Targeting the Phosphoinositide‐3‐kinase/Akt/Mammalian Target of Rapamycin Pathway

Granville, Courtney A.; Memmott, Regan M.; Gills, Joell J.; Dennis, Phillip A.

doi:10.1002/9783527619665.ch38

Cited by 5 publications

(10 citation statements)

References 221 publications

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“…Notably, the last two compounds have multiple targets, since PDK-1 phosphorylates and activates several kinases besides AKT. For this reason and due to the additional inhibitory effect of celecoxib on COX-2, the antineoplastic effects observed with these drugs can not be easily correlated with the inhibition of AKT [87,99]. Actually, to target both AKT and COX-2 with celecoxib is an intriguing possibility for MM, since in this tumor the expression of COX-2 has been associated with a higher proliferative and invasive potential as well as with a worse prognosis [100,101].…”

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 98%

“…The flavonoid LY294002 is a reversible ATP-competitive inhibitor of PI3K while wortmannin is a metabolite antibiotic isolated from Penicillium wortmanni that covalently binds an essential lysine residue in the catalytic subunit of PI3K leading to the irreversible inhibition of the enzyme [86,91,92,95]. Unfortunately, these as well as most inhibitors of PI3K and AKT characterized to date show unfavorable properties that have precluded their clinical development, including limited solubility and bioavailability, low specificity and elevated toxicity [86,87,98,99]. Notable exceptions are represented by the AKT inhibitors perifosine, UCN-01 and celecoxib, whose antineoplastic activity is currently being evaluated in patients with different types of cancer.…”

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 99%

“…Notable exceptions are represented by the AKT inhibitors perifosine, UCN-01 and celecoxib, whose antineoplastic activity is currently being evaluated in patients with different types of cancer. Perifosine is an alkylphospholipid which inhibits AKT by interfering with its translocation to the cell membrane, while UCN-01, a 7-hydroxy-derivative of the microbial alkaloid staurosporine, and celecoxib, a nonsteroidal anti-inflammatory drug and selective inhibitor of COX-2, indirectly target AKT by inhibiting its immediate upstream activator 3-phosphoinositide-dependent kinase 1 (PDK-1) [87,99]. Notably, the last two compounds have multiple targets, since PDK-1 phosphorylates and activates several kinases besides AKT.…”

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 99%

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Molecular Targets and Targeted Therapies for Malignant Mesothelioma

Palumbo

Bei

Procopio

et al. 2008

CMC

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Malignant mesothelioma is a highly invasive tumor originating from the mesothelial linings of the pleura, peritoneum and pericardium. It is seldom amenable to surgical intervention and poorly responsive to radiotherapy, leaving chemotherapy as the main therapeutic option for most patients. The development of effective drug regimens against mesothelioma has proven extremely difficult and a standard first-line treatment for patients with unresectable tumors has not been established until recently. Despite the benefits obtained with this newly validated standard of care, which is based on the combination of pemetrexed and cisplatin, the prognosis for mesothelioma patients remains poor, median survival is still less than two years and more active treatments are urgently needed. This article will focus on the molecular basis providing the rationale for targeted interventions against mesothelioma and will review targeted agents under evaluation as new potential therapeutic options for mesothelioma patients. Such agents include inhibitors of growth factor receptors, ligands and intracellular effectors. The agents targeting vascular endothelial growth factor signaling are of particular interest, due to the involvement of this pathway both in tumor angiogenesis and autocrine stimulation of mesothelioma cell growth. Alternative approaches are based on inhibitors of the ubiquitin-proteasome pathway and of histone deacetylases which, notwithstanding the functional divergence of the corresponding targets, share the ability to determine a wide modulation of the cancer cell phenotype that can lead to cell cycle arrest, apoptosis and sensitization to different antineoplastic treatments. A recombinant immunotoxin targeted to the membrane antigen mesothelin is an additional agent whose activity is being evaluated in mesothelioma patients.

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Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 98%

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 99%

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 99%

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Molecular Targets and Targeted Therapies for Malignant Mesothelioma

Palumbo

Bei

Procopio

et al. 2008

CMC

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“…18 From a clinical perspective, perifosine is the most developed PI3K/Akt inhibitor. 19 We have recently reported the cytotoxic effect of perifosine alone, or combined with etoposide, on the PTEN-null Jurkat T-acute lymphoblastic leukemia (T-ALL) cell line. 20 However, the cytotoxic activity of perifosine has not been tested on cells, which overexpress P-gp in combination with a constitutively active PI3K/Akt network.…”

Section: Introductionmentioning

confidence: 99%

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

et al. 2008

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A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Aktsignaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH 2 -terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.

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“…While these compounds efficiently inhibit the PI3-kinase pathway, that they have a short half-life, are insoluble in aqueous solutions, and have high toxicity, hampers their further clinical development. In the meantime the most promising targeted treatments aiming at the PI3-kinase pathway are the mTOR inhibitors [66]. mTOR is a serine/threonine kinase downstream of AKT which is inhibited by rapamycin, an immunosuppressant that has FDA approval for this indication.…”

Section: Mutations Of the Phosphatidy-linositol 3-kinase Pathwaymentioning

confidence: 99%

Tyrosine Kinase Mutations in Human Cancer

Lengyel¹,

Sawada²,

Salgia³

2007

CMM

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A subset of tyrosine kinases are activated by mutations which contribute to the malignant transformation, growth, and metastasis of human cancers. Mutations change the expression, conformation and/or stability of tyrosine kinases, often leading to constitutive activation of the signaling pathways the kinases regulate. Given that tyrosine kinases are key members of signaling cascades, mutations have multiple effects on various cellular proteins. This review will focus on four kinases (EGFR, c-Met, c-Kit, and PI3-kinase) known to be mutated in human cancer. It will discuss the effects that these mutations have on the biology of tumors, and how our understanding of the structure and function of kinases and their mutations is currently being used to design targeted treatments.

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Targeting the Phosphoinositide‐3‐kinase/Akt/Mammalian Target of Rapamycin Pathway

Cited by 5 publications

References 221 publications

Molecular Targets and Targeted Therapies for Malignant Mesothelioma

Molecular Targets and Targeted Therapies for Malignant Mesothelioma

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

Tyrosine Kinase Mutations in Human Cancer

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