Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma

Marengo, Barbara; Ciucis, Chiara De; Verzola, Daniela; Pistoia, Vito; Raffaghello, Lizzia; Patriarca, Stefania; Balbis, Emanuela; Traverso, Nicola; Cottalasso, Damiano; Pronzato, Maria Adelaide; Marinari, Umberto M.; Domenicotti, Cinzia

doi:10.1016/j.freeradbiomed.2007.10.031

Cited by 71 publications

(47 citation statements)

References 37 publications

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“…On the contrary, depletion of GSH by BSO sensitizes SH-SY5Y cells to diamide and activates apoptosis via the p38 MAPK /p53-mediated signaling pathway. It has been exhaustively reported that BSO enhances apoptotic response of neuroblastoma to different stimuli by increasing the steady-state concentration of ROS [40,41]. Therefore, although not directly investigated in this work, it is reasonable to hypothesize that also in our conditions, BSOdependent GSH depletion results in ROS production, which ultimately activates p38 MAPK /p53 signaling pathway.…”

mentioning

confidence: 76%

“…Several reports indicate that also this pathway is redox sensitive, but independent on the direct oxidation of Keap1 [42][43][44]. Indeed, it has been reported that members of MAPK family, and in particular ERK1/2, are able to phosphorylate Nrf2 on Ser 40 in a way allowing its detachment from Keap1 [32,45]. Interestingly, this signaling pathway has been indicated: (i) to increase antioxidant defense, mainly GSH neo-synthesis and HO-1 expression [44,46]; (ii) to be induced upon stressful conditions, such as chemotherapeutic treatments [44,46,47]; (iii) to be mutually exclusive of the p38 MAPK -mediated apoptotic pathways [14,46,48].…”

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confidence: 99%

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p38MAPK and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y

Filomeni

Piccirillo

Rotilio

et al. 2012

Biochemical Pharmacology

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confidence: 76%

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confidence: 99%

p38MAPK and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y

Filomeni

Piccirillo

Rotilio

et al. 2012

Biochemical Pharmacology

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“…WFA could thus be more efficient if associated with other molecules known to weaken the antioxidant system. For example, buthionine sulfoximine is known to deplete the pool of glutathione in cells [49] and is in clinical trial in association with melphalan to treat patients with persistent malignant melanoma (ClinicalTrials.gov identifier: NCT00661336).…”

Section: Discussionmentioning

confidence: 99%

Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2

et al. 2011

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A high resistance and heterogeneous response to conventional anti-cancer chemotherapies characterize malignant cutaneous melanoma, the most aggressive and deadly form of skin cancer. Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, has been reported for its anti-tumorigenic activity against various cancer cells. For the first time, we examined the death-inducing potential of WFA against a panel of four different human melanoma cells and investigated the cellular mechanisms involved. WFA induces apoptotic cell death with various IC50 ranging from 1.8 to 6.1 μM. The susceptibility of cells toward WFA-induced apoptosis correlated with low Bcl-2/Bax and Bcl-2/Bim ratios. In all cell lines, the apoptotic process triggered by WFA involves the mitochondrial pathway and was associated with Bcl-2 down regulation, Bax mitochondrial translocation, cytochrome c release into the cytosol, transmembrane potential (ΔΨm) dissipation, caspase 9 and caspase 3 activation and DNA fragmentation. WFA cytotoxicity requires early reactive oxygen species (ROS) production and glutathione depletion, the inhibition of ROS increase by the antioxidant N-acetylcysteine resulting in complete suppression of mitochondrial and nuclear events. Altogether, these results support the therapeutic potential of WFA against human melanoma.

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“…To test the second prediction, we cotreated cells with the GSH synthesis inhibitor BSO and BMOV. BSO has been used in clinical trials as an enhancer of anti-cancer drugs in various cancers including neuroblastoma [36][37][38]. BSO alone could deplete GSH by 10-40% in N206, IMR32, LAN-5 and SKNAS (Fig.…”

Section: Bmov Cytotoxicity Is Enhanced By Depletion Of Cellular Glutamentioning

confidence: 99%

Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine

Clark¹,

Park²,

Florio³

et al. 2015

Cancer Letters

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In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.

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Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma

Cited by 71 publications

References 37 publications

p38MAPK and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y

p38MAPK and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y

Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2

Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine

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