Arsenic Trioxide as an Inducer of Apoptosis and Loss of PML/RARα Protein in Acute Promyelocytic Leukemia Cells

Shao, Wenlin; Fanelli, Mirco; Ferrara, Felicetto; Riccioni, Roberta; Rosenauer, Angelika; Davison, Kelly; Lamph, William W.; Waxman, Samuel; Pelicci, PierGiuseppe; Coco, Francesco Lo; Avvisati, Giuseppe; Testa, Ugo; Peschle, Cesare; Gambacorti‐Passerini, Carlo; Nervi, Clara; Miller, Wilson H.

doi:10.1093/jnci/90.2.124

Cited by 336 publications

(258 citation statements)

References 39 publications

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“…Reports indicate that ATRA can induce degradation not only of PML-RARA but of a fraction of wild-type RARA (Gianni et al, 1998;Shao et al, 1998). ATRA induces a speci®c cleavage in a fraction of RARA protein.…”

Section: Prh and Pml Associate In The Apl Patient Derived Cell Line Nb4mentioning

confidence: 99%

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

et al. 1999

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Acute promyelocytic leukemia (APL) is characterized by a block in myeloid cell di erentiation. As a result of a chromosomal translocation in these patients, the promyelocytic leukemia protein PML is disrupted as are the nuclear bodies it forms. Disruption of PML and PML nuclear bodies in APL is linked to a loss of growth control and subsequent leukemogenesis. PML contains a zinc-binding domain known as the RING which is required for formation of these bodies. Using yeast 2-hybrid techniques, we found that PML and a related RING protein, Z, bind the proline rich homeodomain protein (PRH) through their RING domains. Previous reports indicate that PRH functions in hematopoiesis and may act as a transcriptional repressor. Our data indicate that PML and Z both bind the repressor domain of PRH and are the ®rst protein partners reported for PRH. We observe that PRH has a punctate pattern in both the nucleus and cytoplasm of chronic myelogenous leukemia K562 cells and in the APL cell line, NB4. Immunoprecipitation and co-localization studies indicate that PML and PRH interact in both cell lines. The e ect on cell growth by PML and the hematopoietic actions of PRH raises the possibility that the interaction between PML and PRH represents a link between growth control and hematopoiesis.

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Section: Prh and Pml Associate In The Apl Patient Derived Cell Line Nb4mentioning

confidence: 99%

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

et al. 1999

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“…Arsenic trioxide is approved by the FDA for the treatment of acute promyelocytic leukemia (APL) refractory to therapy with all-trans retinoic acid (ATR). Arsenic trioxide's activity against APL was initially thought to involve arsenic-induced degradation of the PML-RARα fusion protein (Shao et al, 1998) which results from a consistent 15:17 chromosomal translocation event associated with the disease (Rowley et al, 1977). However, arsenic was shown to induce apoptosis in myeloid leukemia cell lines that do not express the PML-RARα fusion protein (Wang et al, 1998) …”

Section: Introductionmentioning

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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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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“…[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. 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␣.…”

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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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Arsenic Trioxide as an Inducer of Apoptosis and Loss of PML/RARα Protein in Acute Promyelocytic Leukemia Cells

Cited by 336 publications

References 39 publications

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

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

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