Novel STAT 3 inhibitors for treating gastric cancer

Cafferkey, Catherine; Chau, Ian

doi:10.1080/13543784.2016.1195807

Cited by 49 publications

(48 citation statements)

References 46 publications

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“…Thus, our data suggest that this short peptide may coordinate with IFNα, spatially regulating the signaling of the interferon in the cytokine cascade pathway. It would also be interesting to examine if the alteration of the signal pathway, using reagents as previously reported [38][39][40][41], will affect the therapeutic antitumor activity of the synthetic IFNP.…”

Section: Discussionmentioning

confidence: 99%

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

et al. 2017

Cell Physiol Biochem

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Background/Aims: Adult T-cell leukemia/lymphoma (ATL) is a very aggressive T cell malignancy that carries a poor prognosis, primarily due to its resistance to chemotherapy and to lifethreatening infectious complications. Interferon-alpha (IFNα) has been used in combination with the anti-retroviral drug zidovudine to treat patients with ATL. However, the efficacy of long-term therapy is significantly limited due to the systemic toxicity of IFNα. Methods: We utilized phage display library screening to identify short peptides that specifically bind to Jurkat T lymphocyte leukemia cells. By fusing the Jurkat-binding peptide to the C-terminus of IFNα, we constructed an engineered chimeric IFNα molecule (IFNP) for the treatment of ATL. Results: We found that IFNP exhibited significantly higher activity than wild type IFNα in inhibiting the growth of leukemia cells and inducing cell blockage at the G0/G1 phase. The synthetic IFNP molecule exerted its antitumor activity by upregulating the downstream genes involved in the STAT1 pathway and in apoptosis. Using a cell receptor binding assay, we showed that this Jurkat-binding peptide facilitated the binding affinity of IFNα to the cell surface type I IFN receptor. Conclusion: The isolated Jurkat-binding peptide significantly potentiates the therapeutic activity of IFNα in T lymphocyte leukemia cells. The engineered IFNP molecule may prove to a novel antitumor approach in the treatment of patients with ATL.

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Section: Discussionmentioning

confidence: 99%

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

et al. 2017

Cell Physiol Biochem

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“…The development of napabucasin has reached phase III for oseophageal and gastrointestinal cancers (NCT02178956) and phase II for several other solid tumors (NCT02467361). STA-21 is a natural antibiotic that inhibits STAT3 dimerization and has been tested in phase I and II clinical trials for the treatment of psoriasis (NCT01047943) [126]. STAT3 decoy oligonucleotides bind their DNA-binding domain with a higher degree of selectivity, but they are quickly degraded in vivo .…”

Section: Targeting Transcription Factors: the New Frontier?mentioning

confidence: 99%

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Gadina

Gazaniga

Vian

et al. 2017

Journal of Autoimmunity

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Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

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“…Currently, no STAT3 inhibitors for cancer therapy have yet been approved, regardless of the mechanisms of STAT3 inhibition. There are several literatures that have nicely reviewed the progress of STAT3 inhibitors [10,11,12,13,14]. While many studies demonstrated that over-activation of Janus associated kinase (JAK) or growth factor receptor-associated tyrosine kinase (Src) contribute to the hyper-phosphorylation of STAT3 [15,16], phosphorylation of STAT3 is also tightly regulated by protein tyrosine phosphatases (PTPs) [17,18].…”

Section: Introductionmentioning

confidence: 99%

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

Huang

Su²,

Liu

et al. 2017

IJMS

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The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories.

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Novel STAT 3 inhibitors for treating gastric cancer

Cited by 49 publications

References 46 publications

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy

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