Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage

Shen, Yang; Zx, Shen; Yan, Hu; Chen, J; Xy, Zeng; Jm, Li; Li, XS; Wu, Weiping; Sm, Xiong; Wl, Zhao; Tang, Wei; Wu, Fang; Yf, Liu; Niu, Chen; Zy, Wang; Sj, Chen; Chen, Z

doi:10.1038/sj.leu.2402106

Cited by 141 publications

(103 citation statements)

References 18 publications

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“…1D). The concentration is also close to a clinically relevant dose (0.15-0.3 mg/kg, equal to 0.75-1.5 M) of arsenic trioxide for myeloma patients (45) and the plasma peak values of 1.535-3.424 M in APL patients treated with arsenic trioxide (46). As the concentration was increased to 5-10 M, arsenic further decreased the level of mutant p53 in HaCaT cells (Fig.…”

Section: Arsenic Compounds Increase Wild Type But Inhibit Mutant P5supporting

confidence: 64%

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Yan¹,

Zhang²,

Zhang

et al. 2011

Journal of Biological Chemistry

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p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor ␣ fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time-and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.

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Section: Arsenic Compounds Increase Wild Type But Inhibit Mutant P5supporting

confidence: 64%

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Yan¹,

Zhang²,

Zhang

et al. 2011

Journal of Biological Chemistry

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“…As 2 O 3 treatment, plasma As 2 O 3 levels were basically in the range of 0.1 ± 0.5 mM, corresponding to the concentrations inducing primarily dierentiation of APL cells in vitro Shen et al, 1997Shen et al, , 2001). However, the mechanism underlying As 2 O 3 -induced dierentiation is still poorly understood.…”

Section: Mechanisms Of As 2 O 3 Induced-dierentiation Of Aplmentioning

confidence: 98%

Arsenic trioxide, a therapeutic agent for APL

et al. 2001

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Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the dierentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ). Over the past 5 years, it has been well demonstrated that As 2 O 3 induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85*90%). The side eects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As 2 O 3 as post-remission therapy has given better survival than those treated with As 2 O 3 alone. The eect of As 2 O 3 has been shown to be related to the expression of APLspeci®c PML ± RARa oncoprotein, and there is a synergistic eect between As 2 O 3 and ATRA in an APL mouse model. Cell biology studies have revealed that As 2 O 3 exerts dose-dependent dual eects on APL cells. Apoptosis is evident when cells are treated with 0.5*2.0 mM of As 2 O 3 while partial dierentiation is observed using low concentrations (0.1*0.5 mM) of the drug. The apoptosis-inducing eect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell dierentiation induced by low dose arsenic remain to be explored. Interestingly, As 2 O 3 over a wide range of concentration (0.1*2.0 mM) induces degradation of a key leukemogenic protein, PML ± RARa, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers. Oncogene (2001) 20, 7146 ± 7153.

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“…Arsenic agents have been successfully employed in treatment of acute promyelocytic leukemia (APL), and its efficacy has been confirmed even in patients resistant to conventional chemotherapy (1,2). It has become evident that apoptotic effects of arsenic trioxide (As 2 O 3 ) are not only restricted to APL cells but can also be observed in other malignant cells, including non-APL acute myeloid leukemia cells, myeloma cells, and chronic myeloid leukemia cells, as well as in various solid tumor cells (3 -5).…”

Section: Introductionmentioning

confidence: 99%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

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Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage

Cited by 141 publications

References 18 publications

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Arsenic trioxide, a therapeutic agent for APL

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

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