Current View on the Mechanism of Action of Perifosine in Cancer

Fensterle, Joachim; Aicher, Babette; Seipelt, Irene; Teifel, Michael; Engel, Juergen

doi:10.2174/1871520614666140309225912

Cited by 34 publications

(32 citation statements)

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“…Since AKT activity is required for cellular proliferation, endothelial cell migration and tube-like structure formation, the AKT pathway is considered as one of the most promising targets for cancer therapy [34][35][36]. Taken together with our current results, it is reasonable to assume that CGA-mediated inhibition of AKT phosphorylation may be responsible for the inhibitory effect of CGA on angiogenesis as well as on cellular growth.…”

Section: Discussionsupporting

confidence: 73%

Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway

et al. 2015

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Section: Discussionsupporting

confidence: 73%

Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway

et al. 2015

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“…Mechanisms involved in the action of perifosine include interference with the activation of Akt [1-4, 6, 8-13, 15, 16, 18, 20, 21] and stimulation of death receptor clustering [3, 22] with subsequent triggering of suicidal cell death or apoptosis [3, 8, 11-14, 16-18, 21, 23]. On the other hand, perifosine could activate AMP activated kinase AMPK and protect against cell death [24].…”

Section: Introductionmentioning

confidence: 99%

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

Egler

Läng²

2017

Cell Physiol Biochem

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Background/Aims: The alkylphospholipid perifosine is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. Side effects of perifosine include anemia. At least in theory, perifosine-induced anemia could result from stimulation of suicidal erythrocyte death or eryptosis. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms participating in the orchestration of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, increase of ceramide abundance, as well as activation of staurosporine sensitive protein kinase C and/or of SB203580 sensitive p38 kinase. The present study explored, whether perifosine induces eryptosis and, if so, whether its effect involves and/or requires Ca²⁺ entry, oxidative stress, ceramide and kinase activation. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant. Results: A 24 hours exposure of human erythrocytes to perifosine (2.5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased average forward scatter, significantly increased the percentage of shrunken erythrocytes, and significantly decreased the percentage of swollen erythrocytes. Perifosine significantly increased the percentage of hemolytic erythrocytes. Perifosine significantly increased Fluo3-fluorescence, but decreased DCFDA fluorescence and ceramide abundance. The effect of perifosine on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺ and by addition of staurosporine (1 µM), but not by addition of SB203580 (2 µM). Conclusions: Perifosine triggers eryptosis, an effect at least in part due to Ca²⁺ entry and activation of staurosporine sensitive kinases.

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“…Perifosine was shown to block AKT translocation to the plasma membrane through interacting its PH domain, and to inhibit AKT phosphorylation [8][9][10]. This novel first-in-class oral AKT inhibitor, alone or in combination with other anti-cancer agents, was tested in multiple tumor cell lines both in vivo and in vitro [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…This novel first-in-class oral AKT inhibitor, alone or in combination with other anti-cancer agents, was tested in multiple tumor cell lines both in vivo and in vitro [9][10][11][12][13][14][15]. It was also examined in several clinical studies, showing promising results in renal cell carcinoma (RCC) and neuroblastoma [9,10].…”

Section: Introductionmentioning

confidence: 99%

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

2015

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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.

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Current View on the Mechanism of Action of Perifosine in Cancer

Cited by 34 publications

References 0 publications

Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway

Chlorogenic acid inhibits hypoxia-induced angiogenesis via down-regulation of the HIF-1α/AKT pathway

Triggering of Eryptosis, the Suicidal Erythrocyte Death, by Perifosine

Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

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