Apoptosis and Growth Inhibition in Malignant Lymphocytes After Treatment With Arsenic Trioxide at Clinically Achievable Concentrations

Zhu, Xinhua; Shen, Yulei; Jing, Yongkui; Cai, Xueli; Jia, Pei-Ming; Huang, Ying; Tang, Wei; Shi, Guiying; Sun, Yueping; Dai, Jie; Wang, Zhenyi; Chen, Sai‐Juan; Zhang, Ting-Dong; Waxman, Samuel; Chen, Zhu; Chen, Guoqiang

doi:10.1093/jnci/91.9.772

Cited by 256 publications

(183 citation statements)

References 37 publications

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“…Resistance to chemotherapy is a major concern with the effective management of any cancer but is a particular concern with that of melanoma since malignant melanomas have high intrinsic resistance to chemotherapeutic-induced apoptosis (Soengas and Loewe, 2003). Studies have indicated resistance to the chemotherapeutic application of arsenic may be associated with increased levels of glutathione (Zhu et al, 1999). However, some studies have found no correlation between cellular glutathione content and arsenic sensitivity (Davison et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Regardless as to whether basal glutathione levels are predictive of arsenic sensitivity, it is well established that the suppression of intracellular glutathione by inhibition of glutathione synthesis with buthionine sulfoximine (BSO) does potentiate the cytotoxicity of arsenic (Zhu et al, 1999;Davison et al, 2003;Kito et al, 2002). In the current study, suppression of glutathione in arsenite-resistant SK-Mel-3 and SK-Mel-28 rendered the cells sensitive to pharmacological arsenite concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

McNeely

Belshoff

Taylor

et al. 2008

Toxicology and Applied Pharmacology

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Arsenic induces clinical remission in patients with acute promyelocytic leukemia and has potential for treatment of other cancers. The current study examines factors influencing sensitivity to arsenic using human malignant melanoma cell lines. A375 and SK-Mel-2 cells were sensitive to clinically achievable concentrations of arsenite, whereas SK-Mel-3 and SK-Mel-28 cells required supratherapeutic levels for toxicity. Inhibition of glutathione synthesis, glutathione S-transferase (GST) activity, and multidrug resistance protein (MRP) transporter function attenuated arsenite resistance, consistent with studies suggesting arsenite is extruded from the cell as a glutathione conjugate by MRP-1. However, MRP-1 was not overexpressed in resistant lines and GST-π was only slightly elevated. ICP-MS analysis indicated arsenite-resistant SK-Mel-28 cells did not accumulate less arsenic than arsenite-sensitive A375 cells, suggesting resistance was not attributable to reduced arsenic accumulation but rather to intrinsic properties of resistant cell lines. The mode of arseniteinduced cell death was apoptosis. Arsenite-induced apoptosis is associated with cell cycle alterations. Cell cycle analysis revealed arsenite-sensitive cells arrested in mitosis whereas arsenite-resistant cells did not, suggesting induction of mitotic arrest occurs at lower intracellular arsenic concentrations. Higher intracellular arsenic levels induced cell cycle arrest in S-phase and G 2 -phase in SK-Mel-3 and SK-Mel-28 cells, respectively. The lack of arsenite-induced mitotic arrest in resistant cell lines was associated with a weakened spindle checkpoint resulting from reduced expression of spindle checkpoint protein BUBR1. These data suggest arsenite has potential for treatment of solid tumors but a functional spindle checkpoint is a prerequisite for a positive response to its clinical application.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

McNeely

Belshoff

Taylor

et al. 2008

Toxicology and Applied Pharmacology

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“…1,2-bis(O-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid tetracetoxymethyl ester (BAPTA-AM) was purchased from WAKO Pure Chemical Industries (Osaka, Japan). 3,3Ј-Dihexyloxacarbocyanine iodide [DiOC 6 …”

Section: Reagents and Antibodiesmentioning

confidence: 99%

“…Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) and in patients with APL in whom all-trans-retinoic acid (ATRA) and conventional chemotherapy has failed. [1][2][3][4] Studies in vitro indicate that As 2 O 3 can induce apoptosis in myeloma cell lines, in plasma cells from myeloma patients, 5 in malignant lymphocytic cell lines 6,7 as well as primary cultures of lymphocytic leukemia and lymphoma cells, 6 in myeloid and B-cell leukemia cell lines, 8 in megakaryocytic leukemia cell lines, 9 in neuroblastoma cell lines 10 and in HPV16-immortalized human cervical epithelial cells. 11 The mechanism responsible for the induction of apoptosis has not been fully characterized, but As 2 O 3 induced apoptosis in NB4 cells, cloned from a relapsed patient with APL, by inducing loss of PML/RAR␣ protein 12 and by suppressing expression of the Bcl-2 protein.…”

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confidence: 99%

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

2001

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The mechanism of the induction of apoptosis by arsenic trioxide (As 2 O 3 ), which was demonstrated recently to be an effective inducer of apoptosis in patients with leukemia, was examined in detail in human leukemia U937 cells. Upon treatment of U937 cells with 50 M of As 2 O 3 , complete inactivation of the kinases ERK1 and ERK2 was detected within 30 min. p38 was activated within 3 hr, and the maximum activity was detected at 6 hr, when DNA fragmentation remained undetectable. Experiments with transfected cells that expressed constitutively activated MEK1 and a specific inhibitor of p38 also suggested that inactivation of ERKs and activation of p38 might be associated with the induction of apoptosis by As 2 O 3 . In contrast to the inactivation of ERKs and the activation of p38, activation of JNK by Key words: arsenic trioxide; apoptosis; leukemia cells; superoxide; tumorArsenic has long been used in traditional Chinese medicine. Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) and in patients with APL in whom all-trans-retinoic acid (ATRA) and conventional chemotherapy has failed. 1-4 Studies in vitro indicate that As 2 O 3 can induce apoptosis in myeloma cell lines, in plasma cells from myeloma patients, 5 in malignant lymphocytic cell lines 6,7 as well as primary cultures of lymphocytic leukemia and lymphoma cells, 6 in myeloid and B-cell leukemia cell lines, 8 in megakaryocytic leukemia cell lines, 9 in neuroblastoma cell lines 10 and in HPV16-immortalized human cervical epithelial cells. 11 The mechanism responsible for the induction of apoptosis has not been fully characterized, but As 2 O 3 induced apoptosis in NB4 cells, cloned from a relapsed patient with APL, by inducing loss of PML/RAR␣ protein 12 and by suppressing expression of the Bcl-2 protein. 13 Apoptosis induced by As 2 O 3 and by the organic arsenical melarsoprol in myeloid leukemia cell lines, such as the HL-60, KG-1 and U937 cell lines, was found, however, to be independent of the level of expression of PML and PML-RAR␣. 14 In contrast to its apparent curative effects, As 2 O 3 is known to be a carcinogen in human organs, such as skin and lung, and it has serious side effects such as fluid retention in patients. 15 Other chronic side effects include polyneuropathy, palmar keratosis and skin hyperpigmentation. 15 It is, therefore, desirable to develop other drugs that act by a similar mechanism to that of As 2 O 3 but lack the side effect. While the mechanism of the induction of apoptosis in tumor cells by As 2 O 3 is not well understood, As 2 O 3 has been used to mimic the effects of heat shock on cells. 16 When rat fibroblastic 3Y1 cells and rat PC12 cells are treated with As 2 O 3 , stress-induced kinases such as c-Jun N-terminal kinase (JNK) and p38 are activated. 17 To clarify the mechanism of induction of apoptosis in tumor cells by As 2 O 3 , we examined the effects of As 2 O 3 on the activities of mitogen-activated protein (M...

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“…As 2 O 3 -induced apoptosis were accompanied by activation of death signals: caspase 3, 8 and 9 [10,11]. The generation of ROS appears to consistently accompany arsenic exposure and many evidences suggest that ROS may be a determinant of cellular susceptibility to arsenic [6,[12][13][14][15]. Manipulation of ROS may thus be a way to expend the anticancer therapeutic spectrum of As 2 O 3 .…”

Section: Discussionmentioning

confidence: 99%

Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells

Wang¹,

Yang²,

Hui³

et al. 2005

Cell Res

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Emodin (1,3,8-trihydroxy-6-methylanthraquinone) could enhance the sensitivity of tumor cells to arsenic trioxide (As 2 O 3 )-induced apoptosis via generation of ROS, but the molecular mechanism has not been elucidated. Here, we carried out cDNA microarray-based global transcription profiling of HeLa cells in response to As 2 O 3 /emodin cotreatment, comparing with As 2 O 3 -only treatment. The results showed that the expression of a number of genes was substantially altered at two time points. These genes are involved in different aspects of cell function. In addition to redox regulation and apoptosis, ROS affect genes encoding proteins associated with cell signaling, organelle functions, cell cycle, cytoskeleton, etc. These data suggest that based on the cytotoxicity of As 2 O 3 , emodin mobilize every genomic resource through which the As 2 O 3 -induced apoptosis is facilitated.

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Apoptosis and Growth Inhibition in Malignant Lymphocytes After Treatment With Arsenic Trioxide at Clinically Achievable Concentrations

Abstract: Substantial growth inhibition and apoptosis without evidence of differentiation were induced in most malignant lymphocytic cells treated with 1-2 microM As2O3. As2O3 may prove useful in the treatment of malignant lymphoproliferative disorders.

Cited by 256 publications

References 37 publications

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+-dependent production of superoxide

Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells

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