Two death pathways induced by sorafenib in myeloma cells: Puma-mediated apoptosis and necroptosis

Ramírez-Labrada, Ariel; López-Royuela, Nuria; Jarauta, Vidal; Galán-Malo, Patricia; Azaceta, Gemma; Palomera, Luis; Pardo, Julián; Anel, Alberto; Marzo, Isabel; Naval, Javier

doi:10.1007/s12094-014-1201-y

Cited by 23 publications

(17 citation statements)

References 37 publications

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“…Various triggers induce caspase-mediated MCL-1 degradation, contributing to accelerated apoptosis ( Miller et al , 2009 ; Ramirez-Labrada et al , 2014 ). We examined this potential mechanism using a pan-caspase inhibitor as described ( Miller et al , 2009 ; Ramirez-Labrada et al , 2014 ). Co-treatment of the pan-caspase inhibitor Z-VAD-FMK with the combination blocked caspase 3 activity and PARP cleavage, as expected.…”

Section: Resultsmentioning

confidence: 99%

Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

Mukherjee

Reuland

Lü

et al. 2015

Journal of Investigative Dermatology

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Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the anti-apoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs. The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines (carrying either BRAF or NRAS mutations), but not in normal melanocytes. The combination increased the NOXA expression and caspase-dependent MCL-1 degradation. Knocking-down NOXA protected cells from combination-induced apoptosis, implicating the role of NOXA in the drug synergy. The combination treatment also disrupted primary spheres (a functional assay for MICs) and decreased the percentage of ALDHhigh cells (a marker of MICs) in melanoma cell lines. Moreover, the combination inhibited the self-renewal capacity of MICs, measured by secondary sphere forming assays. In vivo, the combination inhibited tumor growth. Thus, this combination is a promising treatment strategy for melanoma, regardless of mutation status of BRAF or NRAS.

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Section: Resultsmentioning

confidence: 99%

Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

Mukherjee

Reuland

Lü

et al. 2015

Journal of Investigative Dermatology

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“…Induction of apoptosis is a mainstay of sorafenib action in a number of cancers, e.g., hepatocellular carcinoma, endometrial cancer, and myeloma [ 16 , 31 , 32 ]. Therefore, we investigated potential mechanisms impairing the efficacy of sorafenib on activation of apoptosis in UCCs.…”

Section: Resultsmentioning

confidence: 99%

Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer

Knievel

Schulz

Greife

et al. 2014

IJMS

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Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor α/-receptor β, PDGFR-α/-β; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma.

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“…We identified the FDA-approved Sorafenib tosylate (further referred to as Sorafenib) as a potent inhibitor of necroptosis in two independent screening assays using L929 cells. Sorafenib is a multi-kinase inhibitor that induces apoptosis of cancer cells 23, 24, 25 and is clinically used to treat advanced hepatocellular carcinoma (HCC), advanced renal cell carcinoma, 26 and acute myeloid leukemia (AML). 27 Sorafenib exerts anti-tumor effects by inhibiting kinases involved in cell proliferation and survival.…”

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confidence: 99%

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

et al. 2017

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Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia–reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.

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Two death pathways induced by sorafenib in myeloma cells: Puma-mediated apoptosis and necroptosis

Abstract: Our results demonstrate a key role for Puma in the triggering of sorafenib-induced apoptosis and that this drug can also induce death by necroptosis in multiple myeloma cells.

Cited by 23 publications

References 37 publications

Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer

Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

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