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In this study, we investigated the functional role of Akt and c-jun-NH2-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens. Mol Cancer Ther; 11(1); 132–42. ©2011 AACR.

Health effects due to environmental exposure to arsenic are a major health concern world-wide. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. As one of the common nutritional factors, ethanol is also a well-documented risk factor for many malignancies. However, little is known on the effects of co-exposure to arsenic and ethanol in mutagenesis and carcinogenesis. In this study, we investigate the mutagenic effect of co-exposure to arsenic and ethanol in vivo and in vitro. Results show that ethanol could markedly enhance arsenic-induced mutagenesis in colon in Big Blue Mice. This response related to intracellular reactive oxygen species (ROS) generation, NAPDH oxidase activation, and DNA damage/repair functional changes. We conclude that ethanol enhances arsenic-induced mutagenesis in colon in vivo. These results indicated that alcohol consumption should be taken into consideration in the investigation on arsenic-induced carcinogenesis in arsenic-exposure population. Citation Format: Lei Wang, Lisha Kuang, Young-Ok Son, John Andrew Hitron, Pratheeshkumar Poyil, Zhuo Zhang, Jia Luo, Zhigang Wang, Xianglin Shi. Ethanol enhances arsenic-induced mutagenesis in colon. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5360. doi:10.1158/1538-7445.AM2014-5360

Purpose of the study: To investigate the functional role of Akt and JNK signaling cascades in apigenin-induced apoptosis in human leukemia cells (in vitro) and anti-leukemic activity of apigenin in U937 xenografts (in vivo). Experimental Design: Leukemia cells were treated with apigenin in dose and time dependent manners, after which apoptosis, caspases activation, Akt and JNK signaling pathways were evaluated by pharmacologic and genetic approaches. Parallel studies were also conducted in Jurkat, HL60 and normal peripheral blood mononuclear cells. In vivo anti-leukemic activity mediated by apigenin was evaluated using U937 xenograft mouse model. Results: Exposure of apigenin caused pronounced increase in apoptosis in leukemia cells but not in normal peripheral blood mononuclear cells. Apigenin-induced apoptosis by inactivation of Akt with concomitant activation of JNK, cytochrome c release from mitochondria and caspases activation in dose and time dependent manners. Enforced activation of Akt by a constitutively active myristolated Akt prevented apigenin-induced JNK and caspases activation and apoptosis. Conversely, PI3K (phosphatidyl 3-kinase) inhibitor LY294002 and a dominant negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. In addition, Akt kinase activity was diminished after exposure to apigenin in leukemia cells. Interruption of JNK pathway by pharmacologic (SP600125) and genetic (JNK1 siRNA) approaches showed marked reduction in apigenin-induced caspases activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin via intraperitoneal route resulted in attenuation of tumor growth in U937 xenografts accompanied by apoptosis. Conclusions: Collectively, these findings suggested a hierarchical model of apigenin-induced apoptosis in human leukemia cells in which apigenin-induced Akt inactivation represents a primary event resulting in JNK activation and culminating in caspases activation and apoptosis. In addition, attenuation of tumor growth in U937 xenografts by apigenin raise the possibility that apigenin may have clinical implications for therapeutic intervention against leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2011-4593