-expressed cell lines was similar to its activity in MDR-nonexpressed cell lines. Therefore, CTFB is not a substrate for MDR pumps (14).…”

Section: -Chloro-n-{2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-mentioning

confidence: 99%

Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-κB expression and proteasome activation in head and neck squamous carcinoma cell lines

Skvortsov¹,

Skvortsova²,

Stasyk³

et al. 2007

Molecular Cancer Therapeutics

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This study aimed to characterize the antitumor activity of 5-Chloro-N-{2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl}-2-hydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 Mmol/L with 17.16 F 2.08%, 10.92 F 1.22%, and 27.03 F 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G 0 -G 1 phase that was associated with the up-regulation of p21/ WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-KB (NF-KB) and NF-KB p65 phosphorylated at Ser 536 . The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-KB is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer. [Mol Cancer Ther 2007;6(6):1898 -908]

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The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck

Cited by 54 publications

References 20 publications

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-κB expression and proteasome activation in head and neck squamous carcinoma cell lines

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