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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 -
Molecular Cancer Therapeutics Jul 2007The Akt inhibitor, perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The...
The Akt inhibitor, perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The mechanisms by which perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of perifosine on the induction of apoptosis and its underlying mechanisms in human non-small cell lung cancer (NSCLC) cells. Perifosine, at clinically achievable concentration ranges of 10 to 15 micromol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells. Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly, enforced activation of Akt attenuated perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for perifosine-induced apoptosis. Despite the activation of both caspase-8 and caspase-9, perifosine strikingly induced the expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, death receptor 5, and down-regulated cellular FLICE-inhibitory protein (c-FLIP), an endogenous inhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-X(L), PUMA, and survivin. Silencing of either caspase-8 or death receptor 5 attenuated perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP small interfering RNA sensitized cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to perifosine. Collectively, these data indicate that activation of the extrinsic apoptotic pathway plays a critical role in perifosine-induced apoptosis. Moreover, perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of perifosine in combination with TRAIL in the treatment of NSCLC.
Topics: Antineoplastic Agents; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Carcinoma, Non-Small-Cell Lung; Caspase 8; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gene Silencing; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; MAP Kinase Signaling System; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation
PubMed: 17604333
DOI: 10.1158/1535-7163.MCT-07-0004 -
Cancer Research Dec 2009Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. This activity is partly associated with its...
Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. This activity is partly associated with its ability to inhibit Akt activity. It has been shown that the mammalian target of rapamycin (mTOR) axis plays a critical role in regulation of cell proliferation and survival primarily through functioning both downstream and upstream of Akt. The current study reveals a novel mechanism by which perifosine inhibits Akt and the mTOR axis. In addition to inhibition of Akt, perifosine inhibited the assembly of both mTOR/raptor and mTOR/rictor complexes. Strikingly, perifosine reduced the levels of Akt and other major components including mTOR, raptor, rictor, 70-kDa ribosomal S6 kinase, and 4E-binding protein 1 in the mTOR axis by promoting their degradation through a GSK3/FBW7-dependent mechanism. These results thus suggest that perifosine inhibits the mTOR axis through a different mechanism from inhibition of mTOR signaling by classic mTOR inhibitors such as rapamycin. Moreover, perifosine substantially increased the levels of type II light chain 3, a hallmark of autophagy, in addition to increasing poly(ADP-ribose) polymerase cleavage, suggesting that perifosine induces both apoptosis and autophagy. The combination of perifosine with a lysosomal inhibitor enhanced apoptosis and inhibited the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Collectively, we conclude that perifosine inhibits mTOR signaling and induces autophagy, highlighting a novel mechanism accounting for the anticancer activity of perifosine and a potential strategy to enhance the anticancer efficacy of perifosine by preventing autophagy.
Topics: Animals; Autophagy; Cell Cycle Proteins; Cell Line, Tumor; Chloroquine; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Female; Glycogen Synthase Kinase 3; HCT116 Cells; Humans; Lung Neoplasms; Mice; Mice, Nude; Oncogene Protein v-akt; Phosphorylation; Phosphorylcholine; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays
PubMed: 19920197
DOI: 10.1158/0008-5472.CAN-09-2190 -
Journal of Clinical Oncology : Official... Nov 2011Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator,...
Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.
PURPOSE
Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM.
PATIENTS AND METHODS
In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m(2), with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone.
RESULTS
An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients).
CONCLUSION
Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Male; Middle Aged; Multiple Myeloma; Phosphorylcholine; Pyrazines; Recurrence
PubMed: 21990396
DOI: 10.1200/JCO.2010.33.9788 -
Cellular Signalling Sep 2012We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a...
We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a significant increase of reactive oxygen species (ROS) and ceramide production as well as multiple perturbations of diverse cell signaling pathways, shifting to a significant pro-apoptosis outcomes. Perifosine inhibited UVB-induced pro-survival Akt/mammalian target of rapamycin (mTOR) and ERK activation, while facilitating pro-apoptotic AMP-activated protein kinas (AMPK), c-Jun-NH(2)-kinase (JNK), and p53 activation; these signaling changes together promoted a striking increase in skin cell apoptosis and a significantly reduced amount of DNA damages. Our results suggest that perifosine may represent a novel skin cancer prevention strategy.
Topics: Apoptosis; Cells, Cultured; Ceramides; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Humans; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Skin; Skin Neoplasms; Structure-Activity Relationship; Ultraviolet Rays
PubMed: 22584119
DOI: 10.1016/j.cellsig.2012.05.003 -
Cancer Biology & Therapy Sep 2012mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors...
mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors has been modest in most cancer types. We have previously demonstrated that the activation of PI3K/Akt and MEK/ERK signaling pathways attenuates the anticancer efficacy of mTORC1 inhibitors. In this study, we report that mTORC1 inhibition also phosphorylates and inactivates GSK3β, which is a tumor suppressor in lung cancer. Moreover, we show that perifosine, as an Akt inhibitor, decreases rapamycin-induced phosphorylation of GSK3β and elevated p-GSK3β levels in rapamycin-resistant cell lines. Combination of perifosine with mTORC1 inhibitors showed enhanced anticancer efficacy both in cell cultures and in a xenograft mouse model. In addition, perifosine inhibits the growth of both rapamycin sensitive and resistant A549 cells. However, inhibition of GSK3β by a selective inhibitor- LiCl, or downregulation of GSK3β expression by siRNA, reverses the growth inhibitory effects of perifosine on rapamycin resistant cells, suggesting the important role of GSK3β activation in enhancing mTORC1 inhibitors efficacy by perifosine. Thus, our results provide a potential therapeutic strategy to enhance mTORC1-targeted cancer therapy by using perifosine or targeting GSK3β.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Gene Knockdown Techniques; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Molecular Targeted Therapy; Multiprotein Complexes; Phosphorylation; Phosphorylcholine; Proteins; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays
PubMed: 22825337
DOI: 10.4161/cbt.20989 -
Cancer Research Aug 2005Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for...
Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in approximately 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; CDC2-CDC28 Kinases; Cell Growth Processes; Cell Line, Tumor; Cyclin-Dependent Kinase 2; Dacarbazine; Dose-Response Relationship, Drug; Drug Synergism; G1 Phase; G2 Phase; Glioma; Humans; Mice; Mice, Transgenic; Phosphorylcholine; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 16103096
DOI: 10.1158/0008-5472.CAN-05-1042 -
Biochemical and Biophysical Research... Jul 2013Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor...
Perifosine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production via regulation multiple signaling pathways: new implication for Kawasaki disease (KD) treatment.
Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor (TNF)-α is the pleiotropic inflammatory cytokine elevated during the acute phase of KD, which induces damage to vascular endothelial cells to cause systemic vasculitis. We here investigated the potential role of perifosine, a novel Akt inhibitor, on TNFα expression in LPS-stimulated macrophages and in ex-vivo cultured peripheral blood mononuclear cells (PBMCs) of acute KD patients. Here, we found that perifosine inhibited LPS-induced TNFα expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, perifosine administration down-regulated TNFα production in PBMCs isolated from acute KD patients. For the mechanism study, we found that perifosine significantly inhibited Akt and ERK/mitogen-activated protein kinases (MAPK) signaling, while activating AMP-activated protein kinase (AMPK) signaling in both patients' PBMCs and LPS-stimulated macrophages. Interestingly, although perifosine is generally known as an Akt inhibitor, our data suggested that ERK inhibition and AMPK activation, but not Akt inactivation were possibly involved in perifosine-mediated inhibition against TNFα production in monocytes. In conclusion, our data suggested that perifosine significantly inhibited TNFα production via regulation multiple signaling pathways. The results of this study should have significant translational relevance in managing this devastating disease.
Topics: Animals; Cell Line; Enzyme Activation; Lipopolysaccharides; Macrophages; Mice; Mucocutaneous Lymph Node Syndrome; Phosphorylcholine; Protein Kinases; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 23806687
DOI: 10.1016/j.bbrc.2013.06.055 -
British Journal of Haematology Mar 2010
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Death; Drug Screening Assays, Antitumor; Humans; Imidazoles; Leukemia; Phosphorylcholine; Piperazines; Tumor Cells, Cultured
PubMed: 19958355
DOI: 10.1111/j.1365-2141.2009.08018.x -
Cancer Chemotherapy and Pharmacology Aug 2015Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and...
PURPOSE
Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC.
METHODS
The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival.
RESULTS
Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase.
CONCLUSIONS
The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Caspase 9; Cell Proliferation; DNA Transposable Elements; Drug Synergism; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phosphorylcholine; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins p21(ras); RNA, Small Interfering; Sorafenib; Tumor Suppressor Protein p53
PubMed: 26037205
DOI: 10.1007/s00280-015-2787-7