Human pancreatic cancer cells under nutrient deprivation are vulnerable to redox system inhibition.

Abstract

Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.

• Authors: Takefumi Onodera, Isao Momose, Hayamitsu Adachi, Yohko Yamazaki, Ryuichi Sawa, Shun-Ichi Ohba, Manabu Kawada
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 49 Pg. 16678-16690 (12 04 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32978257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Onodera et al.

Chemical References

• Alkenes
• Antineoplastic Agents
• Reactive Oxygen Species
• Spiro Compounds
• papyracillic acid
• Auranofin
• Thioredoxins
• Caspase 3
• Glutathione
• Penicillic Acid

Topics

• Alkenes (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Auranofin (chemistry, pharmacology, therapeutic use)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Glutathione (chemistry, metabolism)
• Humans
• Metabolome (drug effects)
• Mice
• Mice, Nude
• Nutrients (chemistry, deficiency)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Penicillic Acid (chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Spiro Compounds (chemistry, pharmacology)
• Thioredoxins (chemistry, metabolism)
• Up-Regulation (drug effects)