Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo

Nirvanappa, Anilkumar C.; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Ananda, Hanumappa; Sukhorukov, Alexey Yu.; Shanmugam, Muthu K.; Sundaram, Mahalingam S.; Nayaka, S. Chandra; Girish, K. S.; Chinnathambi, Arunachalam; Zayed, Mohamed E.; Alharbi, Sulaiman Ali; Sethi, Gautam; Basappa, Basappa; Rangappa, Kanchugarakoppal S.

doi:10.1371/journal.pone.0163209

Cited by 37 publications

(25 citation statements)

References 51 publications

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“…TNF-Rs comprise a family of 29 structurally-related receptors, which are bound by 19 ligands of the TNF superfamily [ 115 , 116 , 117 , 118 , 119 ]. The usage of anti-TNF antibodies or agents that block the TNF-R, such as infliximab and etanercept, can inhibit TNF-induced NF-κB activation and can have benefits in various autoimmune diseases [ 115 , 120 , 121 ].…”

Section: Inhibitors Of Nf-κb Function and Selected Pharmacologicalmentioning

confidence: 99%

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

et al. 2018

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Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is responsible for the regulation of a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. At the same time, this transcription factor can control the expression of a plethora of genes that promote tumor cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis. The aberrant activation of this transcription factor has been observed in several types of cancer and is known to contribute to aggressive tumor growth and resistance to therapeutic treatment. Although NF-κB has been identified to be a major contributor to cancer initiation and development, there is evidence revealing its role in tumor suppression. This review briefly highlights the major mechanisms of NF-κB activation, the role of NF-κB in tumor promotion and suppression, as well as a few important pharmacological strategies that have been developed to modulate NF-κB function.

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Section: Inhibitors Of Nf-κb Function and Selected Pharmacologicalmentioning

confidence: 99%

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

et al. 2018

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“…indicator of CRC and patients with low ASPP1 levels could be more suitable for therapy with NF-κB inhibitors 55,56 . These results may offer new information for the development of novel drugs in the treatment of CRC.…”

Section: Discussionmentioning

confidence: 99%

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

et al. 2020

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The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin-dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.

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“…Furthermore, ACHP treatment suppressed the IL-6 induced activation of these cascades of proteins in H1299 cells. Activation of executioner caspase (caspase 3/7) is the major biochemical event associated with the cells committed to apoptosis [91], and the activated caspase-3 cleaves PARP to induce apoptosis [54,92].…”

Section: Discussionmentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo

Cited by 37 publications

References 51 publications

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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