Buthionine Sulfoximine and 1,25-Dihydroxyvitamin D Induce Apoptosis in Breast Cancer Cells via Induction of Reactive Oxygen Species

Bohl, Luciana Paola; Liaudat, Ana Cecilia; Picotto, Gabriela; Marchionatti, Ana Maria Estivalete; Narvaez, Carmen J.; Welsh, JoEllen; Rodríguez, Victoria Eli; Talamoni, Nori G. Tolosa de

doi:10.3109/07357907.2012.700985

Cited by 12 publications

(18 citation statements)

References 44 publications

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“…This is consistent with BSO being well tolerated by humans in clinical assays [37,38]. The association of BSO and anticancer drugs in not new, it has been described, for example, with retinoids in neuroblastoma [39], melphalan or cisplatin in ovarian cancer [40,41], vitamin D in breast cancer [42], or azathioprine in colon and hepatic carcinoma [43]. We have no knowledge about PES toxicity in humans.…”

Section: Discussionsupporting

confidence: 65%

2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53

Mattiolo

Barbero-Farran

Yuste

et al. 2014

Biochemical Pharmacology

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2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis.

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Section: Discussionsupporting

confidence: 65%

2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53

Mattiolo

Barbero-Farran

Yuste

et al. 2014

Biochemical Pharmacology

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“…Cells were harvested by trypsinization, collected by centrifugation, fixed in 100% ethanol (-201C), and incubated with 5 mg/ml propidium iodide and 0.015 U/ml RNase in PBS for 20 min at room temperature, as described previously [8]. Cell cycle analysis was carried out using a BD FACSCantoII flow cytometer (BD Biosciences, San Jose, California, USA).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…Numerous nonclassical actions of vitamin D 3 have been described, including the modulation of cell growth and adhesion, cell cycle arrest, induction of differentiation, stimulation of apoptosis, and inhibition of angiogenesis, among others [6,7]. psoriasis) and malignant cells derived from different tissues such as breast, pancreas, intestine, prostate, and skin [8][9][10][11][12][13][14]. psoriasis) and malignant cells derived from different tissues such as breast, pancreas, intestine, prostate, and skin [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the use of compounds that stimulate oxidative stress such as D,L-buthionine-S,Rsulfoximine (BSO), menadione, and azathioprine may increase the sensitivity of malignant cells to conventional chemotherapy. In our laboratory, we have shown that the combination of BSO plus 1,25(OH) 2 D 3 enhances the antiproliferative effect on breast cancer MCF-7 cells produced by each single drug [8]. As tumor resistance is associated with high intracellular GSH levels, BSO is used in clinical practice [15,22].…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress, cell cycle arrest and differentiation contribute toward the antiproliferative action of BSO and calcitriol on Caco-2 cells

et al. 2014

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The prognosis and incidence of colon cancer are linked to vitamin D3 serum levels. To evaluate the effects of D,L-buthionine-S,R-sulfoximine (BSO), 1,25(OH)2D3 and their combination on intestinal Caco-2 cell growth, to elucidate the possible cellular mechanisms involved in their antiproliferative action, and to determine whether BSO acts as a sensitizer to 1,25(OH)2D3 treatment, enabling minimization of the toxic effects caused by high doses of the steroid. Human colon cancer Caco-2 cells were treated with 1,25(OH)2D3, BSO, both, or vehicle. Cell proliferation was evaluated by crystal violet staining. Cell cycle and mitochondrial membrane potential were measured by flow cytometry. Total glutathione, catalase, superoxide dismutase, superoxide anion levels, and alkaline phosphatase activities were analyzed by spectrophotometry. DNA fragmentation was evaluated using the terminal dUTP nick end labeling assay. BSO and 1,25(OH)2D3 inhibited Caco-2 cell growth, an effect that was higher with the combined treatment. The antiproliferative effect produced by the combination could be protected by ascorbic acid. BSO plus 1,25(OH)2D3 induced cell cycle arrest and suppressed cell division. Total glutathione decreased and superoxide anion increased with BSO and BSO plus 1,25(OH)2D3. Catalase activity increased with the combined treatment. Mitochondrial membrane potential and alkaline phosphatase activity were altered by 1,25(OH)2D3 alone or plus BSO. The percentage of terminal dUTP nick end labeling-positive cells was increased. BSO increases the antiproliferative effect of 1,25(OH)2D3 on Caco-2 cells through induction of oxidative stress, which occurs simultaneously with DNA breakage. The antioxidant system can partially compensate the damage induced by BSO plus 1,25(OH)2D3. Cell differentiation induction is also involved in the response to the combined treatment.

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“…Alternatively, cellular GSH can be depleted by inhibiting its synthesis. This is achieved by -glutamylcysteine synthetase inhibitors such as buthionine sulphoximine (BSO) [86] or by the inhibition of cysteine uptake induced by sulphasalazine [87]. In this context, transient GSH-depleting strategy was applied before irradiation to sensitise head and neck squamous cell carcinoma (HNSCC) to radiotherapy (88).…”

Section: Redox-active Compoundsmentioning

confidence: 99%

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

Tomasetti¹,

Santarelli²,

Alleva³

et al. 2015

CMC

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Tumours exhibit higher basal levels of reactive oxygen species (ROS) and altered redox environment compared to normal cells. Excessive level of ROS can be toxic to these cells, thus they become more vulnerable to damage by further ROS insults induced by pharmacological agents. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Therefore, abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. Many redox-modulating agents have been developed. The redox-active system epitomised by ascorbate-driven quinone redox cycling, and the group of redox-silent vitamin E analogues represented by α-tocopheryl succinate have been shown to induce selective cancer cell death in different types of cancer. These compounds synergistically act by destabilising organelles like mitochondria, unleashing their apoptogenic potential, which results in efficient death of malignant cells and suppression of tumour growth. Consistent with this notion, clinical trials that aim to examine the therapeutic performance of novel redox-modulating drugs in cancer patients are currently under way.

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Buthionine Sulfoximine and 1,25-Dihydroxyvitamin D Induce Apoptosis in Breast Cancer Cells via Induction of Reactive Oxygen Species

Cited by 12 publications

References 44 publications

2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53

2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53

Oxidative stress, cell cycle arrest and differentiation contribute toward the antiproliferative action of BSO and calcitriol on Caco-2 cells

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

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