Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice

Abstract

BACKGROUNDNonsmall cell lung carcinomas (NSCLCs) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and vinca alkaloid derivatives, offer patients only slight clinical benefits. Part of the chemoresistance of NSCLC results from the expression in NSCLC cells of a very large set of endogenous proteins, which antagonize chemotherapy‐mediated attacks on these tumor cells.METHODSThe authors set up an orthotopic model of a human NSCLC by grafting A549 cells into the lungs of nude mice. They tried treating these A549 NSCLC orthotopic xenograft–bearing nude mice on the basis of various chemotherapeutic protocols, including chronic administrations of taxol, oxaliplatin, and irinotecan. A cyclooxygenase‐2 (COX‐2) inhibitor (NS‐398) also was assayed in combination with taxol. The immunohistochemical expression levels of COX‐2, prostaglandin E synthetase (PGES), ornithine decarboxylase (ODC), the lung‐related resistance protein (LRP), and glutathione‐S‐transferase‐α (GST‐α), GST‐μ, and GST‐π were quantitatively determined by means of computer‐assisted microscopy in control and drug‐treated NSCLC orthotopic xenografts.RESULTSThe orthotopic A549 xenograft model developed in 100% of the grafted mice, leading to brain metastases in approximately 61% mice and to liver metastases in approximately 40% of mice. The model was resistant to taxol and oxaliplatin and was only weakly sensitive to irinotecan. High levels of chemoresistant markers (i.e., COX‐2, PGES, ODC, LRP, GST‐α, GST‐μ, and GST‐π) were observed in the nontreated A549 xenografts, although with dramatic variations in individual expression. Taxol and oxaliplatin significantly increased the levels of expression of COX‐2, PGES, GST‐μ, and GST‐π in a number of different experimental protocols.CONCLUSIONSThe A549 orthotopic xenograft model could be used to evaluate investigational chemotherapeutic agents to identify drugs rapidly that are more active than the drugs currently in use in hospitals. Cancer 2004. © 2004 American Cancer Society.

The cardenolide UNBS1450 is able to deactivate nuclear factor κB–mediated cytoprotective effects in human non–small cell lung cancer cells

“…14, 15) could deactivate a constitutively activated NF-nB signaling pathway in the experimental A549 NSCLC model. In vivo orthotopic xenografts of human A549 NSCLC cells developing in the lungs of immunodeficient mice clearly metastasize into the brains and livers of the host mice and display a broad panel of mechanisms enabling them to resist chemotherapeutic insults including cyclooxygenase-2, prostaglandin E synthetase, ornithine decarboxylase, the lung-related resistance protein, and glutathione S-transferase-a, -A, and -k (16). The present study clearly shows that A549 NSCLC cells also display a constitutively activated NF-nB signaling pathway.…”

“…The present study clearly shows that A549 NSCLC cells also display a constitutively activated NF-nB signaling pathway. We recently showed that in vivo, various compounds used to treat patients with NSCLC (including taxol, irinotecan, and oxaliplatin) are of very limited therapeutic value in the case of the orthotopic A549 NSCLC model (16). We decided to use a cardenolide in order to try to deactivate the NF-nB signaling pathway in A549 tumor cells because (a) this type of drug [including digitoxin (17), oleandrin (18), and ouabain (19)] has previously been shown to interfere with the NF-nB pathway, and (b) cardenolides have a number of antitumor effects on lung cancers both in vitro (20) and in vivo (21).…”

Quercetin inhibits a large panel of kinases implicated in cancer cell biology

“…Many cancer types also display intrinsic resistance to proapoptotic stimuli even before metastasising, including NSCLC (43)(44)(45), melanoma (46,47), pancreatic cancer (48,49), oesophageal cancer (50) and glioma (51,52). Apart from the lack of response to apoptotic drugs, many cancers also develop an acquired chemoresistance during chronic treatments: the multidrug resistance (MDR) phenotype, which is a phenomenon caused by decreased intracellular drug accumulation in the cancer cells due to enhanced drug efflux (53,54).…”

Potenciais candidatos a novos antineoplásicos: síntese e avaliação da atividade antitumoral de análogos da queleritrina planejados por simplificação molecular

“…Essa concentração ultrapassa os valores escolhidos para a triagem dos compostos nas outras linhagens celulares. Entretanto, a escolha de uma concentração mais alta é justificável uma vez que a A549 é uma linhagem multirresistente (JARAMILLO et al, 2008;LAMORAL-THEYS et al, 2010;MATHIEU et al, 2004).…”

“…Já a alta expressão de transportadores ABC (ATP binding cassete) e de glutationa S-transferase Pi (GST-π), também presentes na A549, aumenta o efluxo de fármacos antineoplásicos e a destoxificação das células tumorais (DONG et al, 2014;MATHIEU et al, 2004;VAN DER DEEN et al, 2005), respectivamente. Estas características conferem resistência da A549 a compostos antitumorais, tais como a cisplatina (BARR et al, 2013;WU et al, 2010), a gencitabina (IKEDA et al, 2011;WANG et al, 2008) e o paclitaxel (GONÇALVES et al, 2001;SUN et al, 2011).…”