Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

García‐Fernández, Luis; Losada, Alejandro; Alcaide, Victoria; Álvarez, Alberto; Cuadrado, Ana; González, Laura; Nakayama, Keiko; Nakayama, Keiichi I.; Fernández-Sousa, J.M.; Múñoz, Alberto; Sánchez-Puelles, José María

doi:10.1038/sj.onc.1205972

Cited by 132 publications

(112 citation statements)

References 66 publications

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“…In All-PO cells at 72 h after drug-washout 80% of the cells treated with 20 nM of Aplidin were apoptotic. As previously reported on other cell type (Garcia-Fernandez et al, 2002), Aplidin was found to induce apoptosis in a caspase-3-dependent manner ( Figure 5). …”

Section: Aplidin-induced Apoptosis On All Cell Linessupporting

confidence: 88%

Effect of Aplidin in acute lymphoblastic leukaemia cells

et al. 2003

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The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G 1 and a G 2 M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (488%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.

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Section: Aplidin-induced Apoptosis On All Cell Linessupporting

confidence: 88%

Effect of Aplidin in acute lymphoblastic leukaemia cells

et al. 2003

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“…In the subsequent studies, the mitochondrial changes were shown to be caused by different interactions. The sustained activation and phosporylation of c-Jun N-terminal kinase (JNK) by reactive oxygen species (ROS) is recognised as one of the crucial mechanisms in the effects of Aplidin on breast cancer cells (Garcia-Fernandez et al, 2002;Cuadrado et al, 2004;GonzalezSantiago et al, 2006;Suarez et al, 2006). This ROS induction was found to be caused by an alteration in the glutathione homeostasis and by a rapid activation of the small GTP-binding protein Rac (Cuadrado et al, 2003;Gonzalez-Santiago et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Studies involving the mechanism of action of Aplidin indicate that this compound acts through a complex number of events that affect proliferation, cell-cycle progression and apoptosis (Erba et al, 2002;Garcia-Fernandez et al, 2002). In 5T33MMvt cells, Aplidin induces a G0/G1 cell-cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

“…These data shown indicate that Aplidin indeed induced BOC-D-FMK-sensitive cell death. Previous works have demonstrated that activation of intrinsic apoptotic pathways through mitochondria is one of the hallmark activities of Aplidin (Garcia-Fernandez et al, 2002;Gajate et al, 2003). In the subsequent studies, the mitochondrial changes were shown to be caused by different interactions.…”

Section: Discussionmentioning

confidence: 99%

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Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Caers

Raeve³

et al. 2008

Br J Cancer

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Aplidin s is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC 50 of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 mg kg À1 daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (Po0.001), while BM invasion with myeloma cells was decreased by 35% (Po0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.

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“…52 On the other hand, rapid posttranscriptionally mediated up-regulation of eEF1A has been demonstrated following oxidative stress-induced apoptosis (e.g., upon treatment with hydrogen peroxide). 53 Remarkably, apoptosis induced by dehydrodidemnin has been shown to involve generation of oxidative stress, which can be largely prevented by the glutathione peroxidase mimetic ebselen, 54 and the very weak apoptotic response that is evoked in human normal peripheral blood lymphocytes by this agent (100 nM for 24 h) has been shown to be greatly enhanced in leukemic cells or mitogen-stimulated T-lymphocytes. 55 Since overexpression of eEF1A results in selective resistance to apoptosis induced by growth factor withdrawal and endoplasmic reticulum stress, but not from nuclear damage or death receptor signaling, 56 a global pivotal role of eEF1A levels in the modulation of apoptosis rate has been suggested.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

et al. 2004

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Didemnins and tamandarins are closely related marine natural products with potent inhibitory effects on protein synthesis and cell viability. On the basis of available biochemical and structural evidence and results from molecular dynamics simulations, a model is proposed that accounts for the strong and selective binding of these compounds to human elongation factor eEF1A in the presence of GTP. We suggest that the p-methoxyphenyl ring of these cyclic depsipeptides is inserted into the same pocket in eEF1A that normally lodges either the 3′ terminal adenine of aminoacylated tRNA, as inferred from two prokaryotic EF-Tu‚GTP‚tRNA complexes, or the aromatic side chain of Phe/Tyr-163 from the nucleotide exchange factor eEF1BR, as observed in several X-ray crystal structures of a yeast eEF1A:eEF1BR complex. This pocket, which has a strong hydrophobic character, is formed by two protruding loops on the surface of eEF1A domain 2. Further stabilization of the bound depsipeptide is brought about by additional crucial interactions involving eEF1A domain 1 in such a way that the molecule fits snugly at the interface between these two domains. In the GDP-bound form of eEF1A, this binding site exists only as two separate halves, which accounts for the much greater affinity of didemnins for the GTP-bound form of this elongation factor. This binding mode is entirely different from those seen in the complexes of the homologous prokaryotic EF-Tu with kirromycin-type antibiotics or the cyclic thiazolyl peptide antibiotic GE2270A. Interestingly, the set of interactions used by didemnins to bind to eEF1A is also distinct from that used by eEF1BR or eEF1B , thus establishing a competition for binding to a common site that goes beyond simple molecular mimicry. The model presented here is consistent with both available biochemical evidence and known structure-activity relationships for these two classes of natural compounds and synthetic analogues and provides fertile ground for future research.

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Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

Cited by 132 publications

References 66 publications

Effect of Aplidin in acute lymphoblastic leukaemia cells

Effect of Aplidin in acute lymphoblastic leukaemia cells

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

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