Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes

Straight, A. M.; Oakley, Karen L.; Moores, Russell R.; Bauer, Andrew J.; Patel, Aneeta; Tuttle, R. Michael; Jimeno, J.; Francis, Gary L.

doi:10.1007/s00280-005-0014-7

Cited by 50 publications

(36 citation statements)

References 37 publications

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“…Plitidepsin also has antiangiogenic properties, because it reduces the expression of several angiogenic genes in cancer xenografts (Straight et al, 2006). Moreover, plitidepsin reduces the secretion of VEGF and blocks the stimulatory VEGF autocrine loop in leukemic MOLT-4 cells .…”

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confidence: 99%

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells

Muñoz-Alonso¹,

González-Santiago²,

Zarich³

et al. 2007

J Pharmacol Exp Ther

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Melanoma is the most aggressive skin cancer and a serious health problem worldwide because of its increasing incidence and the lack of satisfactory chemotherapy for late stages of the disease. The marine depsipeptide Aplidin (plitidepsin) is an antitumoral agent under phase II clinical development against several neoplasias, including melanoma. We report that plitidepsin has a dual effect on the human SK-MEL-28 and UACC-257 melanoma cell lines; at low concentrations (Յ45 nM), it inhibits the cell cycle by inducing G 1 and G 2 /M arrest, whereas at higher concentrations it induces apoptosis as assessed by poly-(ADP-ribose) polymerase cleavage and the appearance of a hypodiploid peak in flow cytometry analyses. Plitidepsin activates Rac1 GTPase and c-Jun NH 2 -terminal kinase (JNK). In addition, it induces AKT and p38 mitogen-activated protein kinase (MAPK) phosphorylation. By using inhibitors, we found that JNK and p38 MAPK activation depends on Rac1 but not on phosphatidylinositol 3-kinase (PI3K), whereas AKT activation is independent of Rac1 but requires PI3K activity. Plitidepsin cytotoxicity diminishes by Rac1 inhibition or by the blockage of JNK and p38 MAPK using 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), but not by PI3K inhibition using wortmannin or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). It is remarkable that plitidepsin and dacarbazine, the alkylating agent most active for treating metastatic melanoma, show a synergistic antiproliferative effect that was paralleled at the level of JNK activation. These results indicate that Rac1/JNK activation is critical for cell cycle arrest and apoptosis induction by plitidepsin in melanoma cells. They also support the combined use of plitidepsin and dacarbazine in in vivo studies.Metastatic melanoma is an aggressive skin cancer whose incidence has rapidly increased over the past five decades. Although patients with early stage melanoma can be treated efficiently by surgical dissection, patients with metastatic melanoma have a very poor prognosis, with a median survival of less than 1 year (Jemal et al., 2005). Effective therapies for advanced stages of this disease have not been defined, because malignant melanoma has proven to be highly resistant to standard antineoplastic treatment. Dacarbazine (DTIC) is an alkylating agent considered the most active agent for treating metastatic melanoma, and it is the only drug approved by both the United States Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for use in this disease. However, dacarbazine has only a response rate Ͻ20%, with complete response observed in Ͻ5% of cases (Lev et al., 2003). It is clear that additional therapeutic agents are needed for advanced resistant melanoma.Aplidin (plitidepsin) is a marine antitumor agent isolated from the Mediterranean tunicate Aplidium albicans that displays a potent activity against human hematological and solid tumors cell lines. The compound has comThis work w...

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confidence: 99%

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells

Muñoz-Alonso¹,

González-Santiago²,

Zarich³

et al. 2007

J Pharmacol Exp Ther

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“…In leukemic Jurkat cells, plitidepsin also activates the Fas/CD95 receptor pathway together with JNK, possibly via the induction of cytoskeleton-mediated concentration in membrane lipid rafts of a large number of molecules including Fas ligand (Gajate et al, 2003;Gajate and Mollinedo, 2005). Plitidepsin has antiangiogenic effects in xenografted mice (Straight et al, 2006), which may result from the inhibition of vascular endothelial growth factor (VEGF) secretion and action Taraboletti et al, 2004) or to the induction of tumor or endothelial cell apoptosis (Biscardi et al, 2005). Plitidepsin blocks VEGF secretion and down-regulates VEGF mRNA in a cell line (ALL-PO) derived from a patient with acute lymphoblastic leukemia.…”

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confidence: 99%

Plitidepsin Cellular Binding and Rac1/JNK Pathway Activation Depend on Membrane Cholesterol Content

Suárez¹,

González-Santiago²,

Zarich³

et al. 2006

Mol Pharmacol

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Plitidepsin (aplidin) is a marine cyclic depsipeptide in phase II clinical development against several neoplasias. Plitidepsin is a potent inducer of apoptosis through the sustained activation of Jun N-terminal kinase (JNK). We have reported that this activation depends on the early induction of oxidative stress, activation of Rac1 small GTPase, and the later down-regulation of MKP-1 phosphatase. Using Scatchard and saturation binding analyses, we have found that 14 C-labeled plitidepsin binds to a moderately high-affinity receptor (K d of 44.8 Ϯ 3.1 and 35.5 Ϯ 4.8 nM, respectively) in MDA-MB-231 breast cancer cells. Two minutes after addition to cells, half of the drug was membranebound and was subsequently found in the cytosolic fraction. At 4°C, plitidepsin cellular binding was around 10-fold lower than at 37°C but sufficed to induce cell death, suggesting that this process is triggered from the membrane. Depletion of plasma membrane cholesterol by short treatment with methyl-␤-cyclodextrin diminished plitidepsin binding and Rac1 and JNK activation. Rac1 is targeted to the plasma membrane by plitidepsin as shown by subcellular fractioning and immunofluorescence analysis followed by confocal microscopy. Methyl-␤-cyclodextrin blocked this effect. A subline of HeLa cells (HeLa-R), partially resistant to plitidepsin, showed similar affinity (K d of 79.5 Ϯ 2.5 versus 37.7 Ϯ 8.2 nM) but 7.5-fold lower binding capacity than wild-type HeLa cells. Moreover, HeLa-R cells had lower total (71%) and membrane (67%) cholesterol content and membrane-bound Rac1, and showed no Rac1 activation upon plitidepsin treatment. In conclusion, cellular plitidepsin uptake and induction of apoptosis via activation of the Rac1-JNK pathway is membrane-cholesterol dependent.

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“…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]. A median of 6 cycles (range, 3-18) of study treatment were given to the 19 patients in which dexamethasone was added because of suboptimal response to single-agent plitidepsin.…”

Section: Patients and Treatmentmentioning

confidence: 99%

“…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%

“…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. [12][13][14][15]. Plitidepsin activity has been studied in vitro and in vivo against several different models at concentrations as low as in the nanomolar range (16).…”

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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 reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes

Abstract: This data supports the hypothesis that APLD may be an effective adjunctive therapy against ATC. The demonstrated molecular impact against angiogenic related genes specifically supports future strategies combining APLD with VEGF interacting agents.

Cited by 50 publications

References 37 publications

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells

Plitidepsin Cellular Binding and Rac1/JNK Pathway Activation Depend on Membrane Cholesterol Content

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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Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes

Abstract: This data supports the hypothesis that APLD may be an effective adjunctive therapy against ATC. The demonstrated molecular impact against angiogenic related genes specifically supports future strategies combining APLD with VEGF interacting agents.

Cited by 50 publications

References 37 publications

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells

Plitidepsin Cellular Binding and Rac1/JNK Pathway Activation Depend on Membrane Cholesterol Content

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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Product

Resources

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Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH₂-Terminal Kinase Activation in Human Melanoma Cells