A New Proteasome Inhibitor, TP-110, Induces Apoptosis in Human Prostate Cancer PC-3 Cells

Momose, Isao; Iijima, Masatomi; Kawada, Manabu; Ikeda, Daishiro

doi:10.1271/bbb.60697

Cited by 20 publications

(16 citation statements)

References 30 publications

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“…Supporting previous work showing that the impairment of proteasome activity induces apoptotic tumor cell death and cell cycle arrest at G 2 /M phase [4] , we prove in this study that inhibition of the proteasome by MG-132 decreases cell proliferation, induced cell death and G 2 /M arrest and activates autophagy in SHG-44 glioma cells. Furthermore, we found that 6.0 µmol/L MG-132 effectively inhibited proteasome activity and induced cell death and cell cycle arrest in SHG- www.nature.com/aps Ge PF et al Acta Pharmacologica Sinica npg 44 glioma cells, which was consistent with a previous report [5] .…”

Section: Discussionsupporting

confidence: 91%

“…The proteasome is involved not only in protein degradation, but also in cellular differentiation, antigen presentation and cell cycle modulation [2] . Therefore, inhibition of proteasome activity has become a new chemotherapy strategy and many chemicals and natural compounds have proven to be effective at inducing tumor cell death by inhibiting proteasome activity [3][4][5][6] . Autophagy, as part of the lysosomal system, is an evolutionarily conserved cellular strategy to engulf and degrade long-lived cytosolic proteins and organelles to provide substrates for energy metabolism and to recycle amino acids, fatty acids, and nucleotides for the biosynthetic needs of cells [7] .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Zhang

Wang

et al. 2009

Acta Pharmacol Sin

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Aim:The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. Methods: The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. Results: MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G 2 /M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G 2 /M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Conclusion: Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Zhang

Wang

et al. 2009

Acta Pharmacol Sin

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“…1) strongly inhibits the growth of various human cell lines and induces apoptosis in their cells. 12) In order to strengthen its therapeutic effects, we established RPMI-8226/TP-110 cells and elucidated their resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…11) TP-110 strongly inhibits the growth of human tumor cells and induces apoptosis. 12) One of the mechanisms of apoptosis induction by TP-110 is down-regulation of inhibitors of apoptosis proteins (IAPs) in multiple myeloma cells. 13) A loss of anti-tumor efficacy responsible for drugresistance in cells is known in cancer chemotherapy.…”

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confidence: 99%

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Iijima

Momose

Ikeda

2010

Bioscience, Biotechnology, and Biochemistry

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, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/ TP-110) cells and elucidated their resistance mechanisms. The IC 50 value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.

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“…Therefore, inhibition of proteasome activity has emerged as a new chemotherapy strategy for malignant tumors. Although studies have shown that inhibition of proteasome activity could inhibit cellular proliferation in several tumor cell lines including melanoma, prostate cancer and glioma cells [3][4][5][6] , its underlying mechanism is not fully understood. The proteasome inhibitor bortezomib has been authorized by the US Food and Drug Administration to enter clinical trials, but it is used mainly in the leukemia field.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor MG-132 induces C6 glioma cell apoptosis via oxidative stress

et al. 2011

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Aim: Proteasome inhibitors have been found to suppress glioma cell proliferation and induce apoptosis, but the mechanisms are not fully elucidated. In this study we investigated the mechanisms underlying the apoptosis induced by the proteasome inhibitor MG-132 in glioma cells. Methods: C6 glioma cells were used. MTT assay was used to analyze cell proliferation. Proteasome activity was assayed using Succinyl-LLVY-AMC, and intracellular ROS level was evaluated with the redox-sensitive dye DCFH-DA. Apoptosis was detected using fluorescence and transmission electron microscopy as well as flow cytometry. The expression of apoptosis-related proteins was investigated using Western blot analysis. Results: MG-132 inhibited C6 glioma cell proliferation in a time-and dose-dependent manner (the IC 50 value at 24 h was 18.5 μmol/L). MG-132 (18.5 μmol/L) suppressed the proteasome activity by about 70% at 3 h. It induced apoptosis via down-regulation of antiapoptotic proteins Bcl-2 and XIAP, up-regulation of pro-apoptotic protein Bax and caspase-3, and production of cleaved C-terminal 85 kDa PARP). It also caused a more than 5-fold increase of reactive oxygen species. Tiron (1 mmol/L) effectively blocked oxidative stress induced by MG-132 (18.5 μmol/L), attenuated proliferation inhibition and apoptosis in C6 glioma cells, and reversed the expression pattern of apoptosis-related proteins. Conclusion: MG-132 induced apoptosis of C6 glioma cells via the oxidative stress.

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A New Proteasome Inhibitor, TP-110, Induces Apoptosis in Human Prostate Cancer PC-3 Cells

Cited by 20 publications

References 30 publications

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

Proteasome inhibitor MG-132 induces C6 glioma cell apoptosis via oxidative stress

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