Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxel-induced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.
[Show abstract][Hide abstract] ABSTRACT: Background
Non-small cell lung cancer (NSCLC) expressed high levels of epidermal growth factor receptor (EGFR). Gefitinib (Iressa) has demonstrated clinical efficacy in NSCLC patients harboring EGFR mutations or refractory to chemotherapy. However, most of NSCLC patients are with wild type EGFR, and showed limited response to gefitinib. Therefore, to develop new effective therapeutic interventions for NSCLC is still required. Our previous study showed Marsdenia tenacissima extract (MTE) restored gefitinib efficacy in the resistant NSCLC cells, but whether MTE acts in the gefitinib-sensitive NSCLC cells is the same as it in the resistant one is unknown.
Dose response curves for gefitinib and MTE were generated for two sensitive NSCLC cell lines with mutant or wild type EGFR status. Three different sequential combinations of MTE and gefitinib on cell growth were evaluated using IC50 and Combination Index approaches. The flow cytometric method was used to detect cell apoptosis and cell cycle profile. The impact of MTE combined with gefitinib on cell molecular network response was studied by Western blotting.
Unlike in the resistant NSCLC cells, our results revealed that low cytotoxic dose of MTE (8 mg/ml) combined gefitinib with three different schedules synergistically or additively enhanced the growth inhibition of gefitinib. Among which, MTE → MTE + gefitinib treatment was the most effective one. MTE markedly prompted cell cycle arrest and apoptosis caused by gefitinib both in EGFR mutant (HCC827) and wild type of NSCLC cells (H292). The Western blotting results showed that MTE → MTE + gefitinib treatment further enhanced the suppression of gefitinib on cell growth and apoptosis pathway such as ERK1/2 and PI3K/Akt/mTOR. This combination also blocked the activation of EGFR and c-Met which have cross-talk with each other. Unlike in gefitinib-resistant NSCLC cells, MTE alone also demonstrated certain unexpected modulation on EGFR related cell signal pathways in the sensitive cells.
Our results suggest that MTE is a promising herbal medicine to improve gefitinib efficacy in NSCLC regardless of EGFR status. However, why MTE acted differently between gefitinib-sensitive and -resistant NSCLC cells needs a further research.
BMC Complementary and Alternative Medicine 05/2014; 14(1):165. DOI:10.1186/1472-6882-14-165 · 2.02 Impact Factor
"Considering that EGFR overexpression is a factor of poor prognosis, discontinuing erlotinib treatment after PD has developed may be an inappropriate option and combining erlotinib with the next stage of chemotherapy may be an appropriate therapy. We have previously reported that the combination of docetaxel with erlotinib showed a synergistic effect in NSCLC cell lines in vivo irrespective of EGFR or K-RAS mutation status (15). "
[Show abstract][Hide abstract] ABSTRACT: Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown to have benefits for non-small cell lung cancer and pancreatic cancer patients; however, almost all patients develop progressive disease during the therapy. On the other hand, it has been reported that a tumor continues to express epidermal growth factor receptor even after developing progressive disease. To demonstrate the clinical relevance of erlotinib treatment after progressive disease, we investigated whether continuous administration of erlotinib in combination with chemotherapy has a useful effect on progressive disease development during erlotinib treatment. For this purpose, we examined the antitumor effect of a combination therapy of a chemotherapeutic agent with erlotinib using two types of erlotinib-resistant tumor xenograft models: a non-small cell lung cancer model, in which EBC-1, H1975 and HCC827TR3 tumors were implanted, and an HPAC pancreatic cancer cell xenograft which generates erlotinib-resistant tumors in vivo. As a result, the combination therapy showed a significantly higher antitumor activity compared with chemomonotherapy in all xenograft models except the H1975 xenografts. Furthermore, erlotinib alone suppressed the phosphorylation of epidermal growth factor receptor in HPAC tumors and the two non-small cell lung cancer cell lines other than H1975. Therefore, combination therapy which uses erlotinib can be considered effective if epidermal growth factor receptor phosphorylation is inhibited by erlotinib, even in erlotinib-resistant tumor xenograft models. Our results suggest that the continuous inhibition of epidermal growth factor receptor phosphorylation by erlotinib after progressive disease enhances the antitumor activity of chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) → Akt → mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC cells and induces gene signatures that are associated with poor survival of NSCLC patients. The present results show that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor GO-203 was associated with downregulation of PI3K → Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C both for activation of the PI3K → Akt pathway and for survival.
Molecular Cancer Therapeutics 03/2011; 10(5):806-16. DOI:10.1158/1535-7163.MCT-10-1050 · 5.68 Impact Factor
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