CS2164 exerts an antitumor effect against human Non-Hodgkin's lymphomas in vitro and in vivo

Deng, Manman; Shi, Yuanfei; Chen, Kai; Zhao, Haijun; Wang, Yan; Xie, Siting; Zhao, Jiang; Luo, Yiming; Fang, Zhihong; Fan, Ya-qun

doi:10.1016/j.yexcr.2018.05.038

Cited by 8 publications

(13 citation statements)

References 30 publications

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“…Previous studies have suggested that Chiauranib exerted anti-tumor activity by inducing apoptosis 9,10 .…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, it is imperative to nd new drugs targeting KRAS wild-type CRC. Recently, the anti-tumor activity of Chiaurinib has been explored in various cancers, including Non-Hodgkin's lymphomas, acute myeloid leukemia, hepatocellular carcinoma, and gastric cancer 9,10 . Surprisingly, in our experiments, we found for the rst time that Chiaurinib selectively inhibited the growth of KRAS wild-type CRC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Chiauranib is a novel oral multi-target small molecule inhibitor of select serine threonine-kinases, including the angiogenesis-related kinases (VEGFR1, VEGFR2, VEGFR3, and c-Kit), the chronic in ammation-related kinase CSF-1R, and the mitosis-related kinase Aurora B, with a variety of potential anti-tumor activities [8][9][10] . Chiauranib reduces hepatocellular carcinoma and gastric cancer cell proliferation by simultaneous inhibiting VEGFR2 and Aurora B 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Chiauranib reduces hepatocellular carcinoma and gastric cancer cell proliferation by simultaneous inhibiting VEGFR2 and Aurora B 8 . Besides, Chiauranib exerts anti-tumor effect against angiogenesis and mitosis in hematologic tumors, such as acute myeloid leukemia and Non-Hodgkin's lymphomas 9,10 . The animal study results illustrate that Chiauranib has impressive e cacy and safety, veri ed in a phase I clinical trial (NCT03074825) 10,11 .…”

Section: Introductionmentioning

confidence: 99%

“…Besides, Chiauranib exerts anti-tumor effect against angiogenesis and mitosis in hematologic tumors, such as acute myeloid leukemia and Non-Hodgkin's lymphomas 9,10 . The animal study results illustrate that Chiauranib has impressive e cacy and safety, veri ed in a phase I clinical trial (NCT03074825) 10,11 . Currently, Chiauranib phase Ib/II clinical trials are undergoing in multiply cancers.…”

Section: Introductionmentioning

confidence: 99%

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Chiaurinib Selectively Inhibits Colorectal Cancer with KRAS Wild-Type by Modulation of ROS through Activating the p53 Signaling Pathway

Yin

Xie²,

Jiang

et al. 2020

Preprint

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Background: Colorectal cancer (CRC) is one of the top three most deadly cancers despite using chemotherapy based on oxaliplatin or irinotecan combined with targeted therapy. Chiaurinib has recently been identified to be a promising anticancer candidate with impressive efficacy and safety. However, the role and molecular mechanisms of Chiaurinib in the treatment of CRC remain to be elucidated.Methods: Cell proliferation and apoptosis were detected by CCK-8, EDU staining, Colony formation assay, TUNEL staining and flow cytometric analysis. ROS production was confirmed by Mito-SOX and DCF-DA fluorescence. RNA-Seq and GSEA analysis were used to explore the mechanisms of the effect of Chiaurinib in KRAS wild-type CRC cells.Results: Our study shows that Chiaurinib inhibits cell proliferation and induces apoptosis in KRAS wild-type CRC cells in a dose- and time-dependent manner, but not mutation ones. Meanwhile, Chiaurinib increases ROS production in KRAS wild-type CRC cells. Moreover, Chiaurinib selectively suppresses KRAS wild-type CRC cells growth in vivo. Mechanistically, Chiaurinib inhibits KRAS wild-type CRC cells by triggering ROS production via activating the p53 signaling pathway. Further, KRAS mutation CRC cells are resistant to Chiaurinib by increasing Nrf2 to stably elevate the basal antioxidant program and thereby lower intracellular ROS induced by Chiaurinib.Conclusions: Taken together, we reveal that Chiauranib induces p53 upregulation, resulting in ROS accumulation, thus inhibiting cell proliferation and inducing apoptosis in KRAS wild-type CRC cells. Our findings provide the rationale for further clinical evaluation of Chiaurinib as a therapeutic agent in treating KRAS wild-type CRC.

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“…Previous studies have suggested that Chiauranib exerted anti-tumor activity by inducing apoptosis 9,10 .…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Chiaurinib Selectively Inhibits Colorectal Cancer with KRAS Wild-Type by Modulation of ROS through Activating the p53 Signaling Pathway

Yin

Xie²,

Jiang

et al. 2020

Preprint

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Low‐dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo

Shi

Zhao

et al. 2020

Molecular Carcinogenesis

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The bromodomain and extra‐terminal (BET) domain inhibitor JQ1 exerts potent anticancer activity in various cancer cells. However, the resistance to BET inhibitors in leukemia stem cells limits its implication in acute myeloid leukemia (AML). High concentration of triptolide (TPL) presents anticancer activities but with adverse effects. Here, we investigated whether the combination of low‐dose TPL with JQ1 could help to circumvent the dilemma of drug resistance and side effect in treating AML. AML cell lines, primary cells from 10 AML patients with different status, as well as AML mice model were subjected to different treatments and apoptotic related protein expression were evaluated. Data showed that low‐dose TPL combined with JQ1 effectively killed AML cell lines and primary cells from AML patients without exerting significantly greater lethal activity against normal cells. Mechanism study revealed that low‐dose TPL combined with JQ1 triggered reactive oxygen species production and induced mitochondrial‐mediated apoptosis in AML cells, in which the inhibition of RNA polymerase II to downregulate c‐Myc was mainly responsible for the enhanced activity of TPL in combination with JQ1. In vivo study presented that cotreatment with low‐dose TPL and JQ1 significantly reduced tumor burden of the NOD/SCID mice engrafted with MOLM‐13 cells. In conclusion, low‐dose TPL enhanced the antitumor effect of JQ1 on AML without increasing the side effects, supporting a potential option for AML treatment.

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Inhibition of extranodal NK/T-cell lymphoma by Chiauranib through an AIF-dependent pathway and its synergy with L-asparaginase

et al. 2023

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Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3β pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib’s positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.

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CS2164 exerts an antitumor effect against human Non-Hodgkin's lymphomas in vitro and in vivo

Cited by 8 publications

References 30 publications

Chiaurinib Selectively Inhibits Colorectal Cancer with KRAS Wild-Type by Modulation of ROS through Activating the p53 Signaling Pathway

Chiaurinib Selectively Inhibits Colorectal Cancer with KRAS Wild-Type by Modulation of ROS through Activating the p53 Signaling Pathway

Low‐dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo

Inhibition of extranodal NK/T-cell lymphoma by Chiauranib through an AIF-dependent pathway and its synergy with L-asparaginase

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