Phenoxazine Compounds Produced by the Reactions with Bovine Hemoglobin Show Antimicrobial Activity Against Non-tuberculosis Mycobacteria

Shimizu, Shigetaka; Suzuki, Mamoru; Tomoda, Akio; Arai, Sadao; Taguchi, Haruhiko; Hanawa, Tomoko; Kamiya, Shigeru

doi:10.1620/tjem.203.47

Cited by 60 publications

(64 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2-Aminophenoxazine-3-one (Phx-3) was prepared according to the method described by Shimizu et al (6). The chemical structure of Phx-3 is shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The agents employed to induce these cellular events in cancer cells may be favorable candidates for the treatment of cancer (4,5). We previously found that 2-aminophenoxazine-3-one (Phx-3), produced by the reactions of o-aminophenol and bovine hemoglobin solutions (6), induced apoptosis in various cancer cells, including the gastric cancer cell lines MKN45 and KATO III (7), the human glioblastoma cell lines A-172 and U-251 (8), human neuroblastoma NB-1 cells (9), and human multiple myeloma U266 cells (10), regardless of caspase-3-dependent or -independent pathways. We previously reported that Phx-3 induced mitochondrial depolarization and apoptosis in human myeloma U266 cells (10); the caspase-3-dependent apoptosis of the cells was preceded by mitochondrial depolarization, induced by Phx-3.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial depolarization and apoptosis associated with sustained activation of c-jun-N-terminal kinasein the human multiple myeloma cell line U266 induced by 2-aminophenoxazine-3-one

Takasaki

Hanyu²,

Iwamoto³

et al. 2009

Mol Med Rep

View full text Add to dashboard Cite

Abstract.We investigated the involvement of c-jun-N-terminal kinase (JNK) in mitochondrial depolarization and apoptosis in a human multiple myeloma cell line, U266, treated with 2-aminophenoxazine (Phx-3). It was found that, with Phx-3 administration to U266 cells, JNK was phosphorylated 2 and 7.5-fold at 6 and 24 h, respectively, compared to the Phx-3-free control. This increasing activation of JNK in U266 cells with Phx-3 correlated with cellular disorders, such as mitochondrial depolarization and cellular apoptosis. When the JNKspecific inhibitor SP6000125 was administered to the U266 cells together with Phx-3, the number of cells exhibiting mitochondrial depolarization and cellular apoptosis was significantly reduced. These results suggest that JNK activation in human multiple myeloma U266 cells may be closely associated with mitochondrial depolarization and apoptosis. IntroductionIt is generally accepted that the loss of mitochondrial membrane integrity causes the release of cytochrome c, caspase-3 activation and cellular apoptosis (1-3). The agents employed to induce these cellular events in cancer cells may be favorable candidates for the treatment of cancer (4,5). We previously found that 2-aminophenoxazine-3-one (Phx-3), produced by the reactions of o-aminophenol and bovine hemoglobin solutions (6), induced apoptosis in various cancer cells, including the gastric cancer cell lines MKN45 and KATO III (7), the human glioblastoma cell lines A-172 and U-251 (8), human neuroblastoma NB-1 cells (9), and human multiple myeloma U266 cells (10), regardless of caspase-3-dependent or -independent pathways. We previously reported that Phx-3 induced mitochondrial depolarization and apoptosis in human myeloma U266 cells (10); the caspase-3-dependent apoptosis of the cells was preceded by mitochondrial depolarization, induced by Phx-3. However, the mechanism by which Phx-3 caused mitochondrial depolarization in the cells was not clarified.It has been demonstrated that c-jun-N-terminal kinase (JNK) plays a crucial role in the activation of the intrinsic apoptotic pathway mediated by mitochondria (11). Tsuruta et al (12) demonstrated that JNK promotes Bax translocation to the mitochondria, resulting in cytochrome c release and cellular apoptosis. JNK was activated in multiple myeloma cell lines, including U266 cells, when treated with arsenic trioxide (ATO). Its activation was sustained for a long time and was associated with the ATO-induced apoptosis of U266 cells (13). Therefore, it is conceivable that the Phx-3-induced mitochondrial depolarization and apoptosis in U266 cells that we observed previously (10) is associated with JNK activation. In the present study, we investigated the role of JNK in Phx-3-induced mitochondrial depolarization and cellular apoptosis in human multiple myeloma U266 cells. Materials and methodsPreparation of 2-aminophenoxazine-3-one. 2-Aminophenoxazine-3-one (Phx-3) was prepared according to the method described by Shimizu et al (6). The chemical structure of Phx-3 is shown in Fig. 1. Phx-3...

show abstract

“…2-Aminophenoxazine-3-one (Phx-3) was prepared according to the method described by Shimizu et al (6). The chemical structure of Phx-3 is shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mitochondrial depolarization and apoptosis associated with sustained activation of c-jun-N-terminal kinasein the human multiple myeloma cell line U266 induced by 2-aminophenoxazine-3-one

Takasaki

Hanyu²,

Iwamoto³

et al. 2009

Mol Med Rep

View full text Add to dashboard Cite

show abstract

“…For this study, Phx-3 was prepared according to the method described by Shimizu et al (19). Chemical structure of Phx-3 is depicted in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…In vivo experiments demonstrated that Phx-3 prevented pulmonary metastasis of mouse B16 melanoma cells (13). In addition to anti-cancer activity, Phx-3 exhibits various biological activities, including a potent anti-inflammatory effect by suppressing the production of nitric oxide (NO) and prostaglandin E2 (14), as well as immunosuppressive, anti-viral and anti-mycobacterial effects and the elimination of Helicobacter pylori (15)(16)(17). All these biological effects suggest the potent therapeutic possibility of Phx-3.…”

Section: Introductionmentioning

confidence: 99%

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

Moriya

Miyazawa

Kawaguchi³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro-apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-κB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-κB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress-mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment.

show abstract

Phenoxazine Compounds Produced by the Reactions with Bovine Hemoglobin Show Antimicrobial Activity Against Non-tuberculosis Mycobacteria

Cited by 60 publications

References 13 publications

Mitochondrial depolarization and apoptosis associated with sustained activation of c-jun-N-terminal kinasein the human multiple myeloma cell line U266 induced by 2-aminophenoxazine-3-one

Mitochondrial depolarization and apoptosis associated with sustained activation of c-jun-N-terminal kinasein the human multiple myeloma cell line U266 induced by 2-aminophenoxazine-3-one

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

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

Contact Info

Product

Resources

About