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.

• Authors: Thilo Gambichler, Britta Majchrzak-Stiller, Ilka Peters, Jürgen C Becker, Johanna Strotmann, Nessr Abu Rached, Thomas Müller, Waldemar Uhl, Marie Buchholz, Chris Braumann
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 149 Issue 12 Pg. 10831-10840 (Sep 2023) ISSN: 1432-1335 [Electronic] Germany
• PMID: 37311987 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• TOR Serine-Threonine Kinases
• Antineoplastic Agents

Topics

• Humans
• Carcinoma, Merkel Cell (pathology)
• Skin Neoplasms (pathology)
• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• Merkel cell polyomavirus (physiology)
• TOR Serine-Threonine Kinases
• Antineoplastic Agents