inostamycin and Carcinoma--Squamous-Cell

Head and neck squamous cell carcinoma is the sixth most common type of neoplasm worldwide, but its prognosis has not improved significantly in recent years. Therefore, efforts need to be intensified to gain a better understanding of this disease and develop novel treatment strategies. Inhibition of cytidine 59-diphosphate 1,2-diacyl-sn-glycerol: inositol transferase by inostamycin, an antibiotic isolated from Streptomyces sp. MH816-AF15, induces G1 cell cycle arrest accompanied by a decrease in cyclin D1 and phosphorylated RB protein levels, along with suppression of in vitro invasive ability through reduced production of matrix metalloproteinases (MMP-2 and MMP-9) and cell motility in head and neck cancer cell lines. Furthermore, inostamycin abrogated the stimulatory effect of VEGF (vascular endothelial growth factor) on growth and migration activities of endothelial cells by targeting extracellular signal-regulated kinase-cyclin D1 and p38 pathways, respectively. Because inostamycin has both antiproliferative and anti-invasive abilities, inhibition of phosphatidylinositol synthesis could be a potent therapeutic strategy for head and neck cancer as the 'cancer dormant therapy', i.e. a therapeutic concept to prolong 'time to treatment failure' or 'time to progression'.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclin D1; Furans; G1 Phase; Head and Neck Neoplasms; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phosphatidylinositols; Vascular Endothelial Growth Factor A

Inostamycin, which was recently isolated from Streptomyces sp. MH816-AF15 as an inhibitor of cytidine 5'-diphosphate 1,2-diacyl-sn-glycerol (CDP-DG): inositol transferase, caused a G1-phase accumulation in the cell cycle of small cell lung carcinomas. To investigate whether the cytostatic effect of inostamycin is restricted to lung carcinoma cell lines or applicable to other type of cells, we tested five oral squamous cell carcinoma (SCC) cell lines. Cell growth was suppressed in 62.5--125 ng/ml inostamycin in the culture medium in all oral cancer cell lines tested, with non-viable cells being <1%, indicating inostamycin is cytostatic on SCC cell lines. Decrease in cyclin D1 mRNA and protein expression due to the inostamycin treatment was accompanied by suppression of phosphorylated retinoblastoma susceptibility gene product (pRB-P) levels. Moreover, flow cytometric analysis showed that inostamycin induced an increase in G1/G0 cells (1.2--3.2 fold) over 24 h. These results suggest that inostamycin is a useful agent for tumour dormant cytostatic therapy for oral SCC.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Cell Cycle; Cell Division; Cyclin D1; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flow Cytometry; Furans; Humans; Membrane Proteins; Mouth Neoplasms; Oligonucleotides, Antisense; Retinoblastoma Protein; RNA, Neoplasm; Transferases (Other Substituted Phosphate Groups); Tumor Cells, Cultured