Abstract
Lipoxygenase metabolites of arachidonic acid can act as growth promoting factors for various cancer cell lines. Here we demonstrate that the 5-lipoxygenase inhibitor nordihydroguaiaretic acid potently inhibits anchorage-independent growth of human pancreatic and cervical cancer cells in soft agar and delays growth of pancreatic and cervical tumours established in athymic mice. Furthermore, nordihydroguaiaretic acid induces apoptosis of these cancer cells in vitro and in vivo. Potential mechanisms mediating these effects of nordihydroguaiaretic acid were examined. Nordihydroguaiaretic acid had no inhibitory effect on growth and survival signals such as tyrosine phosphorylation of the epidermal growth factor receptor or basal and growth factor-stimulated activities of extracellular signal-regulated kinase 1/2, p70s6k and AKT but selectively inhibited expression of cyclin D1 in the cancer cells. In addition, treatment with nordihydroguaiaretic acid lead to a disruption of the filamentous actin cytoskeleton in human pancreatic and cervical cancer cells which was accompanied by the activation of Jun-NH2-terminal kinase and p38mapk. Similar effects were obtained by treatment of the cancer cells with cytochalasin D. These results suggest that nordihydroguaiaretic acid induces anoikis-like apoptosis as a result of disruption of the actin cytoskeleton in association with the activation of stress activated protein kinases. In conclusion, nordihydroguaiaretic acid could constitute a lead compound in the development of novel therapeutic agents for various types of cancer.
Highlights
We demonstrate that nordihydroguaiaretic acid (NDGA) markedly inhibits growth and induces apoptosis of human pancreatic and cervical cancer cells in vitro and in vivo
Treatment of cells with NDGA leads to activation of Jun-NH2 terminal kinase (JNKs) and p38mapk, disruption of the filamentous actin cytoskeleton and cell detachment in a sequential fashion
To establish whether NDGA could inhibit tumour growth in vivo we first examined a panel of various epithelial cancer cell lines for their ability to consistently induce xenograft tumours in nude mice
Summary
We demonstrate that NDGA markedly inhibits growth and induces apoptosis of human pancreatic and cervical cancer cells in vitro and in vivo. NDGA did not prevent constitutive phosphorylation of p70s6k in these cells which regulates autonomous. NDGA did not inhibit major survival pathways such as tyrosine phosphorylation of the EGFR, or TGFa-induced activation of the ERK cascade and AKT. Treatment of cells with NDGA leads to activation of JNKs and p38mapk, disruption of the filamentous actin cytoskeleton and cell detachment in a sequential fashion. Similar results were observed using cytochalasin D. These results provide novel information about the potential mechanisms of action of NDGA in human pancreatic and cervical cancer cells and suggest that this agent may provide a lead compound for new therapies against both cancers
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