GP‐2250, a novel anticancer agent, inhibits the energy metabolism, activates AMP‐Kinase and impairs the NF‐kB pathway in pancreatic cancer cells

Abstract

The oxathiazinane compound GP-2250 (Figure 1A) is a highly effective antineoplastic agent, as has been demonstrated for pancreatic adenocarcinoma in vitro and in vivo. 1,2 GP-2250 inhibited tumour cell proliferation and induced apoptotic cytotoxicity. In vivo, the growth of patient-derived pancreatic tumour tissue was strongly inhibited in xenograft mouse models. 1,2 GP-2250 is presently in a clinical trial for the treatment of pancreatic cancer (NCT 03854110). 3 Its molecular mechanism of action, however, has remained unclear.As GP-2250 showed comparable antineoplastic activity in pancreatic and mesothelioma tumour cell lines, 1,4 GP-2250 was expected to target a common feature of cancer cells such as aerobic glycolysis, a hallmark of cancer metabolism. [5][6][7] As the first step in glycolysis,

Second-Line Treatment of Pancreatic Adenocarcinoma: Shedding Light on New Opportunities and Key Talking Points from Clinical Trials

“… 29 GP-2250 has been shown in preclinical models to inhibit glyceraldehyde-3-phosphate dehydrogenase, thus limiting aerobic glycolysis, and selectively inducing oxidative stress, mitochondrial dysfunction, and apoptosis. 30 When combined with gemcitabine, the drugs act synergistically in a dose-dependent manner. The open-label phase 1/2 trial of GP-2250 with gemcitabine is underway in patients with advanced unresectable or mPDAC who have progressed on prior FOLFIRINOX.…”

In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes

“…GP-2250 (Figure 1) is a relatively novel anti-neoplastic substance that has recently been investigated in different cancers [13][14][15][16]. The substance is an oxathiazinane (tetrahydro-1,4,5-oxathiazin-4,4-dioxide) and has inhibitory effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression and activity, selectively resulting in oxidative stress, mitochondrial dysfunction, and programmed cell death in cancer cells [16].…”

“…As shown in in vitro as well as in vivo experiments, GP-2250 is able to downregulate the viability of pancreatic carcinoma cells, which is also accompanied by the induction of apoptosis as well as necrosis. The same study group reported on the anti-tumor activity of GP-2250, investigating other malignancies as well [13][14][15][16]. Importantly, the substance proved to be safe in nude mice, indicated by acute or chronic toxicity only at extremely high concentrations (acute toxicity at 2000 mg/kg*BW and chronic toxicity at concentrations higher than 1000 mg/kg*BW in nude mice).…”

“…Thus, in a phase I/II trial, GP-2250 is currently being investigated in combination with gemcitabine in patients with advanced pancreatic carcinoma (clinicaltrials.gov: NCT03854110) [15]. Moreover, the anti- The substance is an oxathiazinane (tetrahydro-1,4,5-oxathiazin-4,4-dioxide) and has inhibitory effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression and activity, selectively resulting in oxidative stress, mitochondrial dysfunction, and programmed cell death in cancer cells [16].…”