Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro

Biswas, Surajit; Zhao, Xiaobin; Mone, Andrew P.; Mo, Xiaokui; Vargo, Melissa A.; Jarjoura, David; Byrd, John C.; Muthusamy, Natarajan

doi:10.1016/j.leukres.2010.01.020

Cited by 22 publications

(21 citation statements)

References 36 publications

(32 reference statements)

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“…Our result is similar to the reports that vitamin C enhances ATO-induced cytotoxicity in multiple myeloma cells (50)(51)(52), leukemia cells (53,54) and hepatocellular carcinoma cells (26). Therefore, vitamin C plays a role as a prooxidant rather than antioxidant in ATO-treated cells including HPF cells and it can be used with ATO for treatment of cancer including hematological malignancies.…”

Section: Discussionsupporting

confidence: 90%

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Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

You

Park

2012

Oncology Reports

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Abstract. Arsenic trioxide (ATO; As 2 O 3 ) induces apoptotic cell death in various cancer cells including lung cancer via the induction of reactive oxygen species (ROS). However, little is known about the toxicological effects of ATO on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψ m ). ATO increased ROS levels including O 2•-and GSH depleted cell numbers. NAC attenuated the growth inhibition, death and MMP (∆Ψ m ) loss in ATO-treated HPF cells and also decreased the ROS levels in these cells. However, vitamin C enhanced the growth inhibition, death, MMP (∆Ψ m ) loss and GSH depletion by ATO and even strongly increased mitochondrial O 2•-levels in ATO-treated HPF cells. BSO showed a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth inhibition, cell death, MMP (∆Ψ m ) loss and GSH depletion. Moreover, superoxide dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO, which was not correlated with ROS and GSH level changes. In conclusion, ATO induced the growth inhibition and death of HPF cells, accompanied by increasing ROS levels and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and BSO enhanced the death.

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Section: Discussionsupporting

confidence: 90%

“…The intracellular GSH content has a decisive effect on ATO-induced apoptosis (26,(30)(31)(32). In addition, BSO or vitamin C enhances GSH depletion in ATO-treated cells (26,33,50,54,61). Likewise, ATO dose-dependently increased the number of GSH-depleted cells in HPF cells.…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

You

Park

2012

Oncology Reports

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“…Figure 1A shows that ATO significantly induced apoptosis in a dose-dependent manner, confirming previous reports (19)(20)(21)(22). All samples tested were sensitive to ATO, independently of the clinical stage, the ZAP-70/ CD38 expression, or whether they had been frozen or were freshly isolated.…”

Section: Ato Induces Apoptosis Of B-cll Cells But Not Of Normal Pblsupporting

confidence: 87%

“…In analyses of a small number of B-CLL samples (18) or long exposure times (19), ATO was shown to induce apoptosis of B-CLL cells, concomitant with downregulation of Bcl-2. ATO also induced ROS generation and significantly enhanced the cytotoxic activity of 2-methoxyestradiol and ascorbic acid on B-CLL samples (20,21). It was recently reported that ATO preferentially induced apoptosis in B-CLL cases with unfavorable prognosis (22).…”

mentioning

confidence: 93%

Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway via c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation

Redondo-Muñóz

Escobar-Díaz

Cerro

et al. 2010

Clinical Cancer Research

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Purpose: Arsenic trioxide (ATO) induces B-cell chronic lymphocytic leukemia (B-CLL) cell apoptosis in vitro. We sought to study the mechanism involved in this effect and whether ATO is suitable for combination therapies with protein kinase inhibitors.Experimental Design: B-CLL cells were isolated from the peripheral blood of 28 patients. Cell viability studies with ATO alone or in combination with kinase inhibitors were done by flow cytometry, Western blotting, and immunofluorescence analyses.Results: After 48 hours, 3 μmol/L ATO induced apoptosis (average 75%) in all B-CLL samples studied and with minimal effect on normal peripheral blood lymphocytes. Apoptosis entailed Akt and NF-κB inactivation, XIAP downregulation, and PTEN upregulation, thus implying inhibition of the phosphoinositide 3-kinase (PI3K) survival pathway. Indeed, the combination of ATO and PI3K inhibitors increased the apoptotic effect of either agent alone. ATO also induced c-jun-NH 2 terminal kinase (JNK) activation, and this was crucial and required for subsequent apoptotic events, as inhibiting JNK activity by either gene silencing or specific inhibitors prevented Akt and NF-κB inactivation, caspase activation, and mitochondrial damage. Moreover, JNK activation was the earliest response to ATO, preceding and determining reactive oxygen species production.Conclusions: We identified the mechanism involved in ATO action on B-CLL cells and show that the combination of low doses of ATO and PI3K inhibitors efficiently induces B-CLL cell death. ATO may therefore constitute an efficient treatment for B-CLL, particularly in combined therapies. Clin Cancer Res; 16(17); 4382-91. ©2010 AACR.

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“…However, high ROS levels can also mediate cell death [5]. ROS generating arsenic trioxide in combination with ascorbic acid efficiently kills CLL cells [6]. ROS increase through inhibition of key antioxidant enzymes such as superoxide-dismutase (SOD) also induces CLL cell death [7].…”

Section: Introductionmentioning

confidence: 99%

Targeting the disturbed redox equilibrium in chronic lymphocytic leukemia by novel reactive oxygen species-catalytic ‘sensor/effector’ compounds

Lilienthal

Prinz

Zada

et al. 2011

Leukemia & Lymphoma

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Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro

Cited by 22 publications

References 36 publications

Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion

Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway via c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation

Targeting the disturbed redox equilibrium in chronic lymphocytic leukemia by novel reactive oxygen species-catalytic ‘sensor/effector’ compounds

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