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Expert Opinion on Investigational Drugs Oct 2013Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other... (Review)
Review
INTRODUCTION
Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other rationally selected targeted agents. The evidence from clinical trials supporting the use of perifosine in the therapy of leukemias is limited. The optimal dose and schedule have yet to be defined. However, given its favorable toxicity profile and mechanism of action, the therapeutic potential of perifosine should be evaluated in well-designed clinical trials.
AREAS COVERED
The role of the phosphatidylinositol-3 kinase (PI3K)/Akt zpathway in normal cells, cancer and leukemias is discussed. The mechanism of action of perifosine and the basic information on the development and chemical properties are summarized. The evidence from in vivo and in vitro studies is presented. The efficacy and side effect profile are summarized.
EXPERT OPINION
The safety and tolerability profile of perifosine are satisfactory. The evidence from clinical trials in patients with leukemias is very limited. The preclinical data are encouraging. Perifosine has the potential to play a role in the treatment of leukemias in the future. Its role needs to be confirmed in clinical trials.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Myeloid, Acute; Molecular Structure; Molecular Targeted Therapy; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Signal Transduction; Treatment Outcome
PubMed: 23931614
DOI: 10.1517/13543784.2013.826648 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Feb 2022To explore the biofilm inhibitory efficacy of perifosine against () and its mechanisms. Twenty-fourwell plate was used to form biofilms at the bottom and crystal violet...
To explore the biofilm inhibitory efficacy of perifosine against () and its mechanisms. Twenty-fourwell plate was used to form biofilms at the bottom and crystal violet staining was used to determine the biofilm inhibitory effects of perifosine against , the wells without perifosine was set as control group. Glass tubes combined with crystal violet staining was used to detect the gas-liqud interface related bioiflm inhibitory effects of perifosine, the wells without perifosine was set as control group. Time-growth curved was used to detect the effects of perifosine on the bacteial planktonic cells growth of , the wells without perifosine was set as control group. The interaction model between perifosine and PqsE was assessed by molecular docking assay. The inhibitory effects of perifosine on the catalytic activity of PqsE was determined by detection the production of thiols, the wells without perifosine was set as control group. Binding affinity between perifosine and PqsE was detected by plasma surface resonance. The biofims at the bottom of the microplates and air-liquid interface were effectively inhibited by perifosine at the concentration of 4-8 μg/ml. There was no influence of perifosine on the cells growth of . The resuts of molecular docking assay indicates that perifosine could interacted with PqsE with the docking score of -10.67 kcal/mol. Perifosine could inhibit the catalytic activity of PqsE in a dose-dependent manner. The binding affinity between perifosine and PqsE was comfirmed by plasma surface resonance with KD of 6.65×10mol/L. Perifosine could inhibited the biofilm formation of by interacting with PqsE.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Molecular Docking Simulation; Phosphorylcholine; Pseudomonas aeruginosa; Quorum Sensing
PubMed: 35184449
DOI: 10.3760/cma.j.cn112150-20211020-00970 -
Expert Opinion on Investigational Drugs Feb 2013Perifosine is an oral alkylphospholipid which has recently been assessed clinically in patients with advanced renal cell carcinoma (RCC). Perifosine acts primarily by... (Review)
Review
INTRODUCTION
Perifosine is an oral alkylphospholipid which has recently been assessed clinically in patients with advanced renal cell carcinoma (RCC). Perifosine acts primarily by attenuating the activation of Akt by preventing its pleckstrin homology (PH) domain-dependent localization to the cell membrane.
AREAS COVERED
This review summarizes the therapeutic landscape of RCC including the proposed role of perifosine in patients with advanced RCC. The mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy in RCC and safety of perifosine are all addressed as well.
EXPERT OPINION
Although perifosine has clear clinical activity in RCC, it is not superior to currently available agents and therefore does not appear worthy of further clinical development in RCC as a single agent. Given the observed efficacy and mild toxicity, however, perifosine may have a role in RCC therapy given in combination with other molecularly targeted agents.
Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Kidney Neoplasms; Molecular Structure; Phosphorylcholine; Randomized Controlled Trials as Topic
PubMed: 23253151
DOI: 10.1517/13543784.2013.754422 -
Autophagy Jan 2010Our long-term research goal is to develop efficacious regimens for cancer therapy through our understanding of cancer biology and drug mechanisms. Perifosine is an... (Review)
Review
Our long-term research goal is to develop efficacious regimens for cancer therapy through our understanding of cancer biology and drug mechanisms. Perifosine is an alkylphospholipid exhibiting antitumor activity and is currently being tested in clinical trials. Its activity is partly associated with its ability to inhibit Akt activity. In an effort to understand the mechanism by which perifosine exerts its anticancer activity, our recent work shows that perifosine, in addition to inhibition of Akt, inhibits mTOR signaling through a different mechanism than classical mTOR inhibitors such as rapamycin via facilitating the degradation of major components in the mTOR axis including mTOR, raptor and rictor. Accordingly, perifosine substantially induces autophagy in addition to apoptosis. The combination of perifosine with a lysosomal inhibitor enhances apoptosis and inhibition of the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Thus, our findings highlight a novel mechanism accounting for perifosine's anticancer activity involving degradation-mediated mTOR inhibition and also suggest a potential strategy to enhance perifosine's anticancer efficacy by preventing autophagy.
Topics: Animals; Antineoplastic Agents; Autophagy; Chloroquine; Drug Synergism; Humans; Lysosomes; Mice; Phosphorylcholine; Protease Inhibitors; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 20023422
DOI: 10.4161/auto.6.1.10816 -
Current Oncology Reports Mar 2009The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular... (Review)
Review
The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular survival pathways and an attractive target in cancer therapy. Many inhibitors of Akt are being developed. Perifosine is an oral Akt inhibitor currently being tested in phase 2 clinical trials. Unlike most kinase inhibitors, which target the adenosine triphosphate-binding region, perifosine targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Single-agent activity with perifosine has been observed in sarcoma and Waldenström macroglobulinemia patients. However, the disappointing response rates of common solid tumors to perifosine as a single agent have diminished expectations and prompted further investigation into its mechanism of action. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. In this article, we review the clinical history of perifosine and discuss its many biologic activities.
Topics: Animals; Clinical Trials as Topic; Humans; Membrane Microdomains; Neoplasms; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 19216841
DOI: 10.1007/s11912-009-0016-4 -
Current Topics in Medicinal Chemistry 2020Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the... (Review)
Review
Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.
Topics: Antineoplastic Agents; Benzylamines; Cell Line, Tumor; Diamines; Drug Design; Heterocyclic Compounds, 3-Ring; Humans; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Phospholipids; Piperazines; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Signal Transduction; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Thiophenes
PubMed: 32091335
DOI: 10.2174/1568026620666200224101808 -
Anti-cancer Agents in Medicinal... May 2014Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid... (Review)
Review
Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Membrane; Humans; Lipid Metabolism; Membrane Microdomains; Neoplasms; Neoplastic Stem Cells; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Receptors, Death Domain; Signal Transduction
PubMed: 24628236
DOI: 10.2174/1871520614666140309225912 -
Journal of Cellular and Molecular... Jan 2023An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common...
An acidic environment and hypoxia within the tumour are hallmarks of cancer that contribute to cell resistance to therapy. Deregulation of the PI3K/Akt pathway is common in colon cancer. Numerous Akt-targeted therapies are being developed, the activity of Akt-inhibitors is, however, strongly pH-dependent. Combination therapy thus represents an opportunity to increase their efficacy. In this study, the cytotoxicity of the Akt inhibitor perifosine and the Bcl-2/Bcl-xL inhibitor ABT-737 was tested in colon cancer HT-29 and HCT-116 cells cultured in monolayer or in the form of spheroids. The efficacy of single drugs and their combination was analysed in different tumour-specific environments including acidosis and hypoxia using a series of viability assays. Changes in protein content and distribution were determined by immunoblotting and a "peeling analysis" of immunohistochemical signals. While the cytotoxicity of single agents was influenced by the tumour-specific microenvironment, perifosine and ABT-737 in combination synergistically induced apoptosis in cells cultured in both 2D and 3D independently on pH and oxygen level. Thus, the combined therapy of perifosine and ABT-737 could be considered as a potential treatment strategy for colon cancer.
Topics: Humans; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Tumor Microenvironment; Phosphorylcholine
PubMed: 36523175
DOI: 10.1111/jcmm.17636 -
Oncotarget Sep 2015Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial...
Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms; Phosphorylcholine; Telomerase; Telomere; Xenograft Model Antitumor Assays
PubMed: 26307677
DOI: 10.18632/oncotarget.5200 -
Human Reproduction Update Feb 2022Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including... (Review)
Review
BACKGROUND
Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.
OBJECTIVE AND RATIONALE
We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.
SEARCH METHODS
In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.
OUTCOMES
(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.
WIDER IMPLICATIONS
Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.
Topics: Autophagy; Humans; Infertility, Male; Male; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34967891
DOI: 10.1093/humupd/dmab043