Page 38 - SDIR5 Abstract book 21 12 2021.

IMAGING IN CANCER

Siramesine, a non-opioid σ2 receptor agonist as a potential agent for the development of
novel targeted treatments for pancreatic cancer

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E. Sereti , F. Koutsougianni , C. Tsimplouli , M. Pešić , J. Dinić , A. Divac Rankov , E. Armutak , A. Uvez ,
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K. Papaparaskeva , C. Dervenis , N. Sakellaridis , K. Dimas
1 Lund University, Department of Translational Medicine, Malmö, Sweden.
2 University of Thessaly, Department of Pharmacology, Larisa, Greece.
3 University of Belgrade, Institute for Biological Research "Siniša Stanković, Serbia.
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University of Belgrade, Institute of Mol Genetics and Genetic Engineering, Serbia.
5 Department of Histology and Embryology, Faculty of Veterinary Medicine, Istanbul University-Cerrahpasa,
Istanbul, Turkey.
6 Konstantopouleio General Hospital, Histopathology Department, Athens, Greece.
7 Hepatobiliary and Pancreatic Surgery Clinic, Metropolitan Hospital, Athens

Background: We previously reported that the σ2-receptor ligand, siramesine (SRM), demonstrated the best
activity among five commonly used sigma ligands screened in vitro for anticancer efficacy, with pancreatic
cancer being the most sensitive type of cancer in siramesine’s activity.
Aim: To investigate the efficacy of SRM on primary human pancreatic ductal adenocarcinoma (PDAC).
Materials and methods: The levels of σ receptors were studied by western blot analysis in two patient
derived ex vivo pancreatic cancer cell populations, isolated and developed in our laboratory. In vitro
evaluation of SRM was performed not only by the SRB cytotoxicity method, and the clonogenic assay.
Western blot, used to study the mechanism of action (MoA). SRM was further tested for toxicity in zebrafish
and in NOD/SCID mice. Finally, SRM was tested for in vivo activity in a new, patient-derived, pancreatic
cancer xenograft model (PDAC/PDX) developed in our lab. Results: In vitro studies showed that SRM could
kill primary pancreatic tumor cells via both autophagic death and apoptosis induction in a dose and time
dependent manner. Also, our data show that siramesine could significantly delay the growth of the
PDAC/PDX tumors at non-toxic doses alone or in combination with gemcitabine. Conclusion: Sigma-2
ligand, siramesine, found to exhibit good anticancer activity against a PDAC/PDX developed in our lab either
as monotherapy or as a sensitizer to gemcitabine. This is the first study employing a PDAC/PDX model to
study SRM’s activity. Further studies of SRM are ongoing to optimize its anticancer efficacy and elucidate
its underlying MoA.
Keywords: Siramesine, σ2 agonists, autophagy, apoptosis, pancreatic cancer, patient derived xenograft
This research has been co-financed by the European Union and Greek national funds through the
Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH–
CREATE–INNOVATE, grant T1EDK-01612 (MIS 5030862)

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