Melatonin Sensitizes H1975 Non-Small-Cell Lung Cancer Cells Harboring a T790M-Targeted Epidermal Growth Factor Receptor Mutation to the Tyrosine Kinase Inhibitor Gefitinib

Abstract

Background/Aims: The use of tyrosine kinase inhibitors (TKIs) to target active epidermal growth factor receptor (EGFR)-harbouring mutations has been effective in patients with advanced non-small-cell lung cancer (NSCLC). However, the use of TKIs in NSCLS patients with somatic EGFR mutations, particularly T790M, causes drug resistance. Thus, in the present study, we investigated overcoming resistance against the TKI gefitinib by combination treatment with melatonin in H1975 NSCLC cells harbouring the T790M somatic mutation. Methods: H1975 and HCC827 cells were treated with melatonin in combination with gefitinib, and cell viability, cell cycle progression, apoptosis, and EGFR, AKT, p38, Bcl-2, Bcl-xL, caspase 3 and Bad protein levels were examined. Results: Treatment with melatonin dose-dependently decreased the viability of H1975 cells harbouring the T790M somatic mutation compared to HCC827 cells with an EGFR active mutation. Melatonin-mediated cell death resulted in decreased phosphorylation of EGFR and Akt, leading to attenuated expression of survival proteins, such as Bcl-2, Bcl-xL and survivin, and activated caspase 3 in H1975 cells, but not in HCC827 cells. However, we did not observe a significant change in expression of cell cycle proteins, such as cyclin D, cyclin A, p21 and CDK4 in H1975 cells. Surprisingly, co-treatment of gefitinib with melatonin effectively decreased the viability of H1975 cells, but not HCC827 cells. Moreover, co-treatment of H1975 cells caused consistent down-regulation of EGFR phosphorylation and induced apoptosis compared to treatment with gefitinib or melatonin alone. Conclusions: Our findings demonstrate that melatonin acts as a potent chemotherapeutic agent by sensitising to gefitinib TKI-resistant H1975 cells that harbour a EGFR T790M mutation.

Synergistic Induction of Erlotinib-Mediated Apoptosis by Resveratrol in Human Non-Small-Cell Lung Cancer Cells by Down-Regulating Survivin and Up-Regulating PUMA

“…The development of various chemotherapeutic treatments directed against specific target molecules expressed in NSCLC cells is a promising strategy. There have been multiple studies of chemotherapeutics that target EGFR signaling pathway and thereby inhibiting cells viability in NSCLC [3]. However, therapeutic effects for single EGFR inhibitor remain relatively modest unless the EGFR inhibitor is combined with other chemotherapeutics [23].…”

“…Among those molecularly targeted therapies, EGFRtargeted therapy as one of the most important clinical strategies has been increasingly widely applied in patients with NSCLC [3]. EGFR is a transmembrane glycoprotein with an extracellular EGF-binding domain and an intracellular region containing the tyrosine kinase domain that regulates signaling pathways to control cell proliferation.…”

Somatic Mutation Theory - Why it's Wrong for Most Cancers

“…However, those same targeted therapeutic approaches are subverted over time as resistance develops rendering the treatment less effective and occasionally completely ineffective. A potential way of overcoming resistance against the tyrosine kinase inhibitor, gefitinib, has been recently shown to be effective in vitro by the use of Melatonin (N-acetyl-5-methoxytryptamine) [45].…”

MicroRNA-21 Regulates Non-Small Cell Lung Cancer Cell Invasion and Chemo-Sensitivity through SMAD7

“…Some NSCLCs are resistant to chemotherapy and radiation therapy, and are fast growing and highly invasive [1,2,3,4,5]. Thus, great efforts have been made to elucidate the mechanisms underlying the invasion and chemo-sensitivity of NSCLC [3,4,6,7,8,9]. …”