Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors

Pallavicini, Gianmarco; Berto, Gaia; Cunto, Ferdinando Di

doi:10.3390/ijms20092098

Cited by 11 publications

(13 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The survival rates considerably depend on several factors including age, sex and tumor types [1,2]. The clinical management is often through surgery, radiotherapy, or chemotherapy interventions either individually or in combination [3,4]. Even though tumor resection surgery has improved overall survival rates and other related outcomes, it is not as effective as when it is combined with other available treatments.…”

Section: Introductionmentioning

confidence: 99%

Preparation, Characterization, and Biodistribution of Glutathione PEGylated Nanoliposomal Doxorubicin for Brain Drug Delivery with A Post-insertion Approach

Mehrabian¹,

Vakili‐Ghartavol²,

Mashreghi³

et al. 2021

Preprint

View full text Add to dashboard Cite

Brain cancer treatments have been largely unsuccessful due to the blood-brain barrier. Several publications support the presence of glutathione (GSH) receptors on the surface of the BBB and consequently the products such as the 2B3-101, which is almost 5% pre-inserted GSH PEGylated liposomal doxorubicin, is under process in clinical studies. Here we conducted the PEGylated nanoliposomal doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. The post-insertion methodology is noticeably simpler, faster, and more cost-effective compared to the pre-insertion method which makes it desirable for large-scale pharmaceutical manufacturing. The 25, 50, 100, 200, and 400 ligands of the DSPE PEG(2000) Maleimide-GSH complexes were incorporated into the available Caelyx. According to the animal studies such as biodistribution, fluorescent microscopy, and pharmacokinetic studies, the 200L and 400L treatment arms were the most promising formulations compared to the Caelyx. They proved that post-inserted nanocarriers with 40 times lower levels of GSH micelles compared to the 2B3-101 have significantly increased the penetrance through the blood-brain barrier. Other tissue analysis showed that the doxorubicin will likely accumulate in the liver, spleen, heart, and lung in comparison with the Caelyx due to the expressed GSH receptors on tissues as an endogenous antioxidant. In conclusion, as was expected, the post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, it is highly recommended further investigations to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus the 2B3-101 as a similar formulation with a different preparation method.

show abstract

Section: Introductionmentioning

confidence: 99%

Preparation, Characterization, and Biodistribution of Glutathione PEGylated Nanoliposomal Doxorubicin for Brain Drug Delivery with A Post-insertion Approach

Mehrabian¹,

Vakili‐Ghartavol²,

Mashreghi³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…A previous study reported that PLK4 knockdown reduces invasion, induces epithelial phenotype in breast cancer cells and plays an important role in cancer metastasis . Another study found that increase in PLK4 expression enhances the resistance of GBM cells to radiotherapy, and inhibition of PLK4 enhances the effect of temozolomide via reduction of IKBKE phosphorylation; besides, depletion of PLK4 in glioma cells using CRISPR/CAS9 significantly decreased the proliferation, viability and survival of glioma cells, increasing the susceptibility of cancer cells to DNA damage agents . Another study reported that a combination of bortezomib and PLK inhibitor showed a significantly higher anti‐tumour effect compared with bortezomib treatment alone in multiple types of head and neck cancers .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PLK4 might enhance the anti‐tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway

Wang

Ren

Sun³

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

GBM) is one of the most common aggressive cancers that occurs in the adult brain, and the survival period after initial diagnosis is only 12-15 months. 1 GBM accounts for nearly 70% of all adult brain tumours. 2 Effective treatment for GBM, which is characterized by rapid proliferation ability and highly infiltrative growth, is still lacking. 3 Bortezomib is a selective and reversible proteasome inhibitor that was first developed for the treatment of inflammation and cachexia in the late 90 seconds. 4 Studies using several tumour cells lines from the National Cancer Institute (NCI) confirmed its potency and wide range of anti-tumour effects. 5 Bortezomib was initially approved by US Food and Abstract Glioblastoma (GBM) is one of the most common aggressive cancers of the central nervous system in adults with a high mortality rate. Bortezomib is a boronic acidbased potent proteasome inhibitor that has been actively studied for its anti-tumour effects through inhibition of the proteasome. The proteasome is a key component of the ubiquitin-proteasome pathway that is critical for protein homeostasis, regulation of cellular growth, and apoptosis. Overexpression of polo-like kinase 4 (PLK4) is commonly reported in tumour cells and increases their invasive and metastatic abilities.In this study, we established a cell model of PLK4 knockdown and overexpression in LN-18, A172 and LN-229 cells and found that knockdown of PLK4 expression enhanced the anti-tumour effect of bortezomib. We further found that this effect may be mediated by the PTEN/PI3K/AKT/mTOR signalling pathway and that the apoptotic and oxidative stress processes were activated, while the expression of matrix metalloproteinases (MMPs) was down-regulated. Similar phenomenon was observed using in vitro experiments. Thus, we speculate that PLK4 inhibition may be a new therapeutic strategy for GBM.

show abstract

“…On this ground, genes mutated in primary microcephaly (MCPH) syndromes have already been proposed as possible targets for MB-directed drug development [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

Iegiani

Gai

Cunto

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, more effective therapies are needed. Primary microcephaly (MCPH) is a rare disorder caused by mutations in 25 different genes. Centromere-associated protein E (CENPE) heterozygous mutations cause the MCPH13 syndrome. As for other MCPH genes, CENPE is required for normal proliferation and survival of neural progenitors. Since there is evidence that MB shares many molecular features with neural progenitors, we hypothesized that CENPE could be an effective target for MB treatment. In ONS-76 and DAOY cells, CENPE knockdown induced mitotic defects and apoptosis. Moreover, CENPE depletion induced endogenous DNA damage accumulation, activating TP53 or TP73 as well as cell death signaling pathways. To consolidate CENPE as a target for MB treatment, we tested GSK923295, an allosteric inhibitor already in clinical trial for other cancer types. GSK923295, induced effects similar to CENPE depletion with higher penetrance, at low nM levels, suggesting that CENPE’s inhibition could be a therapeutic strategy for MB treatment.

show abstract

Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors

Cited by 11 publications

References 157 publications

Preparation, Characterization, and Biodistribution of Glutathione PEGylated Nanoliposomal Doxorubicin for Brain Drug Delivery with A Post-insertion Approach

Preparation, Characterization, and Biodistribution of Glutathione PEGylated Nanoliposomal Doxorubicin for Brain Drug Delivery with A Post-insertion Approach

Inhibition of PLK4 might enhance the anti‐tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

Contact Info

Product

Resources

About