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

Abstract

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.

• Authors: Koshi Kawakami, Miho Hattori, Takatsugu Inoue, Yuriko Maruyama, Junko Ohkanda, Nobuo Kato, Miki Tongu, Takaya Yamada, Miho Akimoto, Keizo Takenaga, Takeshi Sassa, Junji Suzumiy, Yoshio Honma
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 12 Issue 7 Pg. 791-800 (Sep 2012) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 22263802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Diterpenes
• Glycosides
• Hypoxia-Inducible Factor 1, alpha Subunit
• ISIR-005
• ISIR-042
• Mycotoxins
• fusicoccin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Diterpenes (chemistry, pharmacology, therapeutic use)
• Female
• Glycosides (chemistry, pharmacology, therapeutic use)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mycotoxins (chemistry, pharmacology, therapeutic use)
• Ovarian Neoplasms (drug therapy, pathology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Transplantation, Heterologous