Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Radhakrishnan, Prakash; Bryant, Vashti C.; Blowers, Elizabeth C.; Rajule, Rajkumar N.; Gautam, Nagsen; Anwar, Muhammad M.; Mohr, Ashley M.; Grandgenett, Paul M.; Bunt, Stephanie K.; Arnst, Jamie L.; Lele, Subodh M.; Alnouti, Yazen; Hollingsworth, Michael A.; Natarajan, Amarnath

doi:10.1158/1078-0432.ccr-12-2909

Cited by 28 publications

(50 citation statements)

References 43 publications

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“…In this study, we used a quinoxaline urea analog called 13-197 which inhibits NF-κB and mTOR pathways via IKKβ in pancreatic cancer cell lines in vitro and in vivo (28). The molecular structure of 13-197 is described in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Together, these data suggest that IKKβ is a key kinase and upon activation it regulates transcription of genes through the NF-κB pathway and translation of the gene products through the mTOR pathway. Recently, IKKβ has made an attractive target for therapeutic development (28–30). Although several IKKβ inhibitors have been used for the treatment of diseases in preclinical studies and so far none have received FDA approval (31).…”

Section: Introductionmentioning

confidence: 99%

“…Synthesis and screening of a focused library of quinoxaline compounds led to a well-defined structure activity relationship and the identification of a quinoxaline urea analog that inhibited growth of cancer cells with low micromolar potency (35, 36). Recent studies by us also suggest that the quinoxaline urea analog 13–197 inhibits the constitutively active form of IKKβ which is an emerging target for therapeutic development (28–30). In cell-based NF-κB driven dual luciferase assay, the potency of 13-197 is comparable to the reported NF-κB inhibitors, Parthenolide, Curcumin and Noscapine (37).…”

Section: Introductionmentioning

confidence: 99%

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Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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“…Although the activities of these phospho-proteins have been reported in previous studies [50-52], our data indicate that multiple uncharacterized mechanisms require further study. Overall, our results demonstrate the crosstalk between EP2/EP4 and IGF-1R signaling mainly in pancreatic cancer cells that produce and secrete PGE 2 .…”

Section: Discussionmentioning

confidence: 53%

Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: Involvement of protein kinase C-θ activation

et al. 2014

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Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-θ activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-θ kinase MAP4K3, which plays a pivotal role in PKC-θ activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-θ and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-θ. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-θ axis is central and could be exploited as a molecular target for cancer therapy.

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“…Fisetin (3,7,3′,4′-tetrahydroxyflavone), a natural flavonoid, inhibits NF-κB activation via the upregulation of IκBα and downregulation of pIkBα [35]. In addition, quinoxaline urea analog, an IKK2 inhibitor, inhibits NF-κB activation by suppressing IκBα phosphorylation [36], and diethyldithiocarbamate inhibits NF-κB translocation by blocking the cellular proteasome activity in biliary tract cancer cells [37]. Combination treatments with NF-κB inhibitors for biliary-pancreatic cancer are also listed in Table 1.…”

Section: Introductionmentioning

confidence: 99%

Effect of NF-κB inhibition on chemoresistance in biliary–pancreatic cancer

Uwagawa

Yanaga

2015

Surg Today

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Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

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Targeting the NF-κB and mTOR Pathways with a Quinoxaline Urea Analog That Inhibits IKKβ for Pancreas Cancer Therapy

Cited by 28 publications

References 43 publications

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: Involvement of protein kinase C-θ activation

Effect of NF-κB inhibition on chemoresistance in biliary–pancreatic cancer

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