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Expert Review of Hematology Feb 2014Waldenström macroglobulinemia (WM) is distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells along... (Review)
Review
Waldenström macroglobulinemia (WM) is distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells along with production of a serum monoclonal (IgM). In this review, we describe the biology of WM, the diagnostic evaluation for WM with a discussion of other conditions that are in the differential diagnosis and clinical manifestations of the disease as well as current treatment options. Within the novel agents discussed are everolimus, perifosine, enzastaurin, panobinostat, bortezomib and carfilzomib, pomalidomide and ibrutinib. Many of the novel agents have shown good responses and have a better toxicity profile compared to traditional chemotherapeutic agents, which makes them good candidates to be used as primary therapies for WM in the future.
Topics: Antibodies, Monoclonal, Murine-Derived; Chromosome Aberrations; Gene Expression Profiling; Humans; Immunoglobulin M; Immunologic Factors; Proteasome Inhibitors; Protein Kinase Inhibitors; Proteomics; Rituximab; Waldenstrom Macroglobulinemia
PubMed: 24405328
DOI: 10.1586/17474086.2014.871494 -
Molecular Cancer Therapeutics Jun 2006Akt has been implicated as a molecular determinant of cellular radiosensitivity. Because it is often constitutively activated or overexpressed in malignant gliomas, it...
Akt has been implicated as a molecular determinant of cellular radiosensitivity. Because it is often constitutively activated or overexpressed in malignant gliomas, it has been suggested as a target for brain tumor radiosensitization. To evaluate the role of Akt in glioma radioresponse, we have determined the effects of perifosine, a clinically relevant alkylphospholipid that inhibits Akt activation, on the radiosensitivity of three human glioma cell lines (U87, U251, and LN229). Each of the glioma cell lines expressed clearly detectable levels of phosphorylated Akt indicative of constitutive Akt activity. Exposure to a perifosine concentration that reduced survival by approximately 50% significantly reduced the level of phosphorylated Akt as well as Akt activity. Cell survival analysis using a clonogenic assay, however, revealed that this Akt-inhibiting perifosine treatment did not enhance the radiosensitivity of the glioma cell lines. This evaluation was then extended to an in vivo model using U251 xenografts. Perifosine delivered to mice bearing U251 xenografts substantially reduced tumor phosphorylated Akt levels and inhibited tumor growth rate. However, the combination of perifosine and radiation resulted in a less than additive increase in tumor growth delay. Thus, in vitro and in vivo data indicate that the perifosine-mediated decrease in Akt activity does not enhance the radiosensitivity of three genetically disparate glioma cell lines. These results suggest that, although Akt may influence the radiosensitivity of other tumor types, it does not seem to be a target for glioma cell radiosensitization.
Topics: Animals; Apoptosis; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Immunohistochemistry; Mice; Mice, Nude; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Stem Cell Assay
PubMed: 16818509
DOI: 10.1158/1535-7163.MCT-06-0091 -
Investigational New Drugs Apr 2012The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and... (Comparative Study)
Comparative Study
The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and oncological malignancies. The in vitro cytotoxicity of perifosine, bortezomib and lenalidomide against 6 cell lines derived from hematological malignancies was investigated using trypan blue staining, flow cytometry-based detection of activated caspases, Annexin V assays, immunohistochemistry studies (KI-67 and caspase-3 staining) and the immature-myeloid-information (IMI) technique. Perifosine and bortezomib induced concentration- and time-dependent cytotoxicity in all cell lines tested. Perifosine together with bortezomib largely exerted additive or synergistic effects with combination indices ranging from 1.13 to 0.22 for combined efficacies of 25% to 75% after 24-hour incubation. Lenalidomide-triggered cytotoxicity was low in all cell lines tested with any assay (less than 10% compared to the negative control). Finally, perifosine, but not bortezomib or lenalidomide, significantly increased the number of cells detected in the IMI channel. Perifosine and bortezomib- but not lenalidomide- trigger substantial cytotoxicity by caspase activation and mainly act additively or synergistically. The IMI technique might be a useful tool for studying cytotoxicity of agents like perifosine that interact mainly with the cellular membrane.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Flow Cytometry; HL-60 Cells; Humans; Immunohistochemistry; Inhibitory Concentration 50; K562 Cells; Ki-67 Antigen; Lenalidomide; Leukemia, Myeloid; Lymphoma; Multiple Myeloma; Phosphorylcholine; Pyrazines; Thalidomide; Time Factors
PubMed: 21080211
DOI: 10.1007/s10637-010-9576-2 -
Parasitology Research Apr 2007Perifosine is a novel alkylphospholipid. Perifosine has displayed significant antiproliferative activity in vitro and in vivo in several human tumor model systems and...
Perifosine is a novel alkylphospholipid. Perifosine has displayed significant antiproliferative activity in vitro and in vivo in several human tumor model systems and has recently entered phase II clinical trials. Other alkylphospholipids have been previously used as antileishmanial agents, and miltefosine (Impavido) is now established as the first oral drug for the treatment of visceral and cutaneous leishmaniasis. Perifosine showed the higher activity against all tested strains. This study demonstrates for, the first time, an in vitro activity of perifosine against different species of Leishmania in the promastigote stage.
Topics: Animals; Antiprotozoal Agents; Humans; Inhibitory Concentration 50; Leishmania; Phosphorylcholine
PubMed: 17206506
DOI: 10.1007/s00436-006-0408-4 -
Mitochondrion Jan 2013Edelfosine and perifosine are alkylphospholipids that have been intensively studied as potential antitumor agents. Apoptotic cell death caused by these two compounds is...
Edelfosine and perifosine are alkylphospholipids that have been intensively studied as potential antitumor agents. Apoptotic cell death caused by these two compounds is mediated, at least in part, through mitochondria. Additionally, previous works demonstrated that edelfosine induces changes in mitochondrial membrane permeability that are somehow reduced by using cyclosporin A. Therefore, the objective of the present study was not only to confirm mitochondrial permeability transition but also identify direct effects of both ether lipids on mitochondrial hepatic fractions, namely on mitochondrial oxidative phosphorylation and generation of hydrogen peroxide (H(2)O(2)) through the respiratory chain. Results show that edelfosine and perifosine inhibit mitochondrial respiration and decrease transmembrane electric potential. However, despite these effects, edelfosine and perifosine were still able to induce mitochondrial permeability transition in non-energized mitochondria. Interestingly, edelfosine decreased H(2)O(2) production through the respiratory chain. In conclusion, the present work demonstrates previously unknown alterations of mitochondrial physiology directly induced by edelfosine and perifosine. The study is relevant in the understanding of mitochondrial-target effects of both compounds, as well as to acknowledge possible toxic responses in non-tumor organs.
Topics: Animals; Antineoplastic Agents; Hydrogen Peroxide; Male; Membrane Potential, Mitochondrial; Mitochondrial Membranes; Oxidative Phosphorylation; Permeability; Phospholipid Ethers; Phosphorylcholine; Rats, Wistar
PubMed: 23164800
DOI: 10.1016/j.mito.2012.11.003 -
Molecular Cancer Dec 2010Perifosine, an alkylphospholipid tested in phase II clinical trials, modulates the extrinsic apoptotic pathway and cooperates with tumor necrosis factor-related...
BACKGROUND
Perifosine, an alkylphospholipid tested in phase II clinical trials, modulates the extrinsic apoptotic pathway and cooperates with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment apoptosis. The current study focuses on revealing the mechanisms by which perifosine enhances TRAIL-induced apoptosis.
RESULTS
The combination of perifosine and TRAIL was more active than each single agent alone in inducing apoptosis of head and neck squamous cell carcinoma cells and inhibiting the growth of xenografts. Interestingly, perifosine primarily increased cell surface levels of DR5 although it elevated the expression of both DR4 and DR5. Blockade of DR5, but not DR4 upregulation, via small interfering RNA (siRNA) inhibited perifosine/TRAIL-induced apoptosis. Perifosine increased phosphorylated c-Jun NH2-terminal kinase (JNK) and c-Jun levels, which were paralleled with DR4 and DR5 induction. However, only DR5 upregulaiton induced by perifosine could be abrogated by both the JNK inhibitor SP600125 and JNK siRNA. The antioxidants, N-acetylcysteine and glutathione, but not vitamin C or tiron, inhibited perifosine-induced elevation of p-c-Jun, DR4 and DR5. Moreover, no increased production of reactive oxygen species was detected in perifosine-treated cells although reduced levels of intracellular GSH were measured.
CONCLUSIONS
DR5 induction plays a critical role in mediating perifosine/TRAIL-induced apoptosis. Perifosine induces DR5 expression through a JNK-dependent mechanism independent of reactive oxygen species.
Topics: Animals; Anthracenes; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Glutathione; Head and Neck Neoplasms; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Nude; Phosphorylcholine; RNA, Small Interfering; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays
PubMed: 21172010
DOI: 10.1186/1476-4598-9-315 -
Human Genomics Sep 2008Perifosine belongs to the class of alkylphospholipid analogues, which act primarily at the cell membrane, thereby targeting signal transduction pathways. In phase I/II...
Perifosine belongs to the class of alkylphospholipid analogues, which act primarily at the cell membrane, thereby targeting signal transduction pathways. In phase I/II clinical trials, perifosine has induced tumour regression and caused disease stabilisation in a variety of tumour types. The genetic determinants responsible for its cytotoxicity have not been comprehensively studied, however. We performed a genome-wide analysis to identify genes whose expression levels or genotypic variation were correlated with the cytotoxicity of perifosine, using public databases on the US National Cancer Institute (NCI)-60 human cancer cell lines. For demonstrating drug specificity, the NCI Standard Agent Database (including 171 drugs acting through a variety of mechanisms) was used as a control. We identified agents with similar cytotoxicity profiles to that of perifosine in compounds used in the NCI drug screen. Furthermore, Gene Ontology and pathway analyses were carried out on genes more likely to be perifosine specific. The results suggested that genes correlated with perifosine cytotoxicity are connected by certain known pathways that lead to the mitogen-activated protein kinase signalling pathway and apoptosis. Biological processes such as 'response to stress', 'inflammatory response' and 'ubiquitin cycle' were enriched among these genes. Three single nucleotide polymorphisms (SNPs) located in CACNA2D1 and EXOC4 were found to be correlated with perifosine cytotoxicity. Our results provided a manageable list of genes whose expression levels or genotypic variation were strongly correlated with the cytotoxcity of perifosine. These genes could be targets for further studies using candidate-gene approaches. The results also provided insights into the pharmacodynamics of perifosine.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Gene Dosage; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genome, Human; Humans; MAP Kinase Signaling System; Oligonucleotide Array Sequence Analysis; Phosphorylcholine; Polymorphism, Single Nucleotide; Sarcoma; Software
PubMed: 19129090
DOI: 10.1186/1479-7364-3-1-53 -
Cancer Chemotherapy and Pharmacology May 2015Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy,...
PURPOSE
Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration.
METHODS
Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves.
RESULTS
Peak plasma concentrations (C max) ranged from 11.7-19.3 µM, and remained >1 µM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502-4705) µM/h, with a median (range) terminal half-life (t 1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T max 64-235 h). CSF AUCs and t 1/2 were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over nM for >35 days. The mean CSF penetration was 0.16 %.
CONCLUSION
CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose.
Topics: Administration, Oral; Animals; Macaca mulatta; Male; Models, Animal; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt
PubMed: 25740692
DOI: 10.1007/s00280-015-2711-1 -
Journal of the National Cancer Institute Jun 2010Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine,...
BACKGROUND
Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine, a nontoxic AKT inhibitor, as a single agent on NB cell growth in vitro and in vivo.
METHODS
Four human NB cell lines (AS, NGP, BE2, and KCNR) were treated with increasing concentrations of perifosine, and a quantitative analysis of cell death (apoptosis) was performed by using MTS and caspase-3/7 activity assays. Survival of mice carrying xenograft NB tumors that were treated with perifosine (n = 6-7 mice per group) was compared with that of untreated mice (n = 7 mice per group) using Kaplan-Meier analysis. Tumor volumes were calculated to determine the effect of perifosine on NB tumor growth. Phosphorylation of AKT and expression of cleaved caspase-3 were measured in proteins from the tumors. All statistical tests were two-sided.
RESULTS
Perifosine, at 30 muM concentration, decreased AKT phosphorylation and increased apoptosis in all four NB cell lines in vitro. Perifosine-treated mice bearing xenograft NB tumors had longer survival than untreated mice (untreated vs treated, median survival: AS, 13 days, 95% confidence interval [CI] = 11 to 16 days vs not reached, P = .003; NGP, 22 days, 95% CI = 20 to 26 days vs not reached, P = .013; BE2, 24 days, 95% CI = 21 to 27 days vs not reached, P < .001; and KCNR, 18 days, 95% CI = 18 to 21 days vs not reached, P < .001). Perifosine treatment induced regression in AS tumors, growth inhibition in BE2 tumors, and slower growth in NGP and KCNR tumors. Inhibition of AKT phosphorylation and induction of caspase-dependent apoptosis were noted in tumors of perifosine-treated mice in all four in vivo NB tumor models.
CONCLUSIONS
Perifosine inhibited the activation of AKT and was an effective cytotoxic agent in NB cells in vitro and in vivo. Our study supports the future clinical evaluation of perifosine for the treatment of NB tumors.
Topics: Analysis of Variance; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Disease Models, Animal; Growth Inhibitors; Humans; In Vitro Techniques; Kaplan-Meier Estimate; Luciferases; Luminescent Agents; Mice; Mutation; NIH 3T3 Cells; Neuroblastoma; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Transplantation, Heterologous
PubMed: 20463309
DOI: 10.1093/jnci/djq125 -
Molecular Biology Reports Oct 2013Primary glioblastoma multiforme is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The combination of novel Akt...
Primary glioblastoma multiforme is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The combination of novel Akt inhibitors with anti-cancer therapeutics has achieved improved anti-tumor efficiency. In the current study, we examined the synergistic anti-cancer ability of Akt inhibitor perifosine in combination with short-chain ceramide (C6) against glioblastoma cells (U87MG and U251MG), and studied the underlying mechanisms. We found that perifosine, which blocked Akt/mammalian target of rapamycin activation, only induced moderate cell death and few cell apoptosis in cultured glioblastoma cells. On the other hand, perifosine administration induced significant protective autophagy, which inhibited cell apoptosis induction. Inhibition of autophagy by 3-methyaldenine or by autophagy-related gene-5 RNA interference significantly enhanced perifosine-induced apoptosis and cytotoxicity. We found that the short chain cell-permeable ceramide (C6) significantly enhanced cytotoxic effects of perifosine in cultured glioblastoma cells. For mechanism study, we observed that ceramide (C6) inhibited autophagy induction to restore cell apoptosis and perifosine sensitivity. In conclusion, our study suggests that autophagy inhibition by ceramide (C6) restores perifosine-induced apoptosis and cytotoxicity in glioblastoma cells.
Topics: Apoptosis; Autophagy; Brain Neoplasms; Cell Membrane Permeability; Cell Proliferation; Cell Survival; Ceramides; Glioblastoma; HEK293 Cells; Humans; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured
PubMed: 24065522
DOI: 10.1007/s11033-013-2666-4