Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 144, Issue -, Pages 359-371Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.024
Keywords
Sigma-2 receptors; Pancreatic cancer; Multifunctional compounds; Thiosemicarbazones; Mithocondrial superoxide
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Funding
- National Institutes of Health [US NIH 5R01CA16376402]
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The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (sigma(2)) receptor was recently proposed as a promising target for pancreatic cancer therapy, we explored our previously developed multifunctional thiosemicarbazones, designed to synergistically impair cell energy levels, by targeting sigma(2) and P-gp proteins and chelating Iron. A deconstruction approach was herein applied by removing one function at a time from the potent multifunctional thiosemicarbazones 1 and 2, to investigate the contribution to cytotoxicity of each target involved. The results from in vitro (panel of pancreatic tumor cells) and in vivo experiments (C57BL/6 bearing KP02 tumor), suggest that while the multifunctional activity was not required for the antitumor activity of these thiosemicarbazones, sigma(2)-targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of sigma(2)-targeting. (C) 2017 Elsevier Masson SAS. All rights reserved.
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