Combination Treatment of IκB Kinase β Inhibitor IMD-0354 and Gemcitabine Suppresses Oncogenic Proliferation of Pancreatic Cancer Cells

Ochiai, Takanori; Shioya, Akihiro; Honma, Hiroshi; Saitoh, Yasunori; Matsumura, Satoshi; Ban, Daisuke; Irie, Tetsumi; Kudo, Akira; Nakamura, Noriaki; Fujikawa, Tomoyuki; Itai, Akiko; Tanaka, Shinji; Arii, Shigeki; Shoji, Yasuhiro; Tanabe, Minoru

doi:10.1016/j.jss.2013.11.157

Cited by 7 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IMD-0354, an inhibitor of the NF-κB pathway, was initially designed to inhibit inflammation [48,49], but recently proven to have anticancer properties [16,50,51]. Here, we wanted to assess if IMD-0354 also affects CSCs, as indicated by prior screening.…”

Section: Resultsmentioning

confidence: 99%

IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

2013

View full text Add to dashboard Cite

Although early detection of breast cancer improved in recent years, prognosis of patients with late stage breast cancer remains poor, mostly due to development of multidrug resistance (MDR) followed by tumor recurrence. Cancer stem cells (CSCs), with higher drug efflux capability and other stem cell-like properties, are concentrated in a side population (SP) of cells, which were proposed to be responsible for MDR and tumor repopulation that cause patients to succumb to breast cancer. Therefore, targeting of CSCs as an adjuvant to chemotherapy should be able to provide a more effective treatment of this disease. Here, we used IMD-0354, an inhibitor of NF-κB, identified for targeting CSCs, in a combination therapy with doxorubicin encapsulated in targeted nanoparticles. IMD-0354 did target CSCs, evidenced by a decrease in the SP, demonstrated by the inhibition of the following: dye/drug efflux, reduction in ABC transporters as well as in colony formation in soft agar and low attachment plates. Decrease of stem-like gene expression of Oct4, Nanog and Sox2, and apoptosis resistance related to the Survivin gene also was observed after treatment with this compound. In addition, IMD-0354 targeted non-CSCs as indicated by reducing viability and increasing apoptosis. Targeted drug delivery, achieved with a legumain inhibitor, proved to enhance drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Together, this allowed a safe, non-toxic delivery of both anticancer agents to the tumor microenvironment of mice bearing syngeneic metastatic breast cancer. Targeting both bulk tumor cells with a chemotherapeutic agent and CSCs with IMD-0354 should be able to reduce MDR. This could eventually result in decreasing tumor recurrences and/or improve the outcome of metastatic disease.

show abstract

Section: Resultsmentioning

confidence: 99%

IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

2013

View full text Add to dashboard Cite

show abstract

“…IKK signalosome phosphorylation of IκB leads to its proteosomal degradation and the translocation of P50/P65 hetrodimers to the nucleus. IMD-0354 is a specific IκB kinase-β (IKKβ) inhibitor 39 that blocks NF-κB nuclear translocation. To ascertain whether members of the NF-κB family are involved in Notch-4/Int3-induced mammary tumorigenesis, first we treated HC11, HC11-Int3 with IMD-0354 in the presence and absence of Int3-siRNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DNA was amplified (94 C for 30 sec., 68 C for 30 sec., 72 C for 30 sec; 35 cycles, 72 C for 2 min) with a product size of 192 bp. To treat WAP-Int3-tumor-bearing mice with IMD-0354 39 , primary mammary tumors were palpated weekly. Tumor weight was determined as described previously 12 .…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis

Raafat

Bargo

McCurdy

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice. Thus, Notch-induced mammary tumor development is Rbpj-independent. Here, we show that Int3 activates NF-κB in HC11 cells in absence of Rbpj through an association with the IKK signalosome. Int3 induced the canonical NF-κB activity and P50 phosphorylation in HC11 cells without altering the NF-κB2 pathway. The minimal domain within the Int3 protein required to activate NF-κB consists of the CDC10/Ankyrin (ANK) repeats domain. Treatment of WAP-Int3 tumor bearing mice with an IKK inhibitor resulted in tumor regression. In a soft agar assay, treatment of HC11-Int3 cells with P50-siRNA caused a significant decrease in colony formation. In addition, Wap-Int3/P50 knockout mice did not develop mammary tumors. This data indicates that the activation of NF-κB canonical signaling by Notch-4/Int3 is ANK repeats dependent, Rbpj-independent, and is mediated by IKK activation and P50 phosphorylation causing mammary tumorigenesis.

show abstract

“…IMD-0354, an inhibitor of the NF-κB pathway, was initially developed to inhibit inflammation [51,52], but recently proven to have anticancer properties [24,53,54]. Here, we wanted to assess if IMD-0354 also affects CSCs, as indicated by prior screening.…”

Section: In Vitro Effects Of Imd-0354 On Human Non-small Cell Lung Cscsmentioning

confidence: 99%

The Nf-κb Inhibitor Imd-0354 Targets Human Non-Small Cell Lung Cancer Stem Cells and Combined with Chemotherapy Reduces Multidrug Resistance

Wrasidlo¹

2013

J Cancer Sci Ther

View full text Add to dashboard Cite

Most lung cancer patients are diagnosed at an advanced stage, when prognosis is poor. Multidrug resistance and tumor recurrence have been major reasons for these patients to succumb to the disease. Recent evidence points to cancer stem cells as being responsible for multidrug resistance and tumor repopulation as a result of their increased drug efflux and other stem cell-like properties. Thus, recent efforts have focused on targeting these cancer stem cells. Here, we combined liposomal nanoparticles targeted with a legumain inhibitor as a safe vehicle for drug delivery to the tumor microenvironment with Doxorubicin, a common chemotherapeutic agent that targets bulk cancer cells, and IMD-0354, an inhibitor of NF-κB targeting cancer stem cells. IMD-0354 decreased side populations, ABC transporters, stem-like and apoptosis resistance genes, and colony formation of human non-small cell lung cancer cells. In addition, IMD-0354 also had a cytotoxic effect on non-cancer stem cells and increased their apoptosis. The targeted delivery method used previously in syngeneic mouse models enhanced drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Further, such targeted delivery reduced in vivo tumor burden in an aggressive model of human non-small cell lung cancer xenografts. Targeting of both bulk tumor cells and cancer stem cells with IMD-0354 as an adjuvant for chemotherapy are likely to reduce multidrug resistance and tumor recurrence, and thereby significantly reduce patient death from non-small cell lung cancer.

show abstract

Combination Treatment of IκB Kinase β Inhibitor IMD-0354 and Gemcitabine Suppresses Oncogenic Proliferation of Pancreatic Cancer Cells

Cited by 7 publications

References 0 publications

IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis

The Nf-κb Inhibitor Imd-0354 Targets Human Non-Small Cell Lung Cancer Stem Cells and Combined with Chemotherapy Reduces Multidrug Resistance

Contact Info

Product

Resources

About