The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)

Duverger, Valérie; Murphy, A-M; Sheehan, Donal; England, Karen; Cotter, Thomas G.; Hayes, Ian; Murphy, Finbarr J

doi:10.1038/sj.bjc.6601824

Cited by 27 publications

(21 citation statements)

References 29 publications

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“…Thus we analyzed the induction of apoptosis in KG1a cells pre-treated with low doses of MMA by three anticancer drugs at clinical relevant doses (40 µM Aracytin, 5 µM Mitoxantrone and 10 µM Etoposide (VP16)) or FasL. At first, in agreement with Duverger's data, 20 we observed that MMA pretreatment sensitized KG1a cells to FasL-induced apoptosis (data not shown). As shown in Figure 6 and in agreement with previous reports, 29-31 chemotherapeutic drugs induced no apoptosis phenomenon in KG1a cells.…”

Section: Mma Regulates Different Protein Expression Levelsupporting

confidence: 85%

“…Nevertheless the effect of MMA alone on tumor cells is not well understood, but it has recently been shown that MMA can sensitize tumor cells to apoptosis induced by TNFα and anti-Fas antibody. 20 Therefore we postulated that MMA could activate Fas death pathway and/or sensitize resistant cells to druginduced apoptosis. Indeed, our study shows that high doses of MMA activate Fas apoptotic signaling pathway in FasL-sensitive Jurkat cells as well as in FasL-insensitive KG1a cells independently of FasL/Fas interaction.…”

Section: Introductionmentioning

confidence: 99%

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Mithramycin A activates Fas death pathway in leukemic cell lines

Leroy¹,

Laurent²,

Quillet‐Mary³

2006

Apoptosis

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Mithramycin A (MMA, trade name Plicamycin) can facilitate TNFα-(Tumor Necrosis Factor) and Fas ligand-induced apoptosis. Besides, several drugs play their anticancer effect through Fas apoptotic pathway. So we investigated the effect of MMA on Fas signaling. In this study we show that MMA induces apoptosis in Fas sensitive Jurkat cells and Fas resistant KG1a cells. This effect involves Fas apoptotic pathway: cell exposure to MMA leads to Fas clustering at the cell surface, DISC (Death Inducing Signaling Complex) formation and caspase cleavage. This phenomenon is independent of Fas ligand/Fas interaction and blockade of Fas death pathway partially inhibits MMA-induced apoptosis. Moreover the activation of Fas apoptotic pathway by MMA is correlated to the modulation of c-Flip L expression. Finally, pre-treatment with sub-lethal doses of MMA sensitizes KG1a cells to chemotherapeutic agents. Thus all these results may have important implications to improve clinical treatments.

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Section: Mma Regulates Different Protein Expression Levelsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Mithramycin A activates Fas death pathway in leukemic cell lines

Leroy¹,

Laurent²,

Quillet‐Mary³

2006

Apoptosis

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“…Also mithramycin considerably increases the direct cytotoxic effect of TNF on tumor cells by acting on the balance of apoptotic factors [195]. In vitro, TNF-induced activation of NFkB-dependent gene expression is not modulated by mithramycin treatment, while FLIP protein levels are downregulated, indicating that mithramycin enhances TNF-induced PCD in an NFkB-independent manner by releasing the apoptotic brake FLIP.…”

Section: Other Tnf Sensitizersmentioning

confidence: 95%

Tumor necrosis factor, cancer and anticancer therapy

Mocellin

Róssi

Pilati

et al. 2005

Cytokine & Growth Factor Reviews

273

216

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“…Its mechanism of action has been proposed to interact with GC-rich domains of DNA contained in genes promoters (9), leading to gene transcription modulation, such as multidrug resistance gene (10), c-myc, or h-ras (11). It has recently been shown that mithramycin A can sensitize tumor cells to apoptosis induced by tumor necrosis factor-a and anti-Fas antibody (12,13). However, the underlying mechanisms of mithramycin A -induced sensitization are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites

Lee

Jung

Lee

et al. 2006

Molecular Cancer Therapeutics

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Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-A -related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In Caki renal cancer cells, which are resistant to TRAIL, cotreatment with subtoxic doses of mithramycin A and TRAIL resulted in a marked increase in apoptosis. This combined treatment was also cytotoxic to Caki cells overexpressing Bcl-2 but not to normal mesengial cells. Moreover, apoptosis by the combined treatment with mithramycin A and TRAIL was dramatically induced in various cancer cell types, thus offering an attractive strategy for safely treating malignant tumors. Mithramycin A -stimulated TRAIL-induced apoptosis was blocked by pretreatment with the broad caspase inhibitor zVAD-fmk or Crm-A overexpression, showing its dependence on caspases. We found that mithramycin A selectively down-regulated XIAP protein levels in various cancer cells. Luciferase reporter assay and the chromatin immunoprecipitation assay using the XIAP promoter constructs show that mithramycin A down-regulates the transcription of XIAP gene through inhibition of Sp1 binding to its promoter. Although XIAP overexpression significantly attenuated apoptosis induced by mithramycin A plus TRAIL, suppression of XIAP expression by transfection with its small interfering RNA prominently enhanced TRAIL-induced apoptosis. We present here for the first time that mithramycin A -induced suppression of XIAP transcription plays a critical role in the recovery of TRAIL sensitivity in various cancer cells.

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The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF)

Cited by 27 publications

References 29 publications

Mithramycin A activates Fas death pathway in leukemic cell lines

Mithramycin A activates Fas death pathway in leukemic cell lines

Tumor necrosis factor, cancer and anticancer therapy

Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites

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