Abstract
We examined the anti-cancer effect of genistein, a soy-derived isoflavone, in human bladder transitional cell carcinoma T24 cells. According to our data, genistein induced G2/M phase arrest of the cell cycle and apoptosis. Genistein down-regulated the levels of cyclin A and cyclin B1, but up-regulated the levels of p21WAF1/CIP1, cyclin-dependent kinase (Cdk) inhibitor, that was complexed with Cdc2 and Cdk2. Furthermore, genistein induced the activation of caspases (caspase-3, -8 and -9), and cleavage of poly (ADP-ribose) polymerase cleavage. However, genistein-induced apoptosis was significantly inhibited by a pan-caspase inhibitor, indicating that the induction of apoptosis by genestein was caspase-dependent. In addition, genistein increased the cytosolic release of cytochrome c by increasing the Bax/Bcl-2 ratio and destroying mitochondria integrity. Moreover, genistein inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of genistein. Genistein further increased the accumulation of reactive oxygen species (ROS), which was significantly suppressed by N-acetyl cysteine (NAC), a ROS scavenger, and in particular, NAC prevented genistein-mediated inactivation of PI3K/Akt signaling, G2/M arrest and apoptosis. Therefore, the present results indicated that genistein promoted apoptosis induction in human bladder cancer T24 cells, which was associated with G2/M phase cell cycle arrest via regulation of ROS-dependent PI3K/Akt signaling pathway.
Highlights
Based on an understanding of the signaling mechanisms that regulate the growth of tumor cells over the past decade, effective therapies have been developed for the treatment of cancer patients.Antioxidants 2019, 8, 327; doi:10.3390/antiox8090327 www.mdpi.com/journal/antioxidants various side effects, including limited efficacy and drug resistance, need to be solved, chemotherapy is still the main approach to cancer therapy [1,2,3,4]
Similar to some studies using other cancer cell lines [13,44,45], our results demonstrate that genistein activated caspase-8, -9 and -3, and induced poly (ADP-ribose) polymerase (PARP) cleavage in T24 cells, which was associated the inhibition of the inhibitor of apoptosis protein (IAP) family proteins that interfere with proteolytic activity by binding to caspases [46,47]
We demonstrated that genistein has anti-cancer effects via the mediation of apoptotic cell death associated with G2/M arrest of the cell cycle in human urinary bladder carcinoma T24 cells
Summary
Based on an understanding of the signaling mechanisms that regulate the growth of tumor cells over the past decade, effective therapies have been developed for the treatment of cancer patients.Antioxidants 2019, 8, 327; doi:10.3390/antiox8090327 www.mdpi.com/journal/antioxidants various side effects, including limited efficacy and drug resistance, need to be solved, chemotherapy is still the main approach to cancer therapy [1,2,3,4]. Based on an understanding of the signaling mechanisms that regulate the growth of tumor cells over the past decade, effective therapies have been developed for the treatment of cancer patients. In order to develop safer and effective therapies that can overcome these problems, there is a growing interest in natural products that can block the proliferation of cancer cells without affecting normal cells [5,6,7,8]. Genistein induced cell cycle arrest at G1 and/or S phase in certain cancer cell lines, this isoflavonoid is known to inhibit cancer cell growth through G2/M inhibition in most cancer cells under conditions that are not toxic to normal cells [13,14]. The excessive production of reactive oxygen species (ROS) in some types of tumor cells plays a critical role in the induction of apoptosis [13,14,15,16,17]
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