Theracurmin® efficiently inhibits the growth of human prostate and bladder cancer cells via induction of apoptotic cell death and cell cycle arrest

Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid and generally found in the bark of birch trees (Betula sp.). Although several studies have been reported that BA has diverse biological activities, including anti-tumor effects, the underlying anti-cancer mechanism in bladder cancer cells is still lacking. Therefore, this study aims to investigate the anti-proliferative effect of BA in human bladder cancer cell lines T-24, UMUC-3, and 5637, and identify the underlying mechanism. Our results showed that BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest. Furthermore, BA decreased the expression of cell cycle regulators, such as cyclin B1, cyclin A, cyclin-dependent kinase (Cdk) 2, cell division cycle (Cdc) 2, and Cdc25c. In addition, BA-induced apoptosis was associated with mitochondrial dysfunction that is caused by loss of mitochondrial membrane potential, which led to the activation of mitochondrial-mediated intrinsic pathway. BA up-regulated the expression of Bcl-2-accociated X protein (Bax) and cleaved poly-ADP ribose polymerase (PARP), and subsequently activated caspase-3, -8, and -9. However, pre-treatment of pan-caspase inhibitor markedly suppressed BA-induced apoptosis. Meanwhile, BA did not affect the levels of intracellular reactive oxygen species (ROS), indicating BA-mediated apoptosis was ROS-independent. Furthermore, we found that BA suppressed the wound healing and invasion ability, and decreased the expression of Snail and Slug in T24 and 5637 cells, and matrix metalloproteinase (MMP)-9 in UMUC-3 cells. Taken together, this is the first study showing that BA suppresses the proliferation of human bladder cancer cells, which is due to induction of apoptosis, necrosis, and cell cycle arrest, and decrease of migration and invasion. Furthermore, BA-induced apoptosis is regulated by caspase-dependent and ROS-independent pathways, and these results provide the underlying anti-proliferative molecular mechanism of BA in human bladder cancer cells.

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Parthenolide Induces Apoptosis and Cell Cycle Arrest of Human 5637 Bladder Cancer Cells In Vitro

Molecules ◽

10.3390/molecules16086758 ◽

2011 ◽

Vol 16 (8) ◽

pp. 6758-6768 ◽

Cited By ~ 24

Author(s):

Guang Cheng ◽

Liping Xie

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Cycle Arrest ◽

Bladder Cancer Cells

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RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

International Journal of Genomics ◽

10.1155/2013/271347 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Toshinori Ozaki ◽

Akira Nakagawara ◽

Hiroki Nagase

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Death ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Apoptotic Cell ◽

Genetic Alterations ◽

Apoptotic Cell Death ◽

Cycle Arrest ◽

Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

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PPM-18, an Analog of Vitamin K, Induces Autophagy and Apoptosis in Bladder Cancer Cells Through ROS and AMPK Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.684915 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huiai Lu ◽

Chunlei Mei ◽

Luhao Yang ◽

Junyan Zheng ◽

Junwei Tong ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Cancer Cells ◽

Vitamin K ◽

Apoptotic Cell ◽

Critical Role ◽

Apoptotic Cell Death ◽

Ampk Activation ◽

Anticancer Activities ◽

Bladder Cancer Cells

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced apoptosis in bladder cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/AKT and mTORC1 pathways in bladder cancer cells. Inhibition of AMPK markedly relieved PPM-18–induced autophagy and apoptosis, indicating that PPM-18 is able to induce autophagy and apoptosis in bladder cancer cells via AMPK activation. Moreover, reactive oxygen species (ROS) were notably accumulated in PPM-18–treated bladder cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder cancer cells from PPM-18–triggered autophagy and apoptotic cell death. In bladder cancer xenografts, the anticancer activities of PPM-18, including suppressing the growth of tumors and inducing autophagy and apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the anticancer effect of PPM-18 on bladder cancer cells in vitro and in vivo through eliciting autophagy and apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder cancer treatment.

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Propylparaben induces apoptotic cell death in human placental BeWo cells via cell cycle arrest and enhanced caspase-3 activity

Molecular & Cellular Toxicology ◽

10.1007/s13273-019-00062-9 ◽

2019 ◽

Vol 16 (1) ◽

pp. 83-92 ◽

Cited By ~ 3

Author(s):

Mi Jin Kim ◽

Chul-Hong Kim ◽

Mi-Jin An ◽

Ju-Hyun Lee ◽

Geun-Seup Shin ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Caspase 3 ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Bewo Cells ◽

Cycle Arrest

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Photothermal exposure of polydopamine-coated branched Au–Ag nanoparticles induces cell cycle arrest, apoptosis, and autophagy in human bladder cancer cells

International Journal of Nanomedicine ◽

10.2147/ijn.s174349 ◽

2018 ◽

Vol Volume 13 ◽

pp. 6413-6428 ◽

Cited By ~ 14

Author(s):

Xiaoming Zhao ◽

Tianyang Qi ◽

Chenfei Kong ◽

Miao Hao ◽

Yuqian Wang ◽

...

Keyword(s):

Cell Cycle ◽

Bladder Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Ag Nanoparticles ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cycle Arrest ◽

Bladder Cancer Cells ◽

Human Bladder Cancer Cells

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p53: The Attractive Tumor Suppressor in the Cancer Research Field

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/603925 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 49

Author(s):

Toshinori Ozaki ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Cancer Research ◽

Cell Death ◽

Tumor Suppressor ◽

Cell Cycle Arrest ◽

Apoptotic Cell ◽

Genetic Alterations ◽

Research Field ◽

Apoptotic Cell Death ◽

Cycle Arrest

p53 is one of the most studied tumor suppressors in the cancer research field. Of note, over 50% of human tumors carry loss of function mutations, and thus p53 has been considered to be a classical Knudson-type tumor suppressor. From the functional point of view, p53 is a nuclear transcription factor to transactivate a variety of its target genes implicated in the induction of cell cycle arrest, DNA repair, and apoptotic cell death. In response to cellular stresses such as DNA damage, p53 is activated and promotes cell cycle arrest followed by the replacement of DNA lesions and/or apoptotic cell death. Therefore, p53 is able to maintain the genomic integrity to prevent the accumulation of genetic alterations, and thus stands at a crossroad between cell survival and cell death. In this paper, we describe a variety of molecular mechanisms behind the regulation of p53.

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