10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase-dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-κB and (BIRC6-XIAP) complexes

• Published in: Drug design, development and therapy Vol. 11; pp. 3045 - 3063
• Main Authors: Zhang, Jianxin, Chen, Ming, Zhang, Wenzhi, Patrick Nwabueze Okechukwu, Morak-Młodawska, Beata, Pluta, Krystian, Jeleń, Malgorzata, Abdah Md Akim, Kok-Pian Ang, Kah Kooi Ooi
• Format: Journal Article
• Language: English
• Published: Macclesfield Taylor & Francis Ltd 2017; Dove Medical Press
• Subjects: anticancer; Anticancer properties; Apoptosis; cancer cell invasion; Cancer therapies; Caspase; Cell cycle; Cell death; Cell proliferation; Chemotherapy; Cytotoxicity; Gastric cancer; Gene expression; Hydrocarbons; Inhibition; Leukemia; Membrane potential; Metastasis; Mitochondria; mitochondrial function disruption; Mutation; NF-κB protein; Original Research; Ovarian cancer; Ovarian carcinoma; oxidative damage; Phenothiazine; programmed cell death; Reactive oxygen species; Side effects; Sulfur; Toxicity; XIAP protein; Poland; Beijing China; Malaysia; China
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S144415

The asymptomatic properties and high treatment resistance of ovarian cancer result in poor treatment outcomes and high mortality rates. Although the fundamental chemotherapy provides promising anticancer activities, it is associated with severe side effects. The derivative of phenothiazine, namely, 10H-3,6-diazaphenothiazine (PTZ), was synthesized and reported with ideal anticancer effects in a previous paper. In this study, detailed anticancer properties of PTZ was examined on A2780 ovarian cancer cells by investigating the cytotoxicity profiles, mechanism of apoptosis, and cell invasion. Research outcomes revealed PTZ-induced dose-dependent inhibition on A2780 cancer cells (IC50 =0.62 µM), with significant less cytotoxicity toward HEK293 normal kidney cells and H9C2 normal heart cells. Generation of reactive oxygen species (ROS) and polarization of mitochondrial membrane potential (Δψm) suggests PTZ-induced cell death through oxidative damage. The RT2 Profiler PCR Array on apoptosis pathway demonstrated PTZ-induced apoptosis via intrinsic (mitochondria-dependent) and extrinsic (cell death receptor-dependent) pathway. Inhibition of NF-κB and subsequent inhibition of (BIRC6-XIAP) complex activities reduced the invasion rate of A2780 cancer cells penetrating through the Matrigel™ Invasion Chamber. Lastly, the cell cycle analysis hypothesizes that the compound is cytostatic and significantly arrests cell proliferation at G2/M phase. Hence, the exploration of the underlying anticancer mechanism of PTZ suggested its usage as promising chemotherapeutic agent.