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J. Antibiot. 60(3): 196200, 2007
THE JOURNAL OF
ORIGINAL ARTICLE
ANTIBIOTICS
Piericidins C7 and C8, New Cytotoxic Antibiotics Produced by a Marine Streptomyces sp.
Yoichi Hayakawa, Shingo Shirasaki, Sayaka Shiba, Takashi Kawasaki, Yoshihide Matsuo, Kyoko Adachi, Yoshikazu Shizuri
Received: January 23, 2007 / Accepted: February 27, 2007 Japan Antibiotics Research Association
Abstract Piericidins C7 and C8, two new members of the piericidin family, were isolated from a marine actinomycete. The producing organism was identied as Streptomyces sp. based on the cultural, biochemical and chemotaxonomical characteristics as well as the 16S rRNA sequence. Piericidins C7 and C8 showed selective cytotoxicity against rat glia cells transformed with the adenovirus E1A gene (IC50 C7: 1.5 nM, C8: 0.45 nM) and
Neuro-2a mouse neuroblastoma cells (IC50 C7: 0.83 nM, C8:0.21 nM).
Keywords piericidin, marine actinomycete, Streptomyces, cytotoxic antibiotic
Introduction
The retinoblastoma tumor suppressor protein (pRB) plays an important role in cell-cycle and apoptosis control in mammalian cells and is inactivated during the development of a wide variety of human cancers [1, 2]. The adenovirus E1A gene product inactivates pRB thereby stimulating host cell DNA synthesis. Although this function of E1A induces the host cells to undergo apoptosis, stable transformants expressing E1A seem to exhibit an attenuated apoptotic response to E1A [3]. Then E1A-transformed cells might be an appropriate model for pRB-inactivated tumor cells. In
the course of screening for antitumor antibiotics against E1A-transformed cells from marine microorganisms [4], an actinomycete was found to produce two new members of the piericidin family, piericidins C7 and C8 (Fig. 1). Both compounds showed selective cytotoxicity against rat glia cells transformed with E1A [5].
This paper describes the taxonomy of the producing organism, and the fermentation, isolation, physico-chemical properties and biological activities of piericidins C7 and C8. The structure elucidation of the piericidins is described in the accompanying paper [6].
Materials and Methods
Taxonomy
The characterization of the culture was carried out by the methods of the International Streptomyces Project (ISP) [7,8]. Cell wall amino acids were analyzed by the methods of Becker [9]. Cellular fatty acid and quinone compositions were analyzed by GC-MS and LC-MS, respectively. The DNA G C content (mol%) of the strain was determined using HPLC analysis of hydrolyzed genome DNA according to Tamaoka and Komagata [10]. Genomic...