Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells

Li, Jianping; Huang, Zhijun; Lu, Xiao‐Jie; Zhou, Yichan; Shao, Yun; He, Xiaopu; Chen, Su-Rong; Wang, Dongdong; Qin, Lei; Sun, Wei

doi:10.18632/oncotarget.12802

Cited by 12 publications

(10 citation statements)

References 25 publications

(73 reference statements)

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“…Tumor growth curve results in Figure 5A display that administration of SF2523 (15/50 mg/kg body weight, every other day) significantly inhibited 786-O tumor growth in SCID mice. Estimated daily tumor growth, in mm 3 per day [ 38 ], was also decreased with SF2523 administration (Figure 5B ). At the end of experiments (“Day-36”), tumors of each group were isolated and weighted.…”

Section: Resultsmentioning

confidence: 99%

Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth

et al. 2017

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Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells. Remarkably, SF2523 was more efficient than Wortmannin (the PI3K inhibitor) and JQ1 (the BRD4 specific inhibitor) in killing RCC cells. In vivo, SF2523 administration at well-tolerated doses suppressed 786-O xenograft tumor growth in severe combined immunodeficient (SCID) mice. Together, our results suggest that concurrent blockage of BRD4 and PI3K-AKT signalings by SF2523 efficiently inhibits RCC cell growth in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth

et al. 2017

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“…In order to test the potential activity of LB-100 on human CRC cells, the established HCT-116 HCC cells [ 5 ] were cultured in complete medium, and were treated with LB-100 at different concentrations. Simple cell counting assay results in Figure 1A displayed that treatment with LB-100, at 2.5 μM and 10 μM, significantly inhibited HCT-116 cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells

Dai

Xuning²,

Xie

et al. 2017

Oncotarget

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LB-100 is a novel PP2A inhibitor. Its activity in human colorectal cancer (CRC) cells was tested. The in vitro studies demonstrated that LB-100 inhibited survival and proliferation of both established CRC cells (HCT-116 and HT-29 lines) and primary human colon cancer cells. Further, LB-100 activated apoptosis and induced G1-S cell cycle arrest in CRC cells. LB-100 inhibited PP2A activity and activated AMPK signaling in CRC cells. AMPKα1 dominant negative mutation, shRNA-mediated knockdown or complete knockout (by CRISPR/Cas9 method) largely attenuated LB-100-induced AMPK activation and HCT-116 cytotoxicity. Notably, microRNA-17-92-mediated silence of PP2A (regulatory B subunit) also activated AMPK and induced HCT-116 cell death. Such effects were again largely attenuated by AMPKα mutation, silence or complete knockout. In vivo studies showed that intraperitoneal injection of LB-100 inhibited HCT-116 xenograft growth in nude mice. Its anti-tumor activity was largely compromised against HCT-116 tumors-derived from AMPKα1-knockout cells. We conclude that targeting PP2A by LB-100 and microRNA-17-92 activates AMPK signaling to inhibit CRC cells.

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“…The size of the tumors was measured by caliper every week, and estimated tumor volume was calculated using the following formula: π/6×width 2 × length. Estimated daily tumor growth was calculated by: (estimated tumor volume at Day-42 deducting tumor volume at Day-1)/42 [ 32 , 33 ]. The animal protocols were approved by Institutional Animal Care and Use Committee (IACUC) and Ethics Board of Anhui Medical University.…”

Section: Methodsmentioning

confidence: 99%

DlgR2 knockdown boosts dendritic cell activity and inhibits hepatocellular carcinoma tumor in-situ growth

Xia

Zhao

et al. 2017

Oncotarget

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Tumor-specific hepatic stellate cells (tHSCs) positively participate in human hepatocellular carcinoma (HCC) tumorigenesis and progression. Our previous studies have shown that tHSCs co-culture with dendritic cells (DCs) induced DIgR2 (dendritic cell-derived immunoglobulin receptor 2) expression. The latter is a member of IgSF inhibitory receptor suppressing DCs-initiated antigen-specific T-cell responses. In the current study, we show that hepatic artery injection of DlgR2 siRNA significantly inhibited in-situ HCC xenograft growth in rat livers. Further, 5-FU-medied inhibition of in-situ HCC growth was dramatically sensitized with DlgR2 silence. DlgR2 siRNA injection indeed downregulated DlgR2 in ex-vivo cultured tumor-derived DCs (tDCs). More importantly, tDCs activity was boosted following DlgR2 siRNA. These cells presented with upregulated CD80, CD86 and MHC-II. Production of interleukin-12 and tumor necrosis factor-α was also increased in the DlgR2-silenced tDCs. We propose that DlgR2 knockdown likely boosts the activity of tumor-associated DCs, and inhibits growth of in-situ HCC xenografts.

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Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells

Cited by 12 publications

References 25 publications

Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth

Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth

Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells

DlgR2 knockdown boosts dendritic cell activity and inhibits hepatocellular carcinoma tumor in-situ growth

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