The effect of GP-2250 on cultured virus-negative Merkel cell carcinoma cells: preliminary results

Abstract

Background Even in the novel immunotherapy era, Merkel cell carcinoma (MCC) remains challenging in its treatment. Apart from Merkel cell polyomavirus (MCPyV) associated MCC, this cancer is linked in about 20% of cases to ultraviolet-induced mutational burden frequently causing aberrations in Notch and PI3K/AKT/mTOR signalling pathways. The recently developed agent GP-2250 is capable to inhibit growth of cells of different cancers, including pancreatic neuroendocrine tumors. The objective of the present study was to investigate the effects of GP-2250 on MCPyV-negative MCC cells. Methods Methods We employed three cell lines (MCC13, MCC14.2, MCC26) which were exposed to different GP-2250doses. GP-2250’s effects on cell viability, proliferation, and migration were evaluated by means of MTT, BrdU, and scratch assays, respectively. Flow cytometry was performed for the evaluation of apoptosis and necrosis. Western blotting was implemented for the determination of AKT, mTOR, STAT3, and Notch1 protein expression. Results Cell viability, proliferation, and migration decreased with increasing GP-2250 doses. Flow cytometry revealed a dose response to GP-2250 in all three MCC cell lines. While the viable fraction decreased, the share of necrotic and in a smaller amount the apoptotic cells increased. Regarding Notch1, AKT, mTOR, and STAT3 expression a comparatively time- and dose-dependent decrease of protein expression in the MCC13 and MCC26 cell lines was observed. By contrast, Notch1, AKT, mTOR, and STAT3 expression in MCC14.2 was scarcely altered or even increased by the three dosages of GP-2250 applied. Conclusions The present study indicates GP-2250 having anti-neoplastic effects in MCPyV-negative tumor cells in regard to viability, proliferation, and migration. Moreover, the substance is capable of downregulating protein expression of aberrant tumorigenic pathways in MCPyV-negative MCC cells.

Current Progress in Vaccines against Merkel Cell Carcinoma: A Narrative Review and Update

“…Other therapeutic approaches currently focus on the energy metabolism, such as glycolysis and enhanced glucose uptake, as well as decreased oxidative metabolism. Energy metabolism is altered in many cancers and may be addressed with the use of antisense oligonucleotides or GAPDH-inhibitors such as fumaric acid esters [33,57,58].…”

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-neoplastic activity of GP-2250 has been investigated in malignant skin cancers, including Merkel cell carcinoma [14].…”