In Vitro and In Vivo Inhibition of Neuroblastoma Tumor Cell Growth by AKT Inhibitor Perifosine

Li, Zhijie; Tan, Fei; Liewehr, David J.; Steinberg, Seth M.; Thiele, Carol J.

doi:10.1093/jnci/djq125

Cited by 63 publications

(67 citation statements)

References 54 publications

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“…In support of our data, Perifosine, a pan Akt inhibitor, was recently shown to impair the growth of neuroblastoma cells in vitro and in vivo 31 . Although the family of PI3Ks is an attractive and promising target for small-molecule inhibitors in cancer therapy, toxicity associated with pan-selective inhibition of PI3Ks and Akt has been a major hurdle preventing the translation of this approach to patients.…”

Section: Discussionsupporting

confidence: 89%

“…11,5 In neuroblastoma, studies have shown that inhibition of key molecules in the PI3K/Akt/mTOR signaling axis have profound effect on the survival of neuroblastoma cells. 5,6,14,22,31 Furthermore, inhibitors of PI3K/Akt or mTOR in combination with chemotherapeutic drugs use in neuroblastoma treatment often exhibit synergistic toxic effects on neuroblastoma cells in vitro.…”

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confidence: 99%

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Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

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Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositidedependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3b (GSK3b) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.Neuroblastomas are peripheral nervous system tumors that originate in the neural crest and are most commonly found in the adrenal medulla or along the sympathetic chain. 1 These tumors show heterogeneous biological and clinical features, in which a subset is prone to regress through spontaneous apoptosis with little or no therapy while another subset differentiates over time to benign ganglioneuromas. However, the majority of neuroblastomas are malignant with metastatic spread that is difficult to cure with current treatment modalities.2 Amplification of the MYCN gene, which occurs in 40-50% of the high-risk neuroblastoma cases, remains the major key predictor of poor outcome and is associated with advanced-stage disease, rapid tumor progression and low survival.3 Advanced-stage tumors and those with MYCN gene amplification typically show emergence of treatment resistance and new treatment alternatives for these patients are highly warranted.Abnormal activation of the PI3K/Akt signaling pathway is a common event in human cancers and has been validated through epidemiological and experimental studies as being essential for several human tumors, including neuroblastoma.4-6 PI3K is a family of lipid kinases, heterodimeric proteins composed of one catalytic and one regulatory subunit. In the class IA PI3Ks, there are currently three isoforms of the catalytic (p110a, b, and d) and five of the regulatory (p50a, p55a, p85a, p85b, and p55c) subunits, where p50a and p55a are splice variants of p85a. PI3Ks functions as signal transducers downstream of cell-surface receptors, such as receptor tyrosine kinases. Activated PI3Ks phosphorylate the lipid phosphatidyl-inositol 4,5-biphosphate (PIP2) to generate phosphatidyl-...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

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“…SMS-KCNR cells exhibit a uniform phenotype with small, round N-type cells that have short neuritic processes (34). This cell line was chosen as a model for mechanistic experiments in the current report since they display MYCN amplification, express caspase-8 (35) and apoptosis can be mediated through the intrinsic as well as extrinsic pathway (36). PAC-1A, however, induced cell death of SMS-KCNR through both apoptotic pathways via: i) modulation of expression of these mitochondrial Bcl-2 family proteins with pro-survival (Bcl-2, Bcl-xL) or pro-apoptotic (Bax, Bad, Bid) function, ii) TNF-family regulated extrinsic/death receptor signaling, and iii) activation of pro-apoptotic MAPK (e.g., SAPK/JNK) and suppression of pro-survival signaling through the PI3K/AKT/mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

Vorsa

2011

Int J Oncol

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Abstract. Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/ retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

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“…Mechanistically, Perifosine exhibits antitumor activity by preventing Akt translocation to the cell membrane [114] . The drug has demonstrated antitumor effects in neuroblastoma, ovarian cancer, Waldenstrom's macroglobulinemia, medulloblastoma, kidney cancer, endometrial cancer, prostate cancer, myelogenous leukemia, multiple myeloma, squamous cell carcinoma, breast cancer, sarcoma, lung cancer, hepatocellular carcinoma, and other solid tumors [115][116][117][118][119][120][121][122][123][124][125][126][127] . With its success in preclinical models, Perifosine reached phase I and II trials for the treatment of only solid tumors, Waldenstrom's macroglobulinemia, and sarcoma [127][128][129] .…”

Section: Akt Inhibitorsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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In Vitro and In Vivo Inhibition of Neuroblastoma Tumor Cell Growth by AKT Inhibitor Perifosine

Abstract: Perifosine inhibited the activation of AKT and was an effective cytotoxic agent in NB cells in vitro and in vivo. Our study supports the future clinical evaluation of perifosine for the treatment of NB tumors.

Cited by 63 publications

References 54 publications

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

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