A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells

Zhao, Chongqiang; Wang, Wenlong; Yu, Wenying; Jou, David; Wang, Yina; Ma, Haiying; Xi, Hui; Hua, Qi; Zhang, Cuntai; Lu, Junlin; Li, Sheng; Li, Chenglong; Lin, Jiayuh; Lin, Li

doi:10.18632/oncotarget.7338

Cited by 40 publications

(36 citation statements)

References 44 publications

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“…A lot of novel small molecular inhibitors of STAT3 have been reported to suppress cancer cells and tumor growth, such as LLL12 [22], LY5 [23], XZH-5 [24] and so on. However, to date, the translation of anti-STAT3 therapies into clinical trials has been difficult [25–26].…”

Section: Discussionmentioning

confidence: 99%

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Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Wang

Zhao

et al. 2017

Oncotarget

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BackgroundInterleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.ResultsRaloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.Materials and MethodsThe inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.ConclusionsOur results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, as an approved drug by FDA, the security and permeability of Raloxifene are superior as compared to other reported novel molecular inhibitors of IL-6/GP130/STAT3, such as MDL-A [15], LLL12 [23], LY5 [24], and XZH-5 [25]. Therefore, Raloxifene is more likely to apply to clinical trails.…”

Section: Discussionmentioning

confidence: 99%

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Wang

Zhao

et al. 2017

Oncotarget

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“…Moreover, the effect of miR-146a expression in hematopoietic cells is similar to that of treatment with LPS (10). Expression of miR-146a was upregulated in the process of leukemia cell apoptosis induced by multiple drugs such as imatinib and all-trans retinoic acid, which may be related to the pro-apoptotic or anti-apoptotic activities of multiple transcription factors (11,12). …”

Section: Discussionmentioning

confidence: 99%

“…The STAT family of proteins is responsible for transducing signals from growth factor receptors on the cytoplasmic membrane into the nucleus in order to regulate gene expression (12). Experiments using mutant cell lines and knockout mice have shown that STAT1 plays a significant role in interferon (IFN)-γ and IFN-α/β mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

The effect of miR-146a on STAT1 expression and apoptosis in acute lymphoblastic leukemia Jurkat cells

Wang¹,

Guo²,

Suo³

et al. 2016

Oncology Letters

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The effect of miR-146a-dependent regulation of STAT1 on apoptosis in acute lymphoblastic leukemia (ALL) Jurkat cells was investigated. The miR-146a mimic and miR-146a inhibitor vectors were constructed in vitro, and experimental grouping was as follows: Control group (untreated Jurkat cells), empty vector group (Jurkat cells transfected with empty vector), agonist group (Jurkat cells transfected with miR-146a mimic) and the inhibitor group (Jurkat cells transfected with miR-146a inhibitor). Western blot analysis was used to observe the expression, respectively, of STAT1, p-STAT1 and Bcl-xL, and flow cytometry was used to test apoptosis in Jurkat cells. STAT1 and p-STAT1 expression in the agonist group was higher than that in the control and empty vector groups, but lower in the inhibitor group, and differences were statistically significant (P<0.05). The rate of apoptosis in the agonist group was significantly higher than that of the control group and blank vector group, and it was significantly lower in the inhibitor group (P<0.05). As a tumor suppressor, miR-146a can regulate expression of apoptosis-promoting factor STAT1, and anti-apoptosis factor Bcl-xL, and is able to promote apoptosis of ALL Jurkat cells.

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“…al. [66] a non-peptide small molecule STAT3 inhibitor, LY5, using in silico site-directed Fragment-based drug design (FBDD) was constructed. The inhibitory effect on STAT3 phosphorylation, cell viability, migration and colony forming ability by LY5 were examined in human liver and colon cancer cells.…”

Section: Gene Therapymentioning

confidence: 99%

Colorectal Cancer from Molecular Pathways to Gene Therapy

Kosmıdis¹,

Efthimidis²,

Baka³

et al. 2017

Oncomedicine

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Nowadays colorectal cancer is still considered the third most common cancer in the world. The tumorigenesis mechanisms of colorectal cancer have been widely studied at a molecular level. It has been observed that morbidity and mortality caused by colorectal cancer impacts on the global economy. This occurs through the loss of productivity and the burden on the healthcare system. Therefore an effort is made by several researchers to expend considerably their resources to develop treatments and preventative strategies to reduce the incidence of colorectal cancer. A Large-scale sequencing of genome, proteome, microbiome, and transcriptome analyses of colorectal cancer tissue has allowed researchers to better understand colorectal cancer subtypes. Until now the following parameters have been identified with the etiology of colorectal cancer genetic mutations, inflammatory processes, diet, and the gut microbes. In the current review we will present the molecular pathways of CRC and discuss novel gene therapy approaches.

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A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells

Cited by 40 publications

References 44 publications

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

The effect of miR-146a on STAT1 expression and apoptosis in acute lymphoblastic leukemia Jurkat cells

Colorectal Cancer from Molecular Pathways to Gene Therapy

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