Aplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation

González-Santiago, Laura; Suárez, Yajaira; Zarich, Natasha; Muñoz-Alonso, María José; Cuadrado, Ana; Martínez, Teresa; Goya, Luis; Iradi, Antonio; Sáez, Guillermo T.; Maier, Jana V.; Moorthy, Anbalagan; Cato, Andrew C. B.; Rojas, José M.; Múñoz, Alberto

doi:10.1038/sj.cdd.4401898

Cited by 74 publications

(62 citation statements)

References 45 publications

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“…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). Next to phosphorylation of JNK, Aplidin also causes cleavage of Bid, a proapoptotic Bcl-2-family member that connects the Fas/CD95 cell death receptor (DR) to the mitochondrial apoptotic pathway, in human leukaemic cell lines (Gajate et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Depending on the cell system, Aplidin either induces a very rapid apoptotic death without previous cell cycle arrest or causes a block in G 1 and/or a delay in the progression from S to G 2 phases of the cell cycle (11,12). Further studies have shown that Aplidin induces apoptosis by altering glutathione homeostasis, thereby increasing the levels of reactive oxygen species and inducing Rac1 GTPase activation and MKP-1 phosphatase down-regulation (14). As part of its antitumoral action in leukemic cells, Aplidin has been shown to reduce the secretion of vascular endothelial growth factor and to down-regulate its receptor, vascular endothelial growth factor receptor-1 (flt-1; refs.…”

Section: Introductionmentioning

confidence: 99%

Levels of p27kip1 determine Aplidin sensitivity

Moneo

Serelde²,

Leal³

et al. 2007

Molecular Cancer Therapeutics

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Aplidin (plitidepsin) is a novel anticancer drug isolated from the marine tunicate Aplidium albicans. Aplidin shows potent antitumor activity in preclinical models against a wide variety of human tumors. Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies. Moreover, clinical studies of Aplidin in combination with other agents are ongoing because it generally lacks cross-resistance with other known cytotoxic drugs. The mode of action of Aplidin in tumor cells is only partially understood. Aplidin induces an early oxidative stress response, which results in a rapid and sustained activation of the epidermal growth factor receptor, the nonreceptor protein tyrosine kinase Src, and the serine threonine kinases c-Jun NH 2 -terminal kinase and p38 mitogen-activated protein kinase. Here, we show that sensitivity to Aplidin correlates inversely with the levels of expression of the cyclin-dependent kinase inhibitor p27 kip1 (p27) in a panel of low passaged human sarcoma cell lines. Aplidin induces p27 through an oxidation-dependent mechanism and the reduction of p27 levels by specific short hairpin RNA increases Aplidin sensitivity. We confirmed these results in p27 null mouse embryonic fibroblasts corroborating the specificity of the p27 role in Aplidin response because p21 waf1 null mouse embryonic fibroblasts do not show this increased sensitivity. We propose a mechanism of action of Aplidin involving p27 and support the analysis of p27 in the response to Aplidin in currently ongoing clinical trials to establish the levels of this protein as response predictor.

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“…A total of 278 plitidepsin cycles were administered during the study, with a median of 4 cycles per patient (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Before the amendment, 23 patients received a median of 4 cycles of single-agent plitidepsin (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Patients and Treatmentmentioning

confidence: 99%

“…Plitidepsin-induced oxidative stress leads to increased levels of cell membrane phospholipid as well as DNA oxidation (8), decreased intracellular levels of glutathione, and sustained activation of the Rac1-JNK pathway that ultimately leads to caspase-dependent apoptosis (9)(10)(11). In addition, plitidepsin has shown antiangiogenic activity in several preclinical models through inhibition of the expression of several angiogenic genes, including the vascular endothelial growth factor (VEGF) and its receptor (VEGFR-1; refs.…”

mentioning

confidence: 99%

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

Mateos

Cibeira

Richardson

et al. 2010

Clinical Cancer Research

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Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m 2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks. Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population. Clin Cancer Res; 16(12); 3260-9. ©2010 AACR.Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin's lymphoma. In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. The disease primarily affects aged individuals, with a median age of 60 years at diagnosis. Despite recent advances in the treatment of multiple myeloma and the availability of novel agents, few patients, if any, can be considered cured, as the vast majority will eventually relapse (1). Thus, new active agents without known cross-resistance with other well-established anti-multiple myeloma agents are needed.Plitidepsin is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans and is currently produced by chemical synthesis. The doselimiting toxicities (DLT) at the phase II recommended dose of 5.0 mg/m 2 over a 3-hour i.v. infusion every two weeks (2-7) included myalgia, muscular weakness, transient and reversible transaminases increase, and fatigue both in patients with solid tumors and in those

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Aplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation

Cited by 74 publications

References 45 publications

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

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

Levels of p27kip1 determine Aplidin sensitivity

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

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