Antitumor activity of 2-amino-4,4α-dihydro-4α, 7-dimethyl-3H-phenoxazine-3-one against Meth A tumor transplanted into BALB/c mice

Mori, Hiroshi; Honda, Katsuaki; Ishida, Ryoji; Nohira, Tomoyoshi; Tomoda, Akio

doi:10.1097/00001813-200009000-00010

Cited by 29 publications

(37 citation statements)

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“…Since drugs absorbed in the human body may be primarily exposed to erythrocytes circulating in the blood, before reaching the liver, where many drugs are detoxified by cytochrome P-450, our results suggest that hemoglobin in erythrocytes may play an important role in detoxifying some drugs, such as pyrogallol. We previously showed that o-aminophenol and its derivatives were metabolized to phenoxazines in human erythrocytes or by hemoglobin, and that these phenoxazines show less adverse effects in vivo using mice (Mori et al 2000), which agrees with the results of Eckert and Eyer (1983) that o-aminophenol does not exhibit nephrotoxicity due to rapid formation of the phenoxazines in dogs. Metabolism of drugs by hemoglobin have been reported by some authors.…”

Section: Discussionsupporting

confidence: 83%

“…Later, Tomoda et al (1984Tomoda et al ( , 1986aTomoda et al ( and 1992 found that 3-hydroxyanthranilic acid, o-aminophenol, and 2-amino-5-methylphenol were metabolized to phenoxazine compounds in the presence of human hemoglobin or human erythrocytes, coupled with the oxidoreductive reactions of hemoglobin. The phenoxazine produced by the reaction of human or bovine hemoglobin with 2-amino-5-methylphenol has been shown to exert anti-cancer effects (Mori et al 2000;Koshibu-Koizumi et al 2002), immunosuppressive effects (Gao et al 2002), and antiviral effects (Iwata et al 2003).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

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Metabolism of Pyrogallol to Purpurogallin by Human Erythrocytic Hemoglobin

Miyazaki

Arai

Iwamoto

et al. 2004

Tohoku J. Exp. Med.

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The aim of this study was to investigate the oxidoreductive reactions of human hemoglobin with pyrogallol and the metabolism of pyrogallol by the protein, which contains a protoporphyrin IX like cytochrome P-450. Pyrogallol, having three hydroxy groups at the adjacent positions in the benzene ring, oxidized human oxyhemoglobin to methemoglobin and reduced human methemoglobin to oxyhemoglobin. Since superoxide dismutase and catalase inhibited these reactions extensively, active oxygens such as superoxide and hydrogen peroxide were considered to be involved in the oxido-reductive reaction of human hemoglobin by pyrogallol. It was also found that the metabolism of pyrogallol to purpurogallin occurred quickly in human erythrocytes, i.e., when pyrogallol was added to human erythrocyte suspension, it oxidized intracellular hemoglobin and produced purpurogallin. The metabolism of pyrogallol to purpurogallin was explained by the pyrogallol oxidation with superoxide and hydrogen peroxide produced during the oxidoreductive reactions of human hemoglobin with pyrogallol. The present results show that human erythrocytes can metabolize pyrogallol, suggesting that the cells may be involved in the metabolism of some drugs in the human body.erythrocytes; hemoglobin; pyrogallol; purpurogallin © 2004 Tohoku University Medical Press Though drug metabolism has been shown to be carried out by cytochrome P-450 in the liver (Omura and Sato 1964;Lu et al. 1972), the contribution of erythrocytic hemoglobin, a protoporphyrin IX containing hemoprotein like cytochrome P-450, to drug metabolism is unlikely to attract much attention. Tomoda et al. (1977a) showed that aniline was metabolized to p-aminophenol by human erythrocytes, in the presence of catalytic amounts of methylene blue. Mieyal and Blumer (1976) demonstrated that oxyhemoglobin can hydroxylate aniline to p-ami-

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Section: Discussionsupporting

confidence: 83%

Section: Materials and Methods Materialsmentioning

confidence: 99%

Metabolism of Pyrogallol to Purpurogallin by Human Erythrocytic Hemoglobin

Miyazaki

Arai

Iwamoto

et al. 2004

Tohoku J. Exp. Med.

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“…Phenoxazine compounds including 2-amino-4, 4·-dihydro-·, 7-dimethyl-3H-phenoxazine-3-one (Phx-1), and 2-aminophenoxazine-3-one (Phx-3), which are synthesized by the reactions of o-aminophenols with bovine hemoglobin (18,19), are oxidative phenoxazines like actinomycin D (20) and exert anticancer activity against various cancer cells in vitro and in vivo, promoting cellular apoptosis (21)(22)(23) 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells caspase-dependent apoptosis in multiple myeloma cells (24), and caspase-independent apoptosis in neuroblastoma cells, glioma cells and gastric cancer cells (25)(26)(27). However, it remains unclear how pHi is affected, and how ROS and NF-κB are implicated in the apoptosis of cancer cells in the presence of Phx-3.…”

Section: Introductionmentioning

confidence: 99%

2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells

Tomoda¹

2010

Int J Oncol

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Abstract. 2-Aminophenoxazine-3-one (Phx-3)-induced apoptosis was investigated. Phx-3 suppressed the viability of human lung adenocarcinoma cell line A549 and induced cellular apoptosis 6 h after treatment. Prior to these events, intracellular pH (pHi) was rapidly decreased from pH 7.65 to 7.10 within 30 min when A549 cells were treated with 7 μM Phx-3. This intracellular acidification continued for 3 h in the cells. Augmented production of reactive oxygen species (ROS) was obseved 1 h after treatment of A549 cells with 7 μM Phx-3, and cell cycle arrest at G 1 was indicated 3 h after treatment. The translocation of NF-κB from the cytosol to the nucleus was clearly indicated 1 h after the administration of Phx-3 to A549 cells, while it was significantly suppressed when Nac, a scavenger of ROS, was added to the cells with Phx-3. The Phx-3-induced apoptosis in A549 cells was significantly suppressed when Nac was administered to the cells. These results suggest that a decrease of pHi, caused by depolarization of the mitochondria, may trigger the dysfunction of mitochondria causing ROS production; therefore, both the translocation of NF-κB from the cytoplasm to the nucleus and apoptosis induction were promoted in A549 cells. Microscopic examination of the cellular localization of Phx-3 in A549 cells revealed that Phx-3 was mainly localized in the cytoplasm and the mitochondria, but not in the nucleus. The present results indicate that Phx-3 might be a strong anticancer drug against lung cancer, which is intractable to chemotherapy, by causing various early events, including the decrease of pHi and ROS production, and finally inducing cellular apoptosis.

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“…In order to overcome such an alarming situation, drugs to prevent colorectal cancer are urgently required. Although few chemotherapeutic agents act effectively against colorectal cancer, it has been demonstrated that 2-amino-4,4·-dihydro-4·,7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3), the oxidative form of phenoxazines, exert strong anticancer activity against a variety of cancer cells in vitro and in vivo (4)(5)(6)(7)(8)(9). However, it is still unclear whether or not these phenoxazines are effective against colon cancers that are intractable to chemotherapeutic agents (2,3).…”

Section: Introductionmentioning

confidence: 99%

Anticancer activity of phenoxazines produced by bovine erythrocytes on colon cancer cells

Nakachi

Tabuchi²,

Takasaki³

et al. 2010

Oncol Rep

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Abstract. The present study investigated the anticancer activity of 2-aminophenoxazine-3-one (Phx-3) and 2-amino-4,4·-dihydro-4·,7-dimethyl-3H-phenoxazine-3-one (Phx-1), which were obtained by improved preparation methods using bovine erythrocyte suspension, on colon cancer cell lines COLO201, DLD1 and PMCO1 in vitro. The preparation methods for Phx-1 and Phx-3 had the advantages of extensively shortening reaction time and reducing sample volumes up to one-seventh during treatment, compared with the conventional method using bovine hemoglobin solution, resulting in extensive reduction of handling time. Phx-1 and Phx-3 thus obtained were identified as pure by the absorption spectra and NMR spectra. These phenoxazines exerted strong, dose-dependent anticancer activity against colon cancer cell lines COLO201, DLD1 and PMCO1 in vitro and induced apoptosis of these cells. The present results demonstrate that Phx-1 and Phx-3, which were prepared by extensively improved methods using bovine erythrocytes, may be useful as therapeutic drugs against colon cancer that is intractable to chemotherapy.

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Antitumor activity of 2-amino-4,4α-dihydro-4α, 7-dimethyl-3H-phenoxazine-3-one against Meth A tumor transplanted into BALB/c mice

Cited by 29 publications

References 10 publications

Metabolism of Pyrogallol to Purpurogallin by Human Erythrocytic Hemoglobin

Metabolism of Pyrogallol to Purpurogallin by Human Erythrocytic Hemoglobin

2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells

Anticancer activity of phenoxazines produced by bovine erythrocytes on colon cancer cells

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