Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

Buchholz, Malte; Majchrzak-Stiller, B; Hahn, Stephan A.; Vangala, Deepak; Pfirrmann, R. W.; Uhl, Waldemar; Braumann, Chris; Chromik, Ansgar M.

doi:10.1186/s12885-017-3204-x

Cited by 14 publications

(36 citation statements)

References 43 publications

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“…By inhibiting some of the specific signal pathways, such as the Src signal pathway or the KRas signal pathway, these medicines also appear to work efficiently on pancreatic carcinoma [ 42 , 43 ]. The manipulation of ROS as in the drug-mediated apoptosis in pancreatic carcinoma has also been widely investigated [ 44 ]. However, ROS-induced apoptosis in pancreatic carcinoma was mediated by specific target pathway or down-stream target transfactors or proteins [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

et al. 2021

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Background/aims Isoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown. Methods In current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects. Results IATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo. Conclusions IATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

et al. 2021

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“…The oxathiazinane derivate GP-2250 (1,4,5-oxathiazan-dioxide-4,4) presents a recent development and has been demonstrated to possess antiproliferative, antineoplastic and migration inhibiting effects on pancreatic tumor cells in vitro [ 20 ]. It has a six-ring structure with oxygen, sulfurdioxide and nitrogen atoms on the positions 1, 4 and 5, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…It has a six-ring structure with oxygen, sulfurdioxide and nitrogen atoms on the positions 1, 4 and 5, respectively. The exact mechanism of action is yet to be fully explored; the findings of our research group suggest the induction of cell death via the increased release of reactive oxygen species as well as mitochondrial dysfunction [ 20 , 21 , 22 ]. In vivo, GP-2250 shows the reduction of tumor growth in the xenografts of established pancreatic cancer cell lines, as well as in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma, accompanied by rarely occurring side effects [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…The exact mechanism of action is yet to be fully explored; the findings of our research group suggest the induction of cell death via the increased release of reactive oxygen species as well as mitochondrial dysfunction [ 20 , 21 , 22 ]. In vivo, GP-2250 shows the reduction of tumor growth in the xenografts of established pancreatic cancer cell lines, as well as in patient-derived xenograft (PDX) models of pancreatic adenocarcinoma, accompanied by rarely occurring side effects [ 20 ]. The evaluation of the maximal tolerable dose revealed acute toxicity at 2000 mg/kg*BW and chronic toxicity at concentrations higher than 1000 mg/kg*BW in nude mice.…”

Section: Introductionmentioning

confidence: 99%

“…The evaluation of the maximal tolerable dose revealed acute toxicity at 2000 mg/kg*BW and chronic toxicity at concentrations higher than 1000 mg/kg*BW in nude mice. No changes in body weight or vital functions were observed at lower concentrations [ 20 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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New Therapy Options for Neuroendocrine Carcinoma of the Pancreas—The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo

Buchholz

Strotmann

Majchrzak-Stiller

et al. 2022

Cancers

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Neuroendocrine carcinoma of the pancreas (pNEC) is an aggressive form of neuroendocrine tumor characterized by a rising incidence without an increase in survival rates. GP-2250 is an oxathiazinane derivate possessing antineoplastic effects, especially in combination with Gemcitabine on the pancreatic adenocarcinoma. The cytotoxic effects of the monotherapy of GP-2250 (GP-2250mono) and Gemcitabine (Gemmono), as well as the combination therapy of both, were studied in vitro using an MTT-assay on the QGP-1 and BON-1 cell lines, along with in vivo studies on a murine xenograft model of QGP-1 and a patient-derived xenograft model (PDX) of Bo99. In vitro, Gemmono and GP-2250mono showed a dose-dependent cytotoxicity. The combination of GP-2250 and Gemcitabine exhibited highly synergistic effects. In vivo, the combination therapy obtained a partial response in QGP-1, while GP-2250mono and Gemmono showed progressive disease or stable disease, respectively. In Bo99 PDX, the combination therapy led to a partial response, while the monotherapy resulted in progressive disease. No development of secondary resistances was observed, as opposed to monotherapy. This study was the first to evaluate the effects of the emerging substance GP-2250 on pNEC. The substance showed synergism in combination with Gemcitabine. The combination therapy proved to be effective in vitro and in vivo, without the development of secondary resistances.

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Mechanism and rational combinations with GP‐2250, a novel oxathiazine derivative, in ovarian cancer

Kim,

Glassman,

Handley

et al. 2024

Cancer Medicine

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BackgroundGP‐2250, a novel analog of taurultam (TRLT), has emerged as a potent anti‐neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP‐2250 using in vitro and in vivo models.MethodsWe carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse‐phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP‐2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP‐2250 alone and in combination with standard‐of‐care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP‐ribose polymerase [PARP] inhibitors).ResultsWe investigated the cytotoxic effect of GP‐2250 in 10 ovarian cancer cell lines and found GP‐2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP‐2250 inhibited hypoxia‐inducible factor‐1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High‐resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP‐2250 exposure. Furthermore, GP‐2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP‐2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP‐2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups.ConclusionsTaken together, our data indicate that GP‐2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti‐tumor efficacy. These findings could have implications for the clinical development of GP‐2250.

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Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

Cited by 14 publications

References 43 publications

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway

New Therapy Options for Neuroendocrine Carcinoma of the Pancreas—The Emergent Substance GP-2250 and Gemcitabine Prove to Be Highly Effective without the Development of Secondary Resistances In Vitro and In Vivo

Mechanism and rational combinations with GP‐2250, a novel oxathiazine derivative, in ovarian cancer

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