Doxorubicin-induced cell death requires cathepsin B in HeLa cells

Bien, Sandra; Rimmbach, Christian; Neumann, Hans‐Günter; Niessen, Juliane; Reimer, Esther N.; Rosskopf, Dieter; Činátl, Jaroslav; Michaelis, Martin; Schroeder, Henry W. S.; Kroemer, Heyo K.

doi:10.1016/j.bcp.2010.07.036

Cited by 25 publications

(15 citation statements)

References 44 publications

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“…An alternative explanation for the decreased cell death observed upon preincubation with the PI3K/mTOR inhibitor might be that doxorubicin-induced apoptosis is inhibited by increased autophagy which can be observed after NVP-BEZ235 treatment. Interestingly, doxorubicin has been previously shown to interact with autophagy mediating proteins [46]. This would be in line with previous reports suggesting that sequential application of drugs can achieve a sensitization to doxorubcin via rewiring apoptotic signaling networks and independently of the cell cycle [13].…”

Section: Resultssupporting

confidence: 88%

“…However, although doxorubicin is frequently classified as a cell cycle-dependent topoisomerase IIα poison [44], [45], our own data (Fig. S3D), as well as a growing body of evidence suggest that it is also a potent inducer of cell death in a cell cycle-independent manner [46], [43], [47], [48]. The antiproliferative effect of NVP-BEZ235 is also seen in multiple myeloma cells, where moderate preincubation of with NVP-BEZ235 leads to an increase in doxorubicin-induced apoptosis [43].…”

Section: Resultsmentioning

confidence: 67%

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Sequential Dosing in Chemosensitization: Targeting the PI3K/Akt/mTOR Pathway in Neuroblastoma

et al. 2013

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Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ∼30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3β and inhibition of GSK3β, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death – at least in part – by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 67%

Sequential Dosing in Chemosensitization: Targeting the PI3K/Akt/mTOR Pathway in Neuroblastoma

et al. 2013

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“…25 Cathepsin B is one of the most stable proteases at physiological pH and has been shown to mediate LMP-associated cell death in response to doxorubicin, bortezomib, tumour necrosis factor and during mammary involution in mice. 26, 27, 28, 29 Released cathepsin B is active in the cytosol, where it can cleave many caspase targets and anti-apoptotic proteins, including Mcl-1 and XIAP. 30, 31, 32 However, the role of lysosome-mediated cell death for the activity of antitumour agents in primary CLL cells is largely unstudied.…”

Section: Introductionmentioning

confidence: 99%

Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

Yoon

Szwajcer

Ishdorj

et al. 2013

Blood Cancer Journal

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Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins.

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“…Cathepsin B is the most abundant in all of the cysteine proteases (Kirschke et al, 1995). Cathepsin B participates in many diverse cellular processes including protein degradation, antigen processing (Zhang et al, 2000), and apoptosis (Bien et al, 2010;Chwieralski et al, 2006;Roberts et al, 1999). It has been implicated in a variety of diseases including cancer invasion and metastasis (Ledakis et al, 1996;Matarrese et al, 2010;Roshy et al, 2003;Sinha et al, 2001;Szpaderska and Frankfater, 2001;Yan et al, 1998), angiogenesis (Im et al, 2005;Kruszewski et al, 2004;Malla et al, 2011;Sinha et al, 1995), inflammation (Hashimoto et al, 2001;Kakegawa et al, 2004), and Alzheimer's Disease (Gan et al, 2004;Hook, 2006;Hook et al, 2008).…”

Section: Cathepsin B and Kmentioning

confidence: 99%

Subcloning and Expression of Functional Human Cathepsin B and K in E. coli: Characterization and Inhibition by Flavonoids

Wen¹,

Tha²,

Sutton³

et al. 2011

Molecular Cloning - Selected Applications in Medicine and Biology

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Doxorubicin-induced cell death requires cathepsin B in HeLa cells

Cited by 25 publications

References 44 publications

Sequential Dosing in Chemosensitization: Targeting the PI3K/Akt/mTOR Pathway in Neuroblastoma

Sequential Dosing in Chemosensitization: Targeting the PI3K/Akt/mTOR Pathway in Neuroblastoma

Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

Subcloning and Expression of Functional Human Cathepsin B and K in E. coli: Characterization and Inhibition by Flavonoids

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