Anti‐cancer agent OK432 induces manganese superoxide dismutase in human granulocytes

Abstract

Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in scavenging 02-. OK432, a Streptococcal preparation, has anti-tumor activity and is also known to be a biological-response modifier. In this study, we have examined the regulation of MnSOD gene by OK432 in human granulocytes. Granulocytes had a low activity of MnSOD OK432 increased MnSOD mRNA levels in a dose-dependent manner and its activity in granulocytes. OK432 also induced the MnSOD mRNA in HL60 promyelocytes, while not affecting the levels of Many forms of acute and chronic inflammation are characterized by local accumulation of inflammatory cells, including granulocytes and macrophagcs. In rcsponse to an exogenous stimulus, granulocytes increase their phagocytic activity and antibody-dependent cellular cytotoxicity (Lopez et al., 1986). They have been also implicatcd in the generation of various cytokines that stimulate fibroblasts and endothelial cells to produce hematopoietic growth factors (Lindemann et al., 1989). Thus, granulocytes mediate inflammation and immune action not only by directly producing cytokines but also by inducing surrounding cells to produce them.Superoxide dismutascs (SODs) are metallo-enzymes that catalyze the dismutation of 02-(superoxide radicals) to H 2 0 z (hydrogen peroxide) and O2 (oxygen). SODS are important as initial components in the cellular defense against 02-. Three forms of SODS with distinctive distributions characterized by their metal requirements have been found (Fridovich, 1989): MnSOD is located in thc mitochondria of eukaryotes and also found in prokaryotes; coppcr-zinc SOD (CuZnSOD) is mainly in the eukaryotes; and iron SOD (FeSOD) is mainly in the cytosol of prokaryotes. Production of CuZnSOD and FeSOD arc constitutive. On the other hand, MnSOD is thought to be involved in the inflammatory rcsponsc, since it is inducible by various stimuli such as IL-1 or TNF, bacterial lipopolysaccharide (LPS). interferon gamma and hypoxia (Wong and Gocddel, 1988; Vinsner et uf., 1990; 'I'aniguchi, 1992).OK432 is a hcat-and penicillin-treated preparation of Streptococcus pyogenes A3 (Uchida et al., 1984). OK432 has been reported to have potent anti-tumor activity both in vivo and in vitro; it has therapeutic effects in patients with cancer (Uchida et ol., 1984). On the other hand, OK432 is also well-known as a biological-rcsponsc modifier (BRM): it induces cytotoxic T cells and augmcnts natural-killer (NK) activity (Saito et al., 1986;Uchida and Klein, 1985). These studies suggest that these anti-tumor cffccts may occur through a host-mediated action. Furthermore. many studies have shown that OK432 has a radioprotective activity in lethally irradiated experimental animals (Kurishita et al., 1991).A major component of granulocytcs in response to microbial invasion is the generation of reactive oxygen species. Since reactive oxygen species are associated with the pathology of DNA damage, which leads to malignant transformation, the presence of SODs plays a critical role in protecting cells against ox...