EGFR inhibition in NSCLC: New findings…. and opened questions?

Passiglia, Francesco; Listì, Angela; Castiglia, Marta; Perez, Alessandro; Rizzo, Sérgio; Bazan, Viviana; Russo, Antonio

doi:10.1016/j.critrevonc.2017.02.009

Cited by 21 publications

(15 citation statements)

References 94 publications

(96 reference statements)

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“…Gefitinib was the first approved tyrosine kinase inhibitors (TKIs) for NSCLC [ 30 ]. However, resistance to gefitinib limits progression-free survival among patients with NSCLC [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells

Huang

Leng

et al. 2017

World J Surg Onc

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BackgroundLung cancer stem cells (CSCs) are considered to be the seed of lung cancer, and CD133 is a marker of lung CSCs. Here, we developed gefitinib-loaded poly(ethylene glycol) 2000-distearoylphosphatidylethanolamine nanomicelles with CD133 aptamers (M-Gef-CD133) to eliminate CD133+ lung CSCs.MethodsM-Gef-CD133 was prepared using a lipid-film-based approach. The targeting and activity of M-Gef-CD133 towards lung CSCs were evaluated.ResultsM-Gef-CD133 were small (25 nm) and showed enhanced cytotoxic effect towards CD133+ lung CSCs compared with non-targeted M-Gef and gefitinib. Notably, M-Gef-CD133 could significantly reduce tumor sphere formation and the percentage of CD133+ lung CSCs, indicating that it possesses selective toxicity against CD133+ lung CSCs.ConclusionsThe interaction of CD133 aptamers and CD133 shows promise in the delivery of gefitinib to CD133+ lung CSCs, and M-Gef-CD133 represents a promising treatment to target lung CSCs.

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“…Gefitinib was the first approved tyrosine kinase inhibitors (TKIs) for NSCLC [ 30 ]. However, resistance to gefitinib limits progression-free survival among patients with NSCLC [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells

Huang

Leng

et al. 2017

World J Surg Onc

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“…is tyrosine kinase inhibitor competes with adenosine triphosphate (ATP) for the binding side of EGFR, prevents the tyrosine phosphorylation, and thus blocks signaling pathway in the target cell. Erlotinib is applied in NSCLC therapy for patients with recognized EGFR-activating mutations [6][7][8]. It shows response rates of 10% to 27% in a broad NSCLC patient population after failure of chemotherapy [5].…”

Section: Introductionmentioning

confidence: 99%

Vibrational Fingerprint of Erlotinib: FTIR, RS, and DFT Studies

Piergies

Paluszkiewicz

Kwiatek

2019

Journal of Spectroscopy

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In this study, we provide the first Fourier-transform infrared absorption spectroscopy (FTIR) and Raman spectroscopy (RS) analysis of a vibrational fingerprint of erlotinib, a drug which is applied in non-small cell lung cancer therapy, in solid state and solution in different pH conditions. Additionally, the performed DFT theoretical calculations in vacuum and PCM models support the interpretation of vibrational spectra and give insight into an optimized spatial configuration of the investigated drug. e present considerations show vibrational structure of erlotinib and details of its molecular geometry. Furthermore, we discuss the pH condition where the protonated -NH + and C�N + forms occur and indicate the spectral changes characteristic for the erlotinib protonation. It is of great of importance to better understand biological activity of the drug and to develop new tyrosine kinase inhibitors.

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“…The afatinib concentrations required for the stimulation of eryptosis are within the range of concentrations encountered in the plasma of patients [43]. The stimulation of eryptosis may thus well explain the anemia following afatinib treatment [31].…”

Section: Discussionmentioning

confidence: 79%

Stimulation of Eryptosis by Afatinib

Bhuyan

Läng

2018

Cell Physiol Biochem

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Background/Aims: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at least partially effective by triggering suicidal tumor cell death. Side effects of afatinib treatment include anemia. At least in theory, afatinib induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ), induction of oxidative stress, and increase of ceramide abundance. The present study explored, whether afatinib induces eryptosis and, if so, whether its effect involves Ca 2+ entry, oxidative stress, and/or ceramide. Methods: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to afatinib (≥ 4 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Afatinib significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance. The effect of afatinib on annexin-V-binding and forward scatter was significantly blunted by removal of extracellular Ca 2+ . Conclusions: Afatinib triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca 2+ entry, oxidative stress, and ceramide.

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EGFR inhibition in NSCLC: New findings…. and opened questions?

Cited by 21 publications

References 94 publications

Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells

Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells

Vibrational Fingerprint of Erlotinib: FTIR, RS, and DFT Studies

Stimulation of Eryptosis by Afatinib

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