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Expert Opinion on Drug Metabolism &... May 2012Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine)...
INTRODUCTION
Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine) and multiple myeloma (MM, in combination with bortezomib and dexamethasone).
AREAS COVERED
The mechanism, preclinical testing, and clinical activity of perifosine in CRC and MM are discussed, with supportive pharmacokinetic information presented. Appropriate literature searches were carried out for background and discussion purposes.
EXPERT OPINION
In preclinical models, perifosine has been shown to target phosphatidylinositol 3-kinase-Akt signaling. In CRC cell lines, preclinical studies indicate that perifosine may enhance the cytotoxic effects of fluorouracil, likely primarily through the nuclear transcription factor-kappa B pathway. A placebo-controlled Phase II randomized trial of capecitabine ± perifosine in previously treated patients with metastatic CRC showed the combination to be superior. In MM, Phase I/II clinical trials have established the optimal dosing schedule for perifosine and bortezomib in combination, and demonstrated that perifosine can sensitize to, or overcome resistance to, bortezomib, associated with prolonged responses and a favorable side effect profile. Ultimately, the favorable tolerability of perifosine will allow for its testing in combination with multiple targeted therapies to improve PFS and OS, which represent an important unmet need in these populations.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Capecitabine; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Dexamethasone; Drug Evaluation, Preclinical; Fluorouracil; Humans; Multiple Myeloma; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Pyrazines; Randomized Controlled Trials as Topic
PubMed: 22512706
DOI: 10.1517/17425255.2012.681376 -
Acta Pharmacologica Sinica Apr 2012The efficacy of the Akt inhibitor perifosine against chronic myeloid leukemia (CML) cells and its mechanisms of action are unknown. In this study, the cytotoxic effects...
AIM
The efficacy of the Akt inhibitor perifosine against chronic myeloid leukemia (CML) cells and its mechanisms of action are unknown. In this study, the cytotoxic effects of perifosine on CML and acute myeloid leukemia (AML) cell lines were compared to elucidate the mechanisms underlying the differences.
METHODS
Human AML cell lines Kasumi-1 and HL-60, and the CML cell line K562 were used. Cell viability was quantitated using MTT assay. Apoptosis was determined using Annexin V-FITC/propidium iodide and Hoechst staining, which were followed by flow cytometry and fluorescence microscopy analysis, respectively. Caspase pathway activation and the expression of autophagy-related genes were examined using Western blot. Autophagy was studied using electron microscopy, the acridine orange staining method, and GFP-LC3 was examined with fluorescence microscopy.
RESULTS
In contrast to AML cell lines, the CML cell lines K562 and K562/G (an imatinib-insensitive CML cell line) were resistant to perifosine (2.5-20 μmol/L) in respect to inhibiting cell growth and inducing apoptosis. Perifosine (2.5, 5, and 10 μmol/L) inhibited Akt and its phosphorylation in AML cells, but not in CML cells. Treatment with perifosine (20 μmol/L) resulted in autophagy in CML cells as shown by the increased formation of acidic vesicular organelles and the accumulation of LC3-II. Treatment of CML cells with perifosine (5, 10, and 20 μmol/L) dose-dependently upregulated AGT5, but not Beclin 1 at the protein level. Furthermore, inhibition of autophagy by chloroquine (40 nmol/L) significantly suppressed the cell growth and induced apoptosis in CML cells treated with perifosine (20 μmol/L).
CONCLUSION
Our results show that CML cell lines were resistant to the Akt inhibitor perifosine in vitro, which is due to perifosine-induced protective autophagy and upregulation of ATG5.
Topics: Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein 5; Cell Line, Tumor; Cell Survival; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MAP Kinase Kinase 4; Microtubule-Associated Proteins; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Up-Regulation
PubMed: 22407228
DOI: 10.1038/aps.2011.192 -
Particle and Fibre Toxicology Jan 2024As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention....
BACKGROUND
As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell-cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiONPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation.
RESULTS
After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation.
CONCLUSION
Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity.
Topics: Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Phosphatidylinositol 3-Kinases; Nanotubes, Carbon; TOR Serine-Threonine Kinases; Neuroglia; Adenosine Triphosphate; Apoptosis; Cell Membrane Structures; Nanotubes
PubMed: 38225661
DOI: 10.1186/s12989-024-00562-0 -
Cancer Letters Aug 2008We analyzed the mechanism of action for perifosine (D-21266), a new synthetic alkylphospholipid Akt inhibitor, using LNCaP and PC-3 prostate cancer cells. Perifosine...
We analyzed the mechanism of action for perifosine (D-21266), a new synthetic alkylphospholipid Akt inhibitor, using LNCaP and PC-3 prostate cancer cells. Perifosine treatment of PC-3 cells resulted in cytostatic and cytotoxic effects. Cytostatic effects were characterized by cell growth arrest, cell cycle block, and morphological changes, such as a cell enlargement and granulation, hallmarks of differentiating PC-3 cells. Specific differentiation markers including prostasomal, secretory and plasma membrane proteins, and keratins were induced by perifosine. Among them, we detected strong induction and secretion of CEACAM5 protein. In contrast, perifosine strongly reduced caveolin-1 RNA levels. Cytotoxic effects included para-apoptosis, apoptosis, and necrosis. To pursue the mechanisms responsible for these activities we focused on signaling pathways that lie downstream of Akt. Perifosine-triggered GSK-3beta activation in PC-3 and LNCaP cells resulted in the expression of GSK-3beta-related differentiation markers. This expression was reduced in the presence of specific siRNA for GSK-3beta or for its target CREB protein. The use of the GSK-3beta inhibitor lithium chloride indicated that GSK-3beta partially protects prostate cancer cells from the cytotoxic effects of perifosine. Together, these findings indicate that perifosine induces GSK-3beta-related differentiation and caspase-independent cell death in prostate cancer PC-3 cells. In addition our results identify specific biomarkers for perifosine therapy.
Topics: Active Transport, Cell Nucleus; Androgens; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Cycle; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Cell Nucleus; Cyclic AMP Response Element-Binding Protein; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Neoplasms, Hormone-Dependent; Phosphorylcholine; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt
PubMed: 18395973
DOI: 10.1016/j.canlet.2008.02.060 -
Blood May 2006Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline...
Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal-related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.
Topics: Cell Division; Cell Line, Tumor; Flow Cytometry; Growth Substances; Humans; Multiple Myeloma; Oncogene Protein v-akt; Phosphorylation; Phosphorylcholine
PubMed: 16418332
DOI: 10.1182/blood-2005-08-3434 -
EJHaem Jul 2020Perifosine, an investigational, oral, synthetic alkylphospholipid, inhibits signal transduction pathways of relevance in multiple myeloma (MM) including PI3K/Akt....
Randomized, placebo-controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib.
Perifosine, an investigational, oral, synthetic alkylphospholipid, inhibits signal transduction pathways of relevance in multiple myeloma (MM) including PI3K/Akt. Perifosine demonstrated anti-MM activity in preclinical studies and encouraging early-phase clinical activity in combination with bortezomib. A randomized, double-blind, placebo-controlled phase 3 study was conducted to evaluate addition of perifosine to bortezomib-dexamethasone in MM patients with one to four prior therapies who had relapsed following previous bortezomib-based therapy. The primary endpoint was progression-free survival (PFS). The study was discontinued at planned interim analysis, with 135 patients enrolled. Median PFS was 22.7 weeks (95% confidence interval 16·0-45·4) in the perifosine arm and 39.0 weeks (18.3-50.1) in the placebo arm (hazard ratio 1.269 [0.817-1.969]; = .287); overall response rates were 20% and 27%, respectively. Conversely, median overall survival (OS) was 141.9 weeks and 83.3 weeks (hazard ratio 0.734 [0.380-1.419]; = .356). Overall, 61% and 55% of patients in the perifosine and placebo arms reported grade 3/4 adverse events, including thrombocytopenia (26% vs 14%), anemia (7% vs 8%), hyponatremia (6% vs 8%), and pneumonia (9% vs 3%). These findings demonstrate no PFS benefit from the addition of perifosine to bortezomib-dexamethasone in this study of relapsed/refractory MM, but comparable safety and OS.
PubMed: 35847734
DOI: 10.1002/jha2.4 -
Translational Cancer Research Dec 2018Perifosine, is a third generation alkylphospholipid analog which has promising anti-tumor efficacy in clinical trials of refractory/recurrent neuroblastoma (NB)....
BACKGROUND
Perifosine, is a third generation alkylphospholipid analog which has promising anti-tumor efficacy in clinical trials of refractory/recurrent neuroblastoma (NB). However, perifosine's mechanism of action remains unclear. Previously, we have shown that perifosine changes global proteome and acetylome profiles in NB.
METHODS
To obtain a more comprehensive understanding of the perifosine mechanism, we performed a quantitative assessment of the lysine ubiquitylome in SK-N-AS NB cells using SILAC labeling, affinity enrichment and high-resolution liquid chromatography combined with mass spectrometry analysis. To analyse the data of ubiquitylome, we performed enrichment analysis with gene ontology (GO), the Encyclopedia of Genes and Genomes (KEGG) pathway, ubiquitylated lysine motif, protein complex and protein domain. Protein-protein interaction was conducted to explore the crosstalk between ubiquitylome and previous global proteome/acetylome. Co-immunoprecipitation and western blotting were used to validate the results of the ubiquitylome analysis.
RESULTS
Altogether, 3,935 sites and 1,658 proteins were quantified. These quantified ubiquitylated proteins participated in various cellular processes such as binding, catalytic activity, biological regulation, metabolic process and signaling pathways involving non-homologous end-joining, steroid biosynthesis and Ras signaling pathway. Ubiquitylome and proteome presented negative connection. We identified 607 sites which were modified with both ubiquitination and acetylation. We selected 14 proteins carrying differentially quantified lysine ubiquitination and acetylation sites at the threshold of 1.5 folds as potential targets. These proteins were enriched in activities associated with ribosome, cell cycle and metabolism.
CONCLUSIONS
Our study extends our understanding of the spectrum of novel targets that are differentially ubiquitinated after perifosine treatment of NB tumor cells.
PubMed: 30761266
DOI: 10.21037/tcr.2018.11.30 -
Computational and Mathematical Methods... 2021To research the molecular mechanism of ghrelin in apoptosis, migratory, and invasion of gastric cancer (GC) cells.
AIM
To research the molecular mechanism of ghrelin in apoptosis, migratory, and invasion of gastric cancer (GC) cells.
METHODS
After GC AGS cells were handled with ghrelin (10 M), cyclooxygenase-2 inhibitor NS398 (100 M), and Akt inhibitor perifosine (10uM), the rates of apoptosis were detected by TUNEL assay and flow cytometry assay. We assessed the expressions of PI3K, p-Akt, and COX-2 proteins by making use of Western blot analysis. The cell migratory and invasion were detected by using wound-healing and transwell analysis.
RESULTS
The migratory and invasion were increased in ghrelin-treated cells, while the rates of apoptosis were decreased. GC AGS cells treated with ghrelin showed an increase in protein expression of p-Akt, PI3K, and COX-2. After cells were treated with Akt inhibitor perifosine, the protein expression of p-Akt, PI3K, and COX-2 and the cell migratory, invasion, and apoptosis were partly recovered. After cells were treated with cyclooxygenase-2 inhibitor NS398, the protein expression of COX-2 and the cell migratory and invasion were decreased, while the rates of apoptosis were increased.
CONCLUSION
Ghrelin regulates cell migration, invasion, and apoptosis in GC cells through targeting PI3K/Akt/COX-2. Ghrelin increases the expression of COX-2 in GC cells by targeting PI3K/Akt. Ghrelin is suggested to be one of the molecular targets in GC.
Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Computational Biology; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Progression; Ghrelin; Humans; Neoplasm Invasiveness; Nitrobenzenes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; Sulfonamides
PubMed: 34122616
DOI: 10.1155/2021/5576808 -
Biology Nov 2023Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not...
Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not fully elucidated yet, it is known that they disrupt the intracellular trafficking of cholesterol and its metabolism. Here, we analyzed whether APLs could also interfere with mitochondrial function. For this purpose, we used HT29 colorectal cancer cells, derived from a primary tumor, and SW620 colorectal cancer cells, derived from a metastasis site. After treatment with the APLs miltefosine and perifosine, we analyzed various mitochondrial parameters, including mitochondrial mass, cardiolipin content, mitochondrial membrane potential, HO production, the levels of oxidative phosphorylation (OXPHOS) complexes, metabolic enzymes activity, the oxygen consumption rate, and the levels of apoptosis and autophagy markers. APLs, especially perifosine, increased mitochondrial mass while OXPHOS complexes levels were decreased without affecting the total oxygen consumption rate. Additionally, we observed an increase in pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH) levels and a decrease in lactate dehydrogenase (LDH) activity, suggesting a metabolic rewiring induced by perifosine. These alterations led to higher mitochondrial membrane potential, which was potentiated by decreased uncoupling protein 2 (UCP2) levels and increased reactive oxygen species (ROS) production. Consequently, perifosine induced an imbalance in mitochondrial function, resulting in higher ROS production that ultimately impacted cellular viability.
PubMed: 38132283
DOI: 10.3390/biology12121457 -
Annals of Oncology : Official Journal... Jun 2011The prognosis of advanced soft tissue sarcoma remains poor. Many phase II trials investigating new regimens have been published in the last 10 years. (Review)
Review
BACKGROUND
The prognosis of advanced soft tissue sarcoma remains poor. Many phase II trials investigating new regimens have been published in the last 10 years.
MATERIALS AND METHODS
Full English-language reports of phase II clinical trials from January 1999 to October 2009 have been reviewed. We have defined those that provided 3- and 6-month progression-free survival rates (PFSR) >39% and 14%, respectively, as promising second-line regimens. For studies enrolling both chemonaive and pretreated patients, we have compared the reported PFSR3 to the expected PFSR3 of an active treatment administered in the same proportions of pretreated and nonpretreated patients.
RESULTS
Forty-nine trials were identified. Among the trials investigating new regimens in pretreated patients alone, the promising second-line regimens were ifosfamide, brostallicin, pazopanib (except in liposarcoma), temozolomide, trabectedin, dacarbazine-gemcitabine and docetaxel (Taxotere)-gemcitabine combinations (in uterine leiomyosarcoma). Among the trials enrolling both chemonaive and pretreated patients, most regimens reached the level of efficacy; moreover, in three trials, the reported PFSR3 was particularly high: weekly paclitaxel (Taxol) in angiosarcoma, docetaxel-gemcitabine combination (in uterine leiomyosarcoma) and oral perifosine.
CONCLUSIONS
In the past 10 years, several drugs or combinations have demonstrated promising activity in exploratory phase II trials and warrant further investigation in appropriate phase III trials.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Prognosis; Sarcoma; Soft Tissue Neoplasms
PubMed: 21183581
DOI: 10.1093/annonc/mdq608