A novel fusicoccin derivative preferentially targets hypoxic tumor cells and inhibits tumor growth in xenografts

• Published in: Anti-cancer agents in medicinal chemistry Vol. 12; no. 7; p. 791
• Main Authors: Kawakami, Koshi, Hattori, Miho, Inoue, Takatsugu, Maruyama, Yuriko, Ohkanda, Junko, Kato, Nobuo, Tongu, Miki, Yamada, Takaya, Akimoto, Miho, Takenaga, Keizo, Sassa, Takeshi, Suzumiy, Junji, Honma, Yoshio
• Format: Journal Article
• Language: English
• Published: Netherlands 01.09.2012
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Hypoxia - drug effects; Cell Line, Tumor; Diterpenes - chemistry; Diterpenes - pharmacology; Diterpenes - therapeutic use; Female; Glycosides - chemistry; Glycosides - pharmacology; Glycosides - therapeutic use; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Mycotoxins - chemistry; Mycotoxins - pharmacology; Mycotoxins - therapeutic use; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Transplantation, Heterologous
• ISSN: 1875-5992
• DOI: 10.2174/187152012802650264

Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1α and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1α and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR- 042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.