Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience

Gerullis, Holger; Wawroschek, Friedhelm; Köhne, Claus‐Henning; Ecke, Thorsten

doi:10.1177/1756287216677903

Cited by 36 publications

(20 citation statements)

References 40 publications

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“…We were pleased that these two indoline hit structures provided mutual confirmation of one another. Furthermore, indolines are a privileged scaffold in medicinal chemistry, as there are several examples of indoline-containing drugs approved for a variety of treatments: advanced or transitional cell carcinoma of the urothelial tract (vinflunine) [ 18 ], glaucoma and severe anticholinergic toxicity (physostigmine) [ 19 ], and schizophrenia in adults (lumateperone) [ 20 , 21 ], or are under investigation, as for benign prostatic hyperplasia (BPH) [ 22 ]. Furthermore, sulfonamides are pervasive in agrochemicals and in pharmaceuticals across therapeutic areas [ 23 , 24 , 25 , 26 , 27 ], and primary sulfonamides have recently been leveraged as versatile intermediates [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

et al. 2020

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Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG).

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Section: Resultsmentioning

confidence: 99%

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

et al. 2020

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“…Homoharringtonine, a clinically approved drug for leukemia, sensitized cancer cells to TRAILinduced necroptosis through the RIPK1/RIPK3/MLKL pathway [3]. Vinflunine has been approved as a secondline therapeutic drug for metastatic and advanced urothelial cancer after failure of platin-containing therapy, and also showed potential therapeutic benefit for EGFR2-positive metastatic breast cancer along with trastuzumab in a phase II clinical trial [4][5][6]. As a potent inhibitor of P-gp efflux pump to reverse multidrug resistance, tetrandrine (CBT-01®) has demonstrated positive results in a phase I clinical trial in combination with paclitaxel, which warranted conducting it's phase II/III trial [7].…”

Section: Introductionmentioning

confidence: 99%

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

et al. 2020

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Background: As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. Methods: The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Results: Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Conclusion: Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

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“…Homoharringtonine, a clinically approved drug for leukemia, sensitized cancer cells to TRAIL-induced necroptosis through the RIPK1/RIPK3/MLKL pathway [3] . Vinflunine showed its effectiveness in the treatment of EGFR2-positive metastatic breast cancer along with trastuzumab in a phase II clinical trial and has been approved for second-line treatment of metastatic and advanced urothelial cancer after failure of platin-containing therapy [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

Peng

Guan

Luo

et al. 2020

Preprint

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Background: This study ought to further explore the anti-tumor effects of Sophoridine on gastric cancer cells.Methods: Cell viability assay (CCK-8 assay) was used to measure the IC50 values of Sophoridine on gastirc cancer AGS and SGC7901 cell lines and normal gastric epithelial cell line GES-1. EdU and colony formation assay were performed to confirm the cytotoxic effect of Sophoridine on AGS and SGC7901 cells. The apoptotic effects of Sophoridine on AGS and SGC7901 cells were measured by Flow cytometry. Transwell assay was used to evaluate the effects of Sophoridine on migration and invasion of AGS and SGC7901 cells. The protein expression of Sophoridine on AGS and SGC7901 cells were detected via Western blot. Results: We demonstrated that Sophoridine exerts potent tumor-suppressive activities, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis of gastric cancer cells. In addition, we further showed that Sophoridine induces G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhances the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine depends on Estrogen-related receptor gamma (ESRRG) to perform tumor-suppressive activities and which leads to the degradation of β-catenin in an ubiquitin-proteasome pathway independent manner.Conclusions: Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

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Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience

Cited by 36 publications

References 40 publications

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

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