Heterocyclic organobismuth(III) induces apoptosis of human promyelocytic leukemic cells through activation of caspases and mitochondrial perturbation

Iuchi, Katsuya; Hatano, Yukichi; Yagura, Tatsuo

doi:10.1016/j.bcp.2008.07.038

Cited by 45 publications

(44 citation statements)

References 37 publications

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“…43 Cell-free in vitro transcription/translation experiments 49 demonstrated that a single-nucleotide polymorphism (T125C) in human caspase-12 is translated into a 38-kD human caspase-12 protein but that this does not occur when there is a stop codon (TGA) in human caspase-12 at amino acid position 125. Other studies documented expression of a 50-kD BASIC RESEARCH www.jasn.org caspase-12 in human promyelocytic leukemia cells (HL-60) 48 and a 60-kD caspase-12 in human gastrointestinal stromal tumors (STI571). 45 It is not clear how a 52-or 60-kD caspase-12 protein can be expressed in the presence of a stop codon; however, these studies raise the possibility that the 52-or 60-kD pro-caspase-12 could be aberrantly expressed in cells undergoing pathologic changes.…”

Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Brezniceanu¹,

Lau²,

Godin³

et al. 2010

Journal of the American Society of Nephrology

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Apoptosis of tubular epithelial cells contributes to the tubular atrophy that accompanies diabetic nephropathy. Reactive oxygen species (ROS) promote tubular apoptosis, but the mechanisms by which this occurs are incompletely understood. Here, we sought proapoptotic genes that ROS differentially upregulate in renal proximal tubular cells of diabetic (db/db) mice. We performed microarray analysis using total RNA from freshly isolated renal proximal tubules of nondiabetic, diabetic, and diabetic transgenic mice overexpressing catalase in the proximal tubule (thereby attenuating ROS). We observed greater expression of caspase-12 in the proximal tubules of the diabetic mice compared with the nondiabetic and diabetic transgenic mice. Quantitative PCR and immunohistochemistry confirmed the enhanced expression of caspase-12, as well as members of the endoplasmic reticulum stress-induced apoptotic pathway. Ex vivo, albumin induced caspase-12 activity and expression (protein and mRNA) and mRNA expression of the CCAT/enhancer-binding protein homologous protein in freshly isolated wildtype proximal tubules but not in catalase-overexpressing proximal tubules. In vitro, albumin stimulated activity of both caspase-12 and caspase-3 as well as expression of caspase-12 and CCAT/enhancerbinding protein homologous protein in a human proximal tubule cell line (HK-2). The free radical scavenger tiron inhibited these effects. Furthermore, knockdown of caspase-12 with small interfering RNA reduced albumin-induced apoptosis in HK-2 cells. Taken together, these studies demonstrate that albuminuria may induce tubular apoptosis through generation of ROS and the subsequent expression and activation of endoplasmic reticulum stress genes in the diabetic kidney.

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Section: Discussionmentioning

confidence: 99%

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Brezniceanu¹,

Lau²,

Godin³

et al. 2010

Journal of the American Society of Nephrology

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“…We have found that heterocyclic organobismuth compounds have potent antiproliferative effects on leukemic cell lines. One of them, bi-chlorodibenzo[c,f] [1,5]thiabismocine (compound 3), induced apoptosis in HL-60 cells through the activation of caspase, production of ROS, and perturbation of mitochondria; and at high doses, it induced necrosis (2). Anticancer activities of metal and metal compounds have been reported (4,6,7), suggesting our bismuth compounds to be useful as chemotherapeutic reagents against tumors.…”

Section: Introductionmentioning

confidence: 98%

“…Our previous studies showed that heterocyclic organobismuth(III) compounds have antibacterial activity and can inhibit the growth of tumor cells (1,2). The compounds induced apoptosis via mitochondrial perturbation in human promyelocytic leukemia cells (HL-60) (2).…”

Section: Introductionmentioning

confidence: 99%

“…The compounds induced apoptosis via mitochondrial perturbation in human promyelocytic leukemia cells (HL-60) (2). Bismuth belongs to group V of the periodic table along with arsenic and antimony and is recognized as a low-toxic metal.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have shown that arsenite-induced mitotic arrest is one of the mechanism of apoptosis in cancer cells (19) suggesting arsenite to be an effective anti-cancer drug. However, the chronic toxicity and carcinogenicity of arsenic trioxide has hampered its acceptance as a firstchoice drug (2,23). In contrast to arsenic, bismuth is recognized as a low-toxic metal in spite of its heavy metal status in the nitrogen family, and bismuth compounds have also been reported as low-toxic compounds (3).…”

Section: Introductionmentioning

confidence: 99%

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Heterocyclic Organobismuth(III) Compound Targets Tubulin to Induce G2/M Arrest in HeLa Cells

2009

Self Cite

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Abstract. Our previous study showed that organobismuth compounds induce apoptosis in human promyelocytic leukemia cells, although solid tumor cell lines were relatively resistant. Herein, we investigated the primary cellular target of these compounds in HeLa cells. One organobismuth compound, bi-chlorodibenzo[c,f][1,5]thiabismocine (compound 3), arrested the cell cycle at G 2 /M as assessed by flow cytometry and by upregulating the expression of cyclin B1. At a low concentration (0.5 μM), compound 3 caused cell cycle arrest at the mitotic phase and induced apoptosis. At a higher concentration (>1.0 μM), it induced an arrest in the G 2 /M phase, leading to apoptosis. In many cells blocked at the M phase, the organization of microtubules was affected, indicating depolymerization of the microtubule network. Western blotting demonstrated that compound 3 depolymerized microtubules similar to colchicine and nocodazole. Experiments in vitro also showed that compound 3 inhibited the assembly of purified tubulin in a concentrationdependent manner by interacting with the colchicine-binding site of tubulin through its SH groups. Heterocyclic organobismuth compounds are novel tubulin ligands.

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Anticancer Activity of Molecular Compounds of Arsenic, Antimony and Bismuth

Tiekink

2010

Biological Chemistry of Arsenic, Antimony and Bismuth

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Heterocyclic organobismuth(III) induces apoptosis of human promyelocytic leukemic cells through activation of caspases and mitochondrial perturbation

Cited by 45 publications

References 37 publications

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Heterocyclic Organobismuth(III) Compound Targets Tubulin to Induce G2/M Arrest in HeLa Cells

Anticancer Activity of Molecular Compounds of Arsenic, Antimony and Bismuth

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