Targeted Therapy and Molecular Genetics

Westin, Shannon N.; Sood, Anil K.; Coleman, Robert L.

doi:10.1016/b978-0-323-40067-1.00018-8

Cited by 3 publications

(4 citation statements)

References 307 publications

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“…Although antibodies can target and inhibit cancer cells, pure antibody-targeted drugs are less effective. The tumor expression level of EGFR is not related to the tumor response to cetuximab, and only some patients respond. , However, in the clinic, some ErbB2 antibodies, such as trastuzumab, have high therapeutic efficiency and have become star molecules in the treatment of breast and gastric cancers. − But the reason why trastuzumab has high therapeutic efficiency has not been clearly explained. Our results here provide a possible explanation: The endocytosis resistance of ErbB2 makes most of the trastuzumab reside on the cell membrane without entering the cell, leading to the enhanced antibody-dependent cellular cytotoxicity (ADCC) effect.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The tumor expression level of EGFR is not related to the tumor response to cetuximab, and only some patients respond. 42,43 However, in the clinic, some ErbB2 antibodies, such as trastuzumab, have high therapeutic efficiency and have become star molecules in the treatment of breast and gastric cancers. 44−46 But the reason why trastuzumab has high therapeutic efficiency has not been clearly explained.…”

Section: Resultsmentioning

confidence: 99%

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Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

2022

ACS Nano

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The ErbB receptor family, including the epidermal growth factor receptor (EGFR) and ErbB2/3/4, regulate cell proliferation, differentiation, apoptosis, motility, etc., and their abnormalities can cause cancer and other diseases. Ligand-induced endocytosis of ErbB receptors is the key to various cancer treatment strategies, and different techniques have been developed to study this important process. Among them, single particle tracking (SPT) can reveal the spatiotemporal heterogeneity of ErbB receptors on the live cell membrane and has been used to characterize the EGFR dimerization process. Herein, we studied the endocytosis dynamics of two different ErbB receptors using dark-field microscopy. With anti-ErbB modified plasmonic gold nanorods (AuNRs) as probes, we compared the trajectories of individual anti-EGFR AuNRs (cAuNRs) and anti-ErbB AuNRs (tAuNRs) interacting with MCF-7 cells in situ in real time. The results revealed that the internalization rate of cAuNRs was faster than that of tAuNRs. Detailed SPT analysis suggests that cAuNRs enter cells through EGFR endocytosis pathway, and multiple intracellular transport modes sort the cAuNRs away from the transmembrane site. In contrast, the endocytosis resistance of ErbB2 slows down the cellular uptake rate of tAuNRs and causes some tAuNRs-ErbB2 complexes to be confined on the membrane with “circular” and “rolling circle” motions for a much longer time. Our results provide insights into the endocytosis process of the ErbB receptor family at the nanometer scale and could be potentially useful to develop cancer treatment strategies.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

2022

ACS Nano

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“…WEE1 inhibitors appear to have potential high efficiency in p53-deficient ovarian cancers, generating a condition of synthetic lethality among p53 mutant tumors. Inhibition of WEE1 has demonstrated its effectiveness in DNA damage as a consequence of unregulated replication and strengthened the effectiveness of DNA-damaging agents [25]. Until now, only one (the most potent and selective) WEE1 inhibitor (Adavosertib, also under the names AZD1775 and MK1775) was found to be useful in clinical trials (in both phases I and II).…”

Section: Replication Stress and Cell Cycle Disturbances In Ovarian Cancermentioning

confidence: 99%

“…WEE1i was highly effective in p53-deficient cells and cells with defects in DNA damage repair pathways [27]. MK1775 was also combined with carboplatin treatment and paclitaxel in platinum-sensitive recurrent ovarian cancer [25]. The first report to present clinical evidence of MK1775 enhancing the efficacy of carboplatin in TP53-mutated tumors was published by Leijen et al in 2016, NCT01164995 [28].…”

Section: Replication Stress and Cell Cycle Disturbances In Ovarian Cancermentioning

confidence: 99%

Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

et al. 2020

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Ovarian cancer is one of the most lethal gynecologic malignancies reported throughout the world. The initial, standard-of-care, adjuvant chemotherapy in epithelial ovarian cancer is usually a platinum drug, such as cisplatin or carboplatin, combined with a taxane. However, despite surgical removal of the tumor and initial high response rates to first-line chemotherapy, around 80% of women will develop cancer recurrence. Effective strategies, including chemotherapy and new research models, are necessary to improve the prognosis. The replication stress response (RSR) is characteristic of the development of tumors, including ovarian cancer. Hence, RSR pathway and DNA repair proteins have emerged as a new area for anticancer drug development. Although clinical trials have shown poly (ADP-ribose) polymerase inhibitors (PARPi) response rates of around 40% in women who carry a mutation in the BRCA1/2 genes, PARPi is responsible for tumor suppression, but not for complete tumor regression. Recent reports suggest that cells with impaired homologous recombination (HR) activities due to mutations in TP53 gene or specific DNA repair proteins are specifically sensitive to ataxia telangiectasia and Rad3-related protein (ATR) inhibitors. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. This review describes the use of DNA repair checkpoint inhibitors as single agents and strategies combining these inhibitors with DNA-damaging compounds for ovarian cancer therapy, as well as the new platforms used for optimizing ovarian cancer therapy.

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Nanotoxicological study of downconversion Y₂O₃:Eu³⁺luminescent nanoparticles functionalized with folic acid for cancer cells bioimaging

et al. 2020

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Luminescent lanthanide downconversion nanoparticles (DCNPs) provide a combination of high luminescence intensity, sharp emission peaks with narrow bandwidth and a large Stokes' shift, leading to high‐performance biomedical applications mainly for imaging. The purpose of this study is to present a nanotoxicological study of DCNPs Y2O3 codoped with Eu3+ and functionalized with folic acid (FA). These assessments include cytotoxicity, genotoxicity, hemocompatibility, and in vitro inflammatory studies. We demonstrated by flow cytometry and confocal microscope the internalization of FA‐DCNPs in breast cancer and melanoma cells. They were synthesized by sol–gel method and coated with a thin silica shell to make them biocompatible; also they were functionalized with amino groups and FA ligands that bind to the folate receptors (FR) located on the surface of the cancer cells studied. This functionalization enables the DCNPs to be internalized into the cancer cells via endocytosis by the conjugation FA‐FR. The DCNPs were characterized with transmission electron microscope, Fourier transform infrared spectroscopy and photoluminescence. The nanotoxicological assessments demonstrated that both nanoparticles (bare and functionalized) are no cytotoxic and no genotoxic at the tested concentrations (0.01–20 μg/mL) in three cell lines (breast, skin cancer, and osteoblasts). Also they are hemocompatible and do not exert nitric oxide production in vitro by macrophages. The FA‐DCNPs were clearly localized into the cell cytoplasm with bright red luminescence. Thus, herein we present a complete nanotoxicological study of FA‐DCNPs Y2O3 codoped with Eu3+ and we conclude that these nanoparticles are biocompatible and can be further used for cancer cells bioimaging.

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Targeted Therapy and Molecular Genetics

Cited by 3 publications

References 307 publications

Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

Nanotoxicological study of downconversion Y₂O₃:Eu³⁺luminescent nanoparticles functionalized with folic acid for cancer cells bioimaging

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Targeted Therapy and Molecular Genetics

Cited by 3 publications

References 307 publications

Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

Direct Observation of Endocytosis Dynamics of Anti-ErbB Modified Single Nanocargoes

Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

Nanotoxicological study of downconversion Y2O3:Eu3+luminescent nanoparticles functionalized with folic acid for cancer cells bioimaging

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Nanotoxicological study of downconversion Y₂O₃:Eu³⁺luminescent nanoparticles functionalized with folic acid for cancer cells bioimaging