(195) Overcoming Tumor Resistance to Gefitinib and Erlotinib in Non-Small Cell Lung Cancer Using Piperlongumine

Objective : Gefinitib and erlotinib are approved as first-line therapies for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring certain EGFR mutations. However, acquired resistance to these therapies have limited their long-term clinical utility and success of therapeutic outcomes. A combinatorial treatment approach with piperlongumine - a natural bioactive from the long pepper fruit (Piper longum) - was pursued to overcome tumor resistance to gefitinib and erlotinib to improve therapeutic outcomes.

Methods: Anticancer efficacy assessment of piperlongumine (PPL), gefitinib (GEF), and erlotinib (ERL) were performed in H1299 and H1975 NSCLC cells. Two-drug combination regimen comprising sub-cytotoxic concentrations of PPL with GEF, or ERL were investigated in both cell lines in a concentration-dependent manner, and scheduling-specific manner. Assay of reactive oxygen species (ROS), apoptosis, and oncogenic protein marker (EGFR, EGFR-L858R, p-EGFR, cleaved-Caspase-3, cleaved-Caspase-7) expression were performed.

Results: Potent anticancer effects were induced by PPL [5.84 ± 0.04 µM and 6.05 ± 0.31 µM, respectively] in H1299 and H1975 cell lines compared to GEF [219.43 ± 22.69 µM and 47.22 ± 3.97 µM, respectively] and ERL [138.88 ± 9.62 µM and 51.92 ± 2.34 µM, respectively]. Combination regimen of PPL [2.5 µM] with varying concentrations of GEF or ERL resulted in significant anticancer activity in a cell- and schedule- specific manner; whereas concurrent treatment potentiated GEF and ERL effects in H1299, pre-treating with PPL followed by GEF or ERL after 1 h was more effective in H1975 cells. These effects were accompanied by apoptosis induction and inhibition of oncogenic protein expression and activation.

Conclusions: Piperlongumine is a viable drug candidate as adjuvant therapy to gefitinib and erlotinib in NSCLC treatment.