BKM-120 (Buparlisib): A Phosphatidyl-Inositol-3 Kinase Inhibitor with Anti-Invasive Properties in Glioblastoma

Speranza, Maria-Carmela; Nowicki, Michal O.; Behera, Prateek; Cho, Choi-Fong; Chiocca, E. Antonio; Lawler, Sean E.

doi:10.1038/srep20189

Cited by 38 publications

(52 citation statements)

References 30 publications

(51 reference statements)

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“…Furthermore, it inhibits the growth of human tumors in xenograft mouse models in a well-tolerated manner and very efficiently penetrates the blood-brain barrier (8)(9)(10). Buparlisib reduced glioblastoma tumor spread in orthotopic xenograft models (11). A phase I clinical trial using buparlisib on a variety of solid tumors showed good disease control and tolerable toxicity (12 (14).…”

Section: Pi3k Inhibition In Melanoma Brain Metastasesmentioning

confidence: 99%

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

Niessner

Schmitz

Tabatabai

et al. 2016

Clinical Cancer Research

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Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases.

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Section: Pi3k Inhibition In Melanoma Brain Metastasesmentioning

confidence: 99%

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

Niessner

Schmitz

Tabatabai

et al. 2016

Clinical Cancer Research

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“…In this type of cancer, PI3K mutations are mutually exclusive of PTEN mutations/deletions with 59% of GBM showing one or the other (TCGA GBM Analysis Working Group). The role of phosphatidylinositol 3,4,5-trisphosphate (PI (3,4,5)P3, the product of class I PI3K) is fundamental in cancer research and often considered as 'oncogenic' but other phosphoinositides (PIs) such as phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) are also critical signal molecules particularly in the control of cell adhesion, migration and invasion [3]. These aspects are particularly important in GBM as this type of tumor is well known for its high migratory and invasive potential.…”

Section: Introductionmentioning

confidence: 99%

“…PI (3,4,5)P3 and PI(4,5)P2 are both recognized by members of the inositol polyphosphate 5-phosphatase family, that is, SYNJ2, OCRL, SHIP1/2, INPP5K, INPP5J [3]. Evidence in databases is provided of a significant correlation between increased INPP5K (SKIP) mRNA expression in GBM and improved long-term survival [5].…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of a tumor suppressor locus telomeric to Tp53 suggested INPP5K as a candidate for tumor suppressor activity [7]. Initial studies using CHO transfected SKIP showed that SKIP overexpression reduced both PI(4,5)P2 and PI (3,4,5) P3 as expected for a PI phosphatase that can take the two lipids as substrate [8]. Later studies reported that SKIP is mainly a PI(4,5)P2 phosphatase as shown in GBM [5] but also a PI (3,4,5)P3 phosphatase as shown in insulin sensitive muscle C2C12 cells [9].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, SKIP has been reported to localize at the surface of the endoplasmic reticulum (ER) which is unique among the various PI 5-phosphatases [11,12]. This location is surprising for a PI 5-phosphatase given the absence of PI(4,5)P2 and PI (3,4,5)P3 in the ER. It is possible that SKIP function is associated with its interaction with key proteins in the ER.…”

Section: Introductionmentioning

confidence: 99%

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Lipid phosphatases SKIP and SHIP2 regulate fibronectin‐dependent cell migration in glioblastoma

et al. 2019

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Cell migration is an important process that occurs during development and has also been linked to the motility of cancer cells. Cytoskeleton reorganization takes place in the migration process leading to lamellipodia formation. Understanding the molecular underpinnings of cell migration is particularly important in studies of glioblastoma, a highly invasive and aggressive cancer type. Two members of the phosphoinositide 5‐phosphatase family, SKIP and SHIP2, have been associated with cell migration in glioblastoma; however, the precise role these enzymes play in the process—and whether they work in concert—remains unclear. Here, we compared phosphoinositide 5‐phosphatases expression in glioblastoma primary cells and cell lines and showed that SHIP2 and SKIP expression greatly varies between different cell types, while OCRL, another phosphoinositide 5‐phosphatase, is constitutively expressed. Upon adhesion of U‐251 MG cells to fibronectin, SHIP2, SKIP, and PI(4,5)P2 colocalized in membrane ruffles. Upregulation of PI(4,5)P2 was observed in SKIP‐depleted U‐251 MG cells compared to control cells, but only when cells were adhered to fibronectin. Both PTEN‐deficient (U‐251) and PTEN‐containing (LN229) glioblastoma cells showed a decrease in cell migration velocity in response to SKIP downregulation. Moreover, a SHIP2 catalytic inhibitor lowered cell migration velocity in the U‐251 MG cell line. We conclude that integrin activation in U‐251 cells leads to colocalization of both SKIP and SHIP2 in ruffles, where they act as potential drivers of cell migration. Depending on their expression levels in glioblastoma, phosphoinositide 5‐phosphatases could cooperate and synergize in the regulation of cell migration and adhesion.

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Bichromophoric Sensors for Ratiometric Measurements of Molecular Microenvironments through the Interplay of Charge Transfer and Energy Transfer Channels

2018

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A new molecular architecture was designed to amplify the sensitivity of bichromophoric probes, in which two sequential kinetic competitions of photophysical channels were used to define the emission yield of the lower energy chromophore. Additionally, the emission from both chromophores can be used for ratiometric measurements, which are concentration independent. Two sensors were synthesized to demonstrate the concept, coupling a boron-dipyrromethene (BODIPY) dye and a cyanine dye. Both the energy transfer from the BODIPY to the cyanine and the cyanine radiative channel compete with a charge transfer state formation, giving the cyanine emission intensity a twofold dependence on polarity. This was confirmed with steady state and time-resolved spectroscopies. Also, the large spectral gap between the two emissions (approx. 280 nm) makes the ratiometric measurements crosstalk-free. The use of the sensors in live cells was demonstrated through the staining and imaging of SK-LU-1 lung cells under normal and apoptotic conditions.[a] A.Changes in the microenvironment of these molecules will affect the kinetics of the last process, and thus, the yields of the three competing processes. The molecules that underwent the RET process will then have the excitation localized in the second chromophore. The polarity-dependent formation of the CT state in the second chromophore will compete with its locally excited emission. This double dependence on the polarity of the medium gives these systems an enhanced sensitivity to different solvent or cell environments.Two prototype molecules were synthesized to demonstrate these design principles (see Figure 1). This was achieved by coupling the commercially available IR780 cyanine with a BODIPY dye trough a bridge formed by an ether bond and two different aromatic moieties: a phenyl group (BBIR) or a naphthyl group (BNIR). The aromatic moieties were selected to analyse the effect of changing the electron donor in the formation of the CT states and the sensitivity of the sensors while maintaining the distances between the energy transfer donor and the acceptor. The precursor cyanine IR780 was chosen due to its optical properties and because it can be easily functionalized at the meso position. Additionally, the IR780 cyanine has been widely used as a near-IR fluorescent probe due to its low toxicity and facile uptake by cells and tissues. [22,23] The water-2 3 4 5 6 7 8

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BKM-120 (Buparlisib): A Phosphatidyl-Inositol-3 Kinase Inhibitor with Anti-Invasive Properties in Glioblastoma

Cited by 38 publications

References 30 publications

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

Lipid phosphatases SKIP and SHIP2 regulate fibronectin‐dependent cell migration in glioblastoma

Bichromophoric Sensors for Ratiometric Measurements of Molecular Microenvironments through the Interplay of Charge Transfer and Energy Transfer Channels

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