Luteolin is effective in the non‐small cell lung cancer model with L858R/T790M EGF receptor mutation and erlotinib resistance

Abstract

Background and Purpose Non‐small cell lung cancer (NSCLC) is one of the most commonly diagnosed malignancies in the world. Small‐molecule inhibitors of the EGF receptor's tyrosine kinase domain (TKIs), including gefitinib and erlotinib, have been widely used for treating NSCLC. Unfortunately, nearly all patients after initially experiencing a marked improvement while on these drugs, eventually progress to acquire resistance to TKIs. Because there is no effective therapeutic strategy to treat TKI‐resistant NSCLC, we evaluated the effects of luteolin, a naturally occurring flavanoid, on T790M mutant NSCLC cells. Experimental Approach The effect of luteolin on the viability of NSCLC and normal cell lines was investigated using the Cell Counting Kit‐8 (CCK‐8) assay. Luteolin‐induced apoptosis was assessed by bivariate FITC‐annexin V/PI assay, and Western blots were used to measured apoptotic proteins. Co‐immunoprecipitation was used to determine the effect of luteolin on the interaction between Hsp90 and mutant EGF receptors. The effect of luteolin on the Akt/mTOR pathway was studied using Western blotting analysis. Its anti‐tumour efficacy in vivo was examined in a mouse xenograft model. Key Results Luteolin exerted significant anti‐tumourigenic effects on the EGF receptor L858R/T790M mutation and erlotinib‐resistant NSCLC both at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association of Hsp90 with the mutant EGF receptor, and, therefore, prevented PI3K/Akt/mTOR signalling, which resulted in NSCLC cell apoptosis. Conclusion and Implications Luteolin may be a potential candidate for NSCLC therapy, especially for treatment of patients with acquired erlotinib‐resistant NSCLC.

Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

“…Gefitinib was found less effective than luteolin in prostate cancer (41,42), while lapatinib and luteolin were similarly effective against breast cancer (43). Combining luteolin with cisplatin or AG1478 unveiled a synergism in SCC-25 cells, similar to previous reports in liver, colorectal, gastric, pancreatic, and lung cancer (44)(45)(46), although not the case in breast and prostate cancer cells (41,43). Given the concern of broad toxicity of cisplatin and the adverse effects of tyrosine kinase inhibitors, such as gefitinib and lapatinib, luteolin appears to be a promising candidate for future clinical application, against OSCC.…”

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

“…Xenografts were allowed to grow until initial measurement (100-150 mm 3 ) was obtained using calipers. Mice were randomly divided into control and ATL-1 (75 mg/kg), erlotinib alone (50 mg/kg), and the combination of ATL-1 and erlotinib groups, which were administered daily via intraperitoneal injection for up to 20 days (n = 10 per group) according to previous studies [36][37][38] Next, mice were anesthetized via inhalation of 2% isoflurane. The substrate D-luciferin (Caliper Life Cellular Physiology and Biochemistry…”

Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes

“…A adição de 5µM de cisplatina não aumentou a citotoxicidade dos fármacos hit (Gráfico 5 e Tabela 7). Estudos prévios confirmaram o sinergismo entre a cisplatina e a luteolin em câncer de fígado (Shi et al, 2007), colorretal (Shi et al, 2007;Chian, Li, et al, 2014), gástrico (Wu et al, 2008), pancreático (Johnson e Gonzalez De Mejia, 2013) e de pulmão (Chian, Thapa, et al, 2014;Hong et al, 2014). Estas investigações, de fato, demonstraram que a luteolin amplifica os efeitos da cisplatina, que é utilizada como referência.…”

“…Mais uma vez, os resultados sugerem superioridade da luteolin em relação à cisplatina no tratamento contra diversos tipos de câncer in vitro. Prosseguindo, dois estudos encontraram melhores efeitos associando inibidores do EGFR com a luteolin em câncer de pulmão (Hong et al, 2014) e próstata (Sakurai et al, 2014) ao passo que outros dois trabalhos não observaram esta otimização em câncer de mama (Menendez et al, 2008) e próstata (Markaverich et al, 2010) (Zhao et al, 2011;Wang, L. et al, 2012). Estes dados mostram que, além de apresentarem citotoxicidade contra as células SCC-25, a luteolin e a nitazoxanide ainda são capazes de reduzir a atividade migratórias destas células, sendo possível aventar a hipótese de que estes fármacos podem auxiliar a prevenir o processo de metástase.…”

“…Além disso, é um composto altamente potente contra alguns tipos de câncer (Tuorkey, 2015) e é capaz de reverter a resistência de alguns tipos de tumores (Tu et al, 2013). A luteolin participa da modulação da apoptose, regulação de ciclo celular, angiogênese e até da regulação epigenética, auxiliando a impedir a invasão e metástase de tumores do fígado (Shi et al, 2007), estômago (Wu et al, 2008), pulmão (Hong et al, 2014) e mama (Lee et al, 2012). Em relação ao câncer de boca, ainda há escassez de informações a respeito do mecanismo de ação deste fármaco (O'prey et al, 2003;Yang et al, 2008;Amin et al, 2010;Verschooten et al, 2012;Majumdar et al, 2014).…”