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Open AccessArticle

Isorhamnetin Induces Cell Cycle Arrest and Apoptosis Via Reactive Oxygen Species-Mediated AMP-Activated Protein Kinase Signaling Pathway Activation in Human Bladder Cancer Cells

1
Department of Molecular Biology, College of Natural Sciences, Dong-eui University, Busan 47340, Korea
2
Department of Parasitology and Genetics, Kosin University College of Medicine, Busan 49267, Korea
3
Anti-Aging Research Center, Dong-eui University, Busan 47227, Korea
4
Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea
5
Department of Molecular Biology, Pusan National University, Busan 46241, Korea
6
Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju 63243, Korea
7
Department of Urology, College of Medicine, Chungbuk National University, Chungbuk 8644, Korea
8
Department of Food and Nutrition, College of Nursing, Healthcare Sciences & Human Ecology, Dong-Eui University, Busan 47340, Korea
*
Authors to whom correspondence should be addressed.
Equally contributed.
Cancers 2019, 11(10), 1494; https://doi.org/10.3390/cancers11101494
Received: 9 July 2019 / Revised: 5 September 2019 / Accepted: 5 September 2019 / Published: 4 October 2019
(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)
Isorhamnetin is an O-methylated flavonol that is predominantly found in the fruits and leaves of various plants, which have been used for traditional herbal remedies. Although several previous studies have reported that this flavonol has diverse health-promoting effects, evidence is still lacking for the underlying molecular mechanism of its anti-cancer efficacy. In this study, we examined the anti-proliferative effect of isorhamnetin on human bladder cancer cells and found that isorhamnetin triggered the gap 2/ mitosis (G2/M) phase cell arrest and apoptosis. Our data showed that isorhamnetin decreased the expression of Wee1 and cyclin B1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdk1. In addition, isorhamnetin-induced apoptosis was associated with the increased expression of the Fas/Fas ligand, reduced ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein (Bax) expression, cytosolic release of cytochrome c, and activation of caspases. Moreover, isorhamnetin inactivated the adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway by diminishing the adenosine triphosphate (ATP) production due to impaired mitochondrial function. Furthermore, isorhamnetin stimulated production of intracellular reactive oxygen species (ROS); however, the interruption of ROS generation using a ROS scavenger led to an escape from isorhamnetin-mediated G2/M arrest and apoptosis. Collectively, this is the first report to show that isorhamnetin inhibited the proliferation of human bladder cancer cells by ROS-dependent arrest of the cell cycle at the G2/M phase and induction of apoptosis. Therefore, our results provide an important basis for the interpretation of the anti-cancer mechanism of isorhamnetin in bladder cancer cells and support the rationale for the need to evaluate more precise molecular mechanisms and in vivo anti-cancer properties. View Full-Text
Keywords: isorhamnetin; G2/M arrest; apoptosis; ROS; AMPK isorhamnetin; G2/M arrest; apoptosis; ROS; AMPK
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Park, C.; Cha, H.-J.; Choi, E.O.; Lee, H.; Hwang-Bo, H.; Ji, S.Y.; Kim, M.Y.; Kim, S.Y.; Hong, S.H.; Cheong, J.; Kim, G.-Y.; Yun, S.J.; Hwang, H.J.; Kim, W.-J.; Choi, Y.H. Isorhamnetin Induces Cell Cycle Arrest and Apoptosis Via Reactive Oxygen Species-Mediated AMP-Activated Protein Kinase Signaling Pathway Activation in Human Bladder Cancer Cells. Cancers 2019, 11, 1494.

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