Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells.

Abstract

Advanced renal cell carcinoma (RCC) remains an incurable disease, and newer anticancer drugs are needed. Bisebromoamide, a novel cytotoxic peptide, was isolated from the marine cyanobacterium Lyngbya species at our laboratory in 2009. This compound specifically inhibited the phosphorylation of ERK in platelet-derived growth factor-activated normal rat kidney cells. The aim of this study was to evaluate the effect and elucidate the potential mechanism of Bisebromoamide actions on human RCC cells. Two renal cancer cell lines, 769-P and 786-O, were used. The effects of Bisebromoamide were analyzed employing assays for water-soluble Tetrazolium-1 salts. Apoptosis was determined by flow cytometric TUNEL analysis. Cell-cycle distributions were analyzed by flow cytometry using BrdU/propidium iodide (PI) staining. Kinases of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway and Raf/MEK/ERK pathway were analyzed by Western blotting. After Bisebromoamide treatment for 48 and 72 h, cell viability was significantly decreased in both cell lines at 1 and 10 μmol/L. After treatment with 1 μmol/L Bisebromoamide for 72 h, apoptosis and the increased percentage of cells in the sub-G1 phase were observed in both cell lines. Bisebromoamide inhibited the phosphorylation of ERK and Akt in both cell lines tested. Similar effects were demonstrated for phosphorylation of mTOR and p70 S6. Bisebromoamide is a promising potential agent against RCC due to its ability to inhibit both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways.

• Authors: Kenjiro Suzuki, Ryuichi Mizuno, Kiyotake Suenaga, Toshiaki Teruya, Nobuyuki Tanaka, Takeo Kosaka, Mototsugu Oya
• Journal: Cancer medicine (Cancer Med) Vol. 2 Issue 1 Pg. 32-9 (Feb 2013) ISSN: 2045-7634 [Electronic] United States
• PMID: 24133625 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Lyngbya Toxins
• Oligopeptides
• bisebromoamide
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (enzymology, pathology)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Humans
• Kidney Neoplasms (enzymology, pathology)
• Lyngbya Toxins (pharmacology)
• Oligopeptides (administration & dosage, pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured