SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells

Abstract Background A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. Methods The underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound. Results C-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy. Conclusions It reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development.

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Cortex Moutan Induces Bladder Cancer Cell Death via Apoptosis and Retards Tumor Growth in Mouse Bladders

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/207279 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Mei-Yi Lin ◽

Ying-Ray Lee ◽

Su-Yin Chiang ◽

Yi-Zhen Li ◽

Yueh-Sheng Chen ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Cancer Cells ◽

Blood Stasis ◽

Blood Stasis Syndrome ◽

Intravesical Therapy ◽

Root Bark ◽

Cortex Moutan ◽

Bladder Cancer Cells

Cortex Moutan is the root bark ofPaeonia suffruticosaAndr. It is the herbal medicine widely used in Traditional Chinese Medicine for the treatment of blood-heat and blood-stasis syndrome. Furthermore, it has been reported that Cortex Moutan has anticancer effect. In this study, the Cortex Moutan extract was evaluated in bladder cancer therapy in vitro and in vivo. Cortex Moutan extract reduces cell viability with IC50between 1~2 mg/ml in bladder cancer cells, and it has lower cytotoxicity in normal urotheliums. It arrests cells in G1 and S phase and causes phosphatidylserine expression in the outside of cell membrane. It induces caspase-8 and caspase-3 activation and poly(ADP-ribose) polymerase degradation. The pan caspase inhibitor z-VAD-fmk reverses Cortex Moutan-induced cell death. Cortex Moutan also inhibits cell invasion activity in 5637 cells. In mouse orthotopic bladder cancer model, intravesical application of Cortex Moutan decreases the bladder tumor size without altering the blood biochemical parameters. In summary, these results demonstrate the antiproliferation and anti-invasion properties of Cortex Moutan in bladder cancer cells and its antibladder tumor effect in vivo. Cortex Moutan may provide an alternative therapeutic strategy for the intravesical therapy of superficial bladder cancer.

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Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-04306-2 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Yadong Sun ◽

Niklas Berleth ◽

Wenxian Wu ◽

David Schlütermann ◽

Jana Deitersen ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Death ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Mtor Inhibitors ◽

Mtor Inhibition ◽

Combined Application ◽

Regulated Cell Death ◽

Bladder Cancer Cells ◽

Dependent Cell

AbstractFerroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines of evidence suggest that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms remain unclear. Fin56, a type 3 ferroptosis inducer, triggers ferroptosis by promoting glutathione peroxidase 4 (GPX4) protein degradation via a not fully understood pathway. Here, we determined that Fin56 induces ferroptosis and autophagy in bladder cancer cells and that Fin56-triggered ferroptosis mechanistically depends on the autophagic machinery. Furthermore, we found that autophagy inhibition at different stages attenuates Fin56-induced oxidative stress and GPX4 degradation. Moreover, we investigated the effects of Fin56 in combination with Torin 2, a potent mTOR inhibitor used to activate autophagy, on cell viability. We found that Fin56 synergizes with Torin 2 in cytotoxicity against bladder cancer cells. Collectively, our findings not only support the concept that ferroptosis is a type of autophagy-dependent cell death but imply that the combined application of ferroptosis inducers and mTOR inhibitors is a promising approach to improve therapeutic options in the treatment of bladder cancer.

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Interactions between Cisplatin and Quercetin at Physiological and Hyperthermic Conditions on Cancer Cells In Vitro and In Vivo

Molecules ◽

10.3390/molecules25143271 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3271

Author(s):

Nada Oršolić ◽

Dyana Odeh ◽

Maja Jazvinšćak Jembrek ◽

Jelena Knežević ◽

Darko Kučan

Keyword(s):

Bladder Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Combined Treatment ◽

Short Term ◽

In Vivo Models ◽

Short Term Exposure ◽

Bladder Cancer Cells

Quercetin (QU), a hyperthermic sensitizer, when combined with cisplatin (CP) affects tumor growth. To determine the effects of QU and CP and their interactions, multimodal treatment in vitro and in vivo models under physiological and hyperthermic conditions was performed. In vitro, different sensitivity of T24 and UMUC human bladder cancer cells was observed after short-term exposure to QU (2 h) and CP (1 h). Effects of both compounds were investigated at low and high micromolar concentrations (1 and 50 µM, respectively) under both thermal conditions. QU acted in additive or synergistic manner in combination with CP between physiological condition and hyperthermia. As determined by 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, short-term application of QU and CP reduced cell viability. Clonal assay also indicated that combined treatment with QU and CP is lethal to bladder cancer cells in both conditions. In vivo, CP (5 or 10 mg kg−1) and QU (50 mg kg−1) acted synergistically with hyperthermia (43 °C) and inhibited tumor growth, activated immune effectors and increased mice survival. Our results demonstrate that combined treatment with CP and QU may increase death of tumor cells in physiological and hyperthermic conditions which could be clinically relevant in locoregional chemotherapy.

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Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells

Scientific Reports ◽

10.1038/s41598-021-89684-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Makoto Isono ◽

Kazuki Okubo ◽

Takako Asano ◽

Akinori Sato

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Combined Treatment ◽

Annexin V ◽

Cell Number ◽

Checkpoint Kinases ◽

Bladder Cancer Cells ◽

Damage Response ◽

Chk1 Inhibitor

AbstractCheckpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemcitabine with MK-8776, a novel CHK1 inhibitor, in four bladder cancer cell lines. The effects of gemcitabine and MK-8776 on cell viability, clonogenicity, cell cycle, and apoptosis were examined alongside in vivo efficacy using murine xenograft tumor models. Combined treatment inhibited the viability and colony formation of bladder cancer cells compared to either single treatment. Although gemcitabine (10 nM) alone increased the cell number in S-phase, it increased the cell number in sub-G1 phase when combined with MK-8776 (0.5 µM). Combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin-V-positive cells, indicating the induction of apoptosis. In vivo, administration of gemcitabine and MK-8776 was well tolerated and suppressed tumor growth. Mechanistically, the combined treatment elevated γH2A.X and suppressed Rad51 expression. Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.

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ENHANCED SENSITIVITY OF BLADDER CANCER CELLS TO CISPLATIN MEDIATED CYTOTOXICITY AND APOPTOSIS IN VITRO AND IN VIVO BY THE SELECTIVE CYCLOOXYGENASE-2 INHIBITOR JTE-522

The Journal of Urology ◽

10.1097/01.ju.0000131945.74377.ad ◽

2004 ◽

Vol 172 (4 Part 1) ◽

pp. 1474-1479 ◽

Cited By ~ 18

Author(s):

YOICHI MIZUTANI ◽

HIROYUKI NAKANISHI ◽

YONG NAN LI ◽

NODOKA SATO ◽

AKIHIRO KAWAUCHI ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Cyclooxygenase 2 ◽

Enhanced Sensitivity ◽

Bladder Cancer Cells

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Inhibition of growth, migration and invasion of human bladder cancer cells by antrocin, a sesquiterpene lactone isolated from Antrodia cinnamomea, and its molecular mechanisms

Cancer Letters ◽

10.1016/j.canlet.2015.11.046 ◽

2016 ◽

Vol 373 (2) ◽

pp. 174-184 ◽

Cited By ~ 32

Author(s):

Kun-Yuan Chiu ◽

Chun-Chi Wu ◽

Chi-Hao Chia ◽

Shih-Lan Hsu ◽

Yew-Min Tzeng

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Sesquiterpene Lactone ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Human Bladder Cancer ◽

Human Bladder ◽

Inhibition Of Growth ◽

Bladder Cancer Cells ◽

Human Bladder Cancer Cells

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Evaluation of Su Fu’ning Lotion’s Inhibitory Effects on Bladder Cancer Cells In Vitro and In Vivo by Intravesical Instillation

Integrative Cancer Therapies ◽

10.1177/1534735415596569 ◽

2015 ◽

Vol 15 (1) ◽

pp. 80-86 ◽

Cited By ~ 1

Author(s):

Liansheng Ren ◽

Xihua Yang ◽

Lili Zhao ◽

Hong Zhang ◽

Jing Wang

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Intravesical Instillation ◽

Inhibitory Effects ◽

Bladder Cancer Cells

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DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1

Cell Death and Disease ◽

10.1038/s41419-020-03190-6 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Chin-Hui Lai ◽

Kexin Xu ◽

Jianhua Zhou ◽

Mingrui Wang ◽

Weiyu Zhang ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Malignant Tumors ◽

Tumor Grade ◽

In Vivo Studies ◽

Mechanistic Study ◽

Tumor Promotor ◽

Bladder Cancer Cells

AbstractBladder cancer is one of the most commonly diagnosed malignant tumors in the urinary system and causes a massive cancer-related death. DEPDC1B is a DEP domain-containing protein that has been found to be associated with a variety of human cancers. This study aimed to explore the role and mechanism of DEPDC1B in the development of bladder cancer. The analysis of clinical specimens revealed the upregulated expression of DEPDC1B in bladder cancer, which was positively related to tumor grade. In vitro and in vivo studies showed that DEPDC1B knockdown could inhibit the growth of bladder cancer cells or xenografts in mice. The suppression of bladder cancer by DEPDC1B was executed through inhibiting cell proliferation, cell migration, and promoting cell apoptosis. Moreover, a mechanistic study found that SHC1 may be an important route through which DEPDC1B regulates the development of bladder cancer. Knockdown of SHC1 in DEPDC1B-overexpressed cancer cells could abolish the promotion effects induced by DEPDC1B. In conclusion, DEPDC1B was identified as a key regulator in the development of bladder cancer, which may be used as a potential therapeutic target in the treatment of bladder cancer.

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