FR901228, a novel antitumor bicyclic depsipeptide produced by chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity.

Abstract

A novel antitumor bicyclic depsipeptide, FR901228, was isolated from a broth culture of Chromobacteriumviolaceum No. 968 as colorless prisms and the molecular formula was determined as C24H36N4O6S2. This antibiotic reverted the transformed morphology of a Ha-ras transformant to normal, and exhibited prominent antitumor activities against murine and humantumor cell lines both in vitro and in vivo. 301 Recent studies showed that a family of ras oncogenes was frequently found to harbor mutations in human tumors1}. The presence of these genes in human tumors play an important role in the development of tumors. A relationship between the levels of expression of the H&-ras oncogene and tumorigenic potential was clearly demonstrated2>3). In addition, it was shownthat morphological reversion of the ras transformed phenotype was achieved through micro-injection of antibodies specific for the Ha-ras gene product4*. Consequently, activated ras expression is thought to be critical in maintaining the transformed phenotype. These data show that if an agent selectively reversed the phenotype of a ras transformant, it would be a new class of anticancer drug targeting the components of ras-mediated signaling transduction pathways. For this reason, we have searched for novel products from fermentation broths which would reverse a r<zs-transformed phenotype to normal, and which could also show inhibitory effects on the growth of tumor cells.

Biochemical Analysis of Transcriptional Repression byDrosophila Histone Deacetylase 1

“…1B). Whereas sodium butyrate and TSA are well known HDAC inhibitors, FR901228 has recently been found to be a potent and specific inhibitor of histone deacetylases (36,37). In fact, FR901228 inhibits HDAC activity at a lower concentration than TSA (37).…”

Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP

“…4,5 HDAC inhibitors, which have been reported to cause not only cell cycle arrest and differentiation but also apoptosis, can inhibit proliferation and survival of tumor cells. 6 Consequently, various HDAC inhibitors, including the natural cyclic depsipeptide FR901228, [7][8][9][10] are under clinical development as novel drugs for cancer therapy. 6 Apoptosis has been shown to be induced through two main signaling pathways.…”

Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report

“…6,7 These include the human A549 lung adenocarcinoma, MCF-7 and ZR-75-1 breast adenocarcinoma, and LOX IMVI melanoma cell lines. 6,7 Depsipeptide shows a lack of cross-resistance with several commonly used cytotoxic agents; however, it has been identified as a P-glycoprotein (Pgp) substrate. 8 Depsipeptide is a member of a novel class of antineoplastic agents, the HDAC inhibitors (HDIs).…”