Inhibitors of insulin-like growth factor-1 receptor tyrosine kinase are preferentially cytotoxic to nutrient-deprived pancreatic cancer cells

• Published in: Biochemical and biophysical research communications 2009-02, Vol.380 (1), p.171-176
• Main Authors: Momose, Isao, Kunimoto, Setsuko, Osono, Michiyo, Ikeda, Daishiro
• Format: Article
• Language: English
• Subjects: AG1024; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Cell Survival - drug effects; Drug Screening Assays, Antitumor; Humans; IGF-1R; IGF-1R kinase inhibitor; Nutrient starvation; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - isolation & purification; Protein Kinase Inhibitors - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Tyrphostins - chemistry; Tyrphostins - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2009.01.065

Chronic deprivation of nutrients is rare in normal tissues, however large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Some cancers show an inherent ability to tolerate severe growth conditions. Therefore, we screened chemical compounds to identify cytotoxic agents that function preferentially in nutrient-deprived conditions. We found that AG1024, a specific inhibitor of insulin-like growth factor-1 receptor tyrosine kinase (IGF-1R), showed preferential cytotoxicity to human pancreatic cancer cells in nutrient-deprived conditions relative to cells in nutrient-sufficient conditions. The cytotoxicity of I-OMe-AG538 (another specific inhibitor of IGF-1R kinase) was also enhanced in nutrient-deprived cells. In addition, AG1024 and I-OMe-AG538 potently inhibited IGF-1R activation to nutrient-deprived cells. In contrast, conventional chemotherapeutic drugs, as well as inhibitors of PDGFR and EGFR kinases, elicited weak cytotoxicity. These data indicate that nutrient-deprived human pancreatic cancer cells have increased sensitivity to inhibition of IGF-1R activation. IGF-1R inhibitors offer a promising strategy for anticancer therapeutic approaches that are oriented toward tumor microenvironment.