Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia

Cai, Xueli; Shen, Yulei; Zhu, Qi; Jia, Pei-Min; Yu, Yonghao; Zhou, Li; Huang, Ying; Zhang, J W; Xiong, Shangwu; Chen, S J; Wang, Z Y; Chen, Z; Chen, G Q

doi:10.1038/sj.leu.2401650

Cited by 236 publications

(194 citation statements)

References 26 publications

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“…Thus, the peroxide-removing systems of the two cell lines would be central to the potential toxicity of this H 2 O 2 . We have found that U937 cells have a somewhat higher level of GSH and twice the catalase activity of HL-60 cells, consistent with the observations of Cai et al [75]. They also found that the GPx-1 and total SOD activity of these two cell lines to be similar.…”

Section: Discussionsupporting

confidence: 92%

Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells

Kramarenko

Wilke

Dayal

et al. 2006

Free Radical Biology and Medicine

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As a reducing agent, ascorbate serves as an antioxidant. However, its reducing function can in some settings initiate an oxidation cascade, i.e. appear to be a "pro-oxidant". This dichotomy also appears to hold when ascorbate is present during photosensitization. Ascorbate can react with singlet oxygen producing hydrogen peroxide. Thus, if ascorbate is present during photosensitization the formation of highly diffusible hydrogen peroxide could enhance the toxicity of the photodynamic action. On the other side, ascorbate could decrease toxicity by converting highly reactive singlet oxygen to less reactive hydrogen peroxide, which can be removed via peroxide-removing systems such as glutathione and catalase. To test the influence of ascorbate on photodynamic treatment we incubated leukemia cells (HL-60 and U937) with ascorbate and a photosensitizer (verteporfin, VP) and examined: AscH − uptake; levels of glutathione; changes in membrane permeability; cell growth; and toxicity. Accumulation of VP was similar in each cell line. Under our experimental conditions, HL-60 cells were found to accumulate less ascorbate and have lower levels of intracellular GSH compared to U937 cells. Without added ascorbate, HL-60 cells were more sensitive to VP and light treatment than U937 cells. When cells were exposed to VP and light ascorbate acted as an antioxidant in U937 cells, while it was a "pro-oxidant" for HL-60 cells. One possible mechanism to explain these observations is that HL-60 cells express myeloperoxidase activity, while in U937 cells it is below detection limit. Inhibition of myeloperoxidase activity with 4-aminobenzoic acid hydrazide (4-ABAH) had minimal influence on the phototoxicity of VP in HL-60 in the absence of ascorbate. However, 4-ABAH decreased the toxicity of ascorbate on HL-60 cells during VP-photosensitization, but had no affect on ascorbate toxicity in U937 cells. These data demonstrate that ascorbate increases hydrogen peroxide production by VP and light. This hydrogen peroxide activates MPO, producing toxic oxidants. These observations suggest that in some settings, ascorbate may enhance the toxicity of photodynamic action.

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Section: Discussionsupporting

confidence: 92%

Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells

Kramarenko

Wilke

Dayal

et al. 2006

Free Radical Biology and Medicine

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“…The levels of H 2 O 2 -scavenging enzymes, such as catalase and glutathione peroxidase, in U937 cells are much higher than those in H 2 O 2 -sensitive NB4 cells. 40,48 Therefore, even if H 2 O 2 were produced during treatment of U937 cells with As 2 O 3 , it might be immediately broken down by these enzymes.…”

Section: Discussionmentioning

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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“…ATO is also a potent inducer of apoptosis in a number of other cell types such as acute myeloid leukemia (AML) (3), multiple myeloma (4), and lymphocytic leukemia (5) cells. Several mechanisms have been proposed to explain ATO-induced apoptosis, including the down-regulation of the PML-RARα fusion protein (6), the involvement of a mitochondrial pathway (7)(8)(9), production of superoxides (8,10), triggering of apoptosis-associated factors (3), and signal transduction (4,10). However, the sensitivity of different types of cells to ATO differs, and the low sensitivity of some cells has restricted its clinical application.…”

Section: Introductionmentioning

confidence: 99%

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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Arsenic trioxide (ATO) is a strong inducer of apoptosis in malignant hematological cells. Inducible phosphatidyl inositol 3 kinase (PI3K)-Akt activation promotes resistance to ATO. In the present study, we evaluated whether E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in the action of ATO. The effect of ATO on cell viability was measured by the Trypan blue exclusion assay or by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry and protein expression was assayed by Western blotting. ATO decreased the viability of HL60 cells and induced cellular apoptosis, which was accompanied by transient activation of Akt. The PI3K/Akt inhibitor, LY294002, significantly increased ATO-induced apoptosis (P < 0.05). In addition, ATO up-regulated the expression of Cbl-b proteins. Furthermore, ATO inhibited cell viability with an IC 50 of 18.54 μM at 24 h in rat basophilic leukemia-2H3 cells. ATO induced cellular apoptosis with transient activation of Akt and Cbl-b was also up-regulated. Rat basophilic leukemia-2H3 cells transfected with a dominant negative (DN) Cbl-b mutation showed overexpression of Cbl-b (DN) and enhanced Akt activation. Compared with cells transfected with vector, ATO-induced apoptosis was decreased and G2/M phase cells were increased at the same concentration (P < 0.05). The PI3K/Akt inhibitor, LY294002, re-sensitized Cbl-b (DN) overexpressing cells to ATO and reversed G2/M arrest (P < 0.05). Taken together, these results suggest that Cbl-b potentiates the apoptotic action of ATO by inhibition of the PI3K/Akt pathway.

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Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia

Cited by 236 publications

References 26 publications

Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells

Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells

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

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

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