Abstract
The aggressiveness of pancreatic cancer urgently requires more efficient treatment options. Because the sigma-2 (σ2) 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 σ2 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, σ2-targeting appeared to allow alternative tumor cell death mechanisms, leading to potent and less toxic off-targets toxicities compared to other thiosemicarbazones devoid of σ2-targeting.
Keywords:
Mithocondrial superoxide; Multifunctional compounds; Pancreatic cancer; Sigma-2 receptors; Thiosemicarbazones.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Death / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Chelating Agents / chemical synthesis
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Chelating Agents / chemistry
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Chelating Agents / pharmacology*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Humans
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Receptors, sigma / antagonists & inhibitors*
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Receptors, sigma / metabolism
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Structure-Activity Relationship
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Thiosemicarbazones / chemical synthesis
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Thiosemicarbazones / chemistry
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Thiosemicarbazones / pharmacology*
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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Chelating Agents
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Receptors, sigma
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Thiosemicarbazones
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sigma-2 receptor