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Blood Jun 2007In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM.... (Review)
Review
In the past 36 months, new developments have occurred both in the understanding of the biology of Waldenström macroglobulinemia (WM) and in therapeutic options for WM. Here, we review the classification, clinical features, and diagnostic criteria of the disease. WM is a B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and a monoclonal immunoglobulin M (IgM) protein. The symptoms of WM are attributable to the extent of tumor infiltration and to elevated IgM levels. The most common symptom is fatigue attributable to anemia. The prognostic factors predictive of survival include the patient's age, beta(2)-microglobulin level, monoclonal protein level, hemoglobin concentration, and platelet count. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. Novel agents such as bortezomib, perifosine, atacicept, oblimersen sodium, and tositumomab show promise as rational targeted therapy for WM.
Topics: Antineoplastic Agents; Cytogenetic Analysis; Diagnosis, Differential; Humans; Immunoglobulin M; Immunophenotyping; Neoplasm Invasiveness; Waldenstrom Macroglobulinemia
PubMed: 17303694
DOI: 10.1182/blood-2006-11-055012 -
Pediatric Blood & Cancer Jul 2017The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model...
BACKGROUND
The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.
PROCEDURE
We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m /day) and temsirolimus (25-75 mg/m IV weekly) were investigated.
RESULTS
Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.
CONCLUSIONS
The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Neoplasms; Phosphorylcholine; Sirolimus; Young Adult
PubMed: 28035748
DOI: 10.1002/pbc.26409 -
American Journal of Clinical Oncology Jun 2015The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation,... (Review)
Review
The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat).
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Multiple Myeloma; Oligopeptides; Phosphorylcholine; Proteasome Inhibitors; Signal Transduction; Thalidomide
PubMed: 23934133
DOI: 10.1097/COC.0b013e3182a4676b -
ACS Omega Aug 2023Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers,... (Review)
Review
Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers, including NSCLC. These therapeutic molecules serve as important sources for new drugs that interfere with cellular proliferation, apoptosis, metastasis, and angiogenesis by regulating signaling pathways. These molecules affect several cellular signaling cascades, including p53, NF-κB, STAT3, RAS, MAPK/ERK, Wnt, and AKT/PI3K, and are thus implicated in the therapeutic management of cancers. This review aims to describe the bioactive compounds and small-molecule inhibitors, their anticancer action, and targeting cellular signaling cascades in NSCLC. We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.
PubMed: 37546685
DOI: 10.1021/acsomega.3c02424 -
Cancer Letters Oct 2008In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is...
In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5-6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Humans; Lenalidomide; Prognosis; Proteasome Inhibitors; Rituximab; Signal Transduction; Thalidomide; Waldenstrom Macroglobulinemia
PubMed: 18555588
DOI: 10.1016/j.canlet.2008.04.040 -
Biochimica Et Biophysica Acta Feb 2008Perifosine is a promising anticancer alkylphospholipid (ALP) that induces apoptosis in tumor cells. Here we report evidences against a role of endocytosis in perifosine...
Perifosine is a promising anticancer alkylphospholipid (ALP) that induces apoptosis in tumor cells. Here we report evidences against a role of endocytosis in perifosine uptake by human KB carcinoma cells. We have generated a KB cell line resistant to perifosine (KB PER(R) clone10), which shows cross-resistance to the ALPs miltefosine and edelfosine, a marked impairment in the uptake of (14)C-perifosine at both 37 degrees C and 4 degrees C, and no signs for active efflux of the drug. KB PER(R) clone10 cells show a similar rate of raft-dependent endocytosis with respect to the parental cells, and silencing of both clathrin and dynamin in the latter causes only minor changes in the rate of perifosine uptake. Perifosine uptake is a temperature- and ATP-dependent, N-ethylmaleimide- and orthovanadate-sensitive process in parental cells. Accumulation of (14)C-perifosine and the fluorescent phospholipid analogue 6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl]-phosphatidylethanolamine (NBD-PE) is inhibited by perifosine in a concentration-dependent manner in parental cells. Moreover, NBD-PE accumulation is slower in PER(R) clone10 cells and correlated with phosphatidylserine exposure in their plasma membrane surface. Together, all these data suggest a role of plasma membrane translocation by a putative phospholipid translocase, rather than endocytosis, as the true mechanism for ALPs uptake in KB carcinoma cells.
Topics: Adenosine Triphosphate; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Membrane; Clathrin; Dynamin I; Endocytosis; Humans; Phospholipid Transfer Proteins; Phosphorylcholine; RNA, Small Interfering
PubMed: 18005660
DOI: 10.1016/j.bbamem.2007.10.017 -
Frontiers in Oncology 2021Chemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases;...
Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells.
BACKGROUND
Chemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases; however, its roles in NB have not been established. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK-2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells.
METHODS
The expressions of ATXN3 and BCL-2 family members were detected by Western blot. Cell survival was evaluated by CCK8, cell confluence was measured by IncuCyte, and apoptosis was detected by flow cytometry. AS and BE2 were treated with AKT inhibitors or chemotherapeutics, respectively.
RESULTS
Downregulation of ATXN3 did not block, but significantly increased the perifosine/MK-2206-induced cell death. Among the BCL-2 family members, the expression of pro-apoptotic protein BIM and anti-proapoptotic protein Bcl-xl expression increased significantly when ATXN3 was down-regulated. Downregulation of BIM protected NB cells from the combination of perifosine/MK-2206 and ATXN3 downregulation. Downregulation of ATXN3 did not increase, but decrease the sensitivity of NB cells to etoposide/cisplatin, and knockdown of Bcl-xl attenuated this decrease in sensitivity.
CONCLUSION
Downregulation of ATXN3 enhanced AKT inhibitors (perifosine or MK-2206) induced cell death by BIM, but decreased the cell death induced by chemotherapeutic drugs (etoposide or cisplatin) Bcl-xl. The expression of ATXN3 may be an indicator in selecting different treatment regimen.
PubMed: 34322387
DOI: 10.3389/fonc.2021.686898 -
Tumour Biology : the Journal of the... Jul 2015Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor...
Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK\ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co-administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival-related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Drug Synergism; Humans; Lung Neoplasms; MAP Kinase Kinase Kinases; Mice; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 25697899
DOI: 10.1007/s13277-015-3244-2 -
Molecular Medicine Reports Feb 2013MicroRNA-27a (miR‑27a) is an oncogene that contributes to drug resistance in various types of cancer. However, the involvement of miR‑27a in gastric cancer has yet...
MicroRNA-27a (miR‑27a) is an oncogene that contributes to drug resistance in various types of cancer. However, the involvement of miR‑27a in gastric cancer has yet to be elucidated. Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. The effects of perifosine on gastric cancer have yet to be determined. Therefore, this study was conducted to detect the role of miR‑27a and perifosine in human gastric cancer. miR‑27a was found to be expressed in human gastric cancer tissues and cell lines by quantitative reverse-transcription polymerase chain reaction (qRT‑PCR). The correlation between miR‑27a expression and clinicopathological characteristics of gastric cancer. We also explored the growth inhibitory effect of perifosine on human gastric cancer cells with or without co‑targeting miR‑27a by sulforhodamine B (SRB) assay. The results showed that miR‑27a expression was significantly upregulated in gastric cancer tissues, compared with their non‑tumor adjacent tissues. High expression levels of miR‑27a were associated with poor tumor histological grade (P=0.037). MiR‑27a inhibitors suppressed the growth of MGC‑803 cells. Assay results showed that perifosine exerted its activity selectively on the AGS cell line and the growth inhibitory effect of perifosine was enhanced significantly in combination with miR‑27a inhibitors in MGC‑803 cells. In conclusion, our results demonstrated that miR‑27a may be a therapeutic target and potential prognostic biological marker in gastric cancer. MiR‑27a inhibitors alone or in combination with perifosine may be a novel therapeutic approach against gastric cancer.
Topics: Adult; Aged; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Gene Expression; Humans; Male; MicroRNAs; Middle Aged; Oligonucleotides, Antisense; Phosphorylcholine; Stomach Neoplasms
PubMed: 23175237
DOI: 10.3892/mmr.2012.1191 -
Cancer Research Mar 2002Alkylphospholipids (ALKs) are a novel class of antineoplastic compounds that display potent antiproliferative activity against several in vitro and in vivo human tumor...
Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest.
Alkylphospholipids (ALKs) are a novel class of antineoplastic compounds that display potent antiproliferative activity against several in vitro and in vivo human tumor models. However, the mechanism by which these agents exert this desired effect is still unclear. In this study, we investigated the effect of perifosine, a p.o.-bioavailable ALK, on the cell cycle kinetics of immortalized keratinocytes (HaCaT) as well as head and neck squamous carcinoma cells. All cells were sensitive to the antiproliferative properties of perifosine with an IC(50) of similar0.6-8.9 microM. Cell cycle arrest at the G(1)-S and G(2)-M boundaries was observed in HN12, HN30, and HaCaT cells independent of p53 function, and this effect was preceded by loss in cdc2 and cyclin-dependent kinase (cdk) 2 activity. Analysis of cdk complexes in vitro demonstrated that perifosine, up to 20 microM, did not directly interfere with these enzymes. However, aphidicolin-synchronized HN12 cells released in the presence of perifosine (10 microM) demonstrated increased expression of total p21(WAF1) and increased association of p21(WAF1) with cyclin-cdk complexes resulting in reduced cdc2 activity. HCT116 isogenic cell lines were used to assess the role of p21(WAF1) induction by perifosine. This compound (20 microM) induced both G(1)-S and G(2)-M cell cycle arrest, together with p21(WAF1) expression in both p53 wild-type and p53(-/-) clones. By contrast, p21(-/-) variants demonstrated no p21(WAF1) induction or cell cycle arrest. Similar results were obtained with other ALK congeners (miltefosine and edelfosine). These data, therefore, indicate that perifosine blocks cell cycle progression of head and neck squamous carcinoma cells at G(1)-S and G(2)-M by inducing p21(WAF1), irrespective of p53 function, and may be exploited clinically because the majority of human malignancies harbor p53 mutations.
Topics: Antineoplastic Agents; CDC2 Protein Kinase; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; DNA; Head and Neck Neoplasms; Humans; Phosphorylcholine; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 11888912
DOI: No ID Found