Abstract
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.
Highlights
New therapies for treating cancer patients are being developed, chemotherapy is still the main approach for the treatment of cancer
Our findings demonstrate that isorhamnetin exerted an anti-proliferative effect on human bladder cancer cells through the induction of cell cycle arrest during the gap 2/ mitosis (G2/M) phase and apoptosis
Isorhamnetin-induced G2/M arrest was attributed to the decrease in Wee1 and cyclin B1 expression and the upregulation of p21
Summary
New therapies for treating cancer patients are being developed, chemotherapy is still the main approach for the treatment of cancer. Numerous naturally occurring agents have been reported to cause cell cycle arrest and induce apoptosis, which are important strategies for the control of proliferation in cancer cells, without inducing toxicity in normal cells [6,7]. These agents have emerged as an alternative to chemopreventive and chemotherapeutic agents because they can regulate various cellular signaling pathways in cancer cells [8,9]
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