Gefitinib dihydrochloride

Gefitinib (ZD 1839) dihydrochloride is a potent, selective and orally active EGFR tyrosine kinase inhibitor with an IC50 of 33 nM. Gefitinib dihydrochloride selectively inhibits EGF-stimulated tumor cell growth (IC50 of 54 nM) and blocks EGF-stimulated EGFR autophosphorylation in tumor cells. Gefitinib dihydrochloride also induces autophagy and cell apoptosis, which can be used for cancer related research, such as Lung cancer and breast cancer [1][2][5].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> EGFR

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> EGFR

Signaling Pathways >> Autophagy >> Autophagy

IC50: 37 nM (Tyr1173 site, in NR6wtEGFR cells), 37 nM (Tyr992 site, in NR6wtEGFR cells)[1].

Gefitinib dihydrochloride (0.01–0.1  μM, 72 h) results in increased phosphotyrosine load of the receptor, increased signalling to ERK and stimulation of proliferation and anchorage-independent growth[2]. Gefitinib dihydrochloride (1-2 μM, 72 h) significantly decreases EGFRvIII phosphotyrosine load, EGFRvIII-mediated proliferation and anchorage-independent growth[2]. Gefitinib dihydrochloride (0.62 μM, 24-72 h) inhibits IL-13-induced M2-like polarization of RAW 264.7 cells through the STAT6-dependent signaling pathway[3]. Gefitinib dihydrochloride (0.62 μM, 72 h) inhibits M2-like macrophage-promoted invasion and migration[3]. Gefitinib dihydrochloride (0-10 μM, 72 h) induces apoptosis (induction of BIM protein) in NSCLC Cell Lines (H3255 and HCC827 cells)[4]. Western Blot Analysis[2] Cell Line: NR6wtEGFR, NR6W and NR6M Concentration: 1, 10, 100 μM Incubation Time: 5 h Result: Inhibited EGFR tyrosine phosphorylations. Cell Migration Assay [3] Cell Line: LLCs cell Concentration: 0.62 μM Incubation Time: 72 h Result: Abrogated M2-like macrophage promoted invasion and migration of LLCs.

Gefitinib dihydrochloride (Oral administration, 75 mg/kg/d, 21 days) inhibits the M2-like polarization of macrophages in LLC mice metastasis model[3]. Gefitinib dihydrochloride (Oral administration, 75 mg/kg for the initial week, daily for 5 consecutive days per week) eliminates phosphorylation of HER2 and HER3 and signaling through MAPK and Akt in lobular hyperplasias and carcinomas, increases MAPK activity and cytokine production in splenocytes and lymph nodes[5]. Animal Model: LLC mice metastasis model[3] Dosage: 75 mg/kg/d, for 21 days. Administration: Oral administration Result: Reduced the number of lung metastasis nodules, down-regulated the expression of M2 marker genes and the percentages CD206+ and CD68+ macrophages in tumor tissues. Animal Model: BALB-NeuT transgenic mouse model[5] Dosage: 75 mg/kg for the initial week, and increased by 15 mg/kg every other week, daily for 5 consecutive days per week, followed by 2 days without treatment and repeated for 8–9 weeks. Administration: Oral administration Result: Reduced tumor multiplicity from 9.6 to 0.58 (83%), and reduced the number and size of lobules and lobular nodules in treated mice.

[1]. Wakeling AE, et al. ZD1839: an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002 Oct 15;62(20):5749-54.

[2]. Pedersen MW, et al. Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br J Cancer. 2005 Oct 17;93(8):915-23.

[3]. Muhammad Tariq, et al. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol Sin. 2017 Nov;38(11):1501-1511.

[4]. Mark S Cragg, et al. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 2007 Oct;4(10):1681-89; discussion 1690.

[5]. Marie P Piechocki, et al. Gefitinib prevents cancer progression in mice expressing the activated rat HER2/neu. Int J Cancer. 2008 Apr 15;122(8):1722-9.