Curcumin Lowers Erlotinib Resistance in Non-Small Cell Lung Carcinoma Cells With Mutated EGF Receptor

Abstract

Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) are responsive to erlotinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation was determined by MTT assay. Apoptosis was examined using TUNEL staining. Protein expression of genes was determined by Western blot. Tumor growth was assessed in a xenograft mouse model. Results showed that erlotinib had a stronger effect on the induction of apoptosis in erlotinib-sensitive PC-9 cells but showed a weaker effect on erlotinib-resistant H1975 and H1650 cells than cisplatin and curcumin. Furthermore, curcumin significantly increased the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, downregulated the expressions of EGFR, p-EGFR, and survivin, and inhibited the NF-κB activation in erlotinib-resistant NSCLC cells. The combination of curcumin and erlotinib exhibited the same effects on apoptosis as the combination of curcumin and cisplatin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that curcumin is a potential adjuvant for NSCLC patients during erlotinib treatment.

Dietary agents for prevention and treatment of lung cancer

“…Treatment with curcumin caused significant increase in the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, decreased the expressions of EGFR, p-EGFR, survivin and inhibited NF-κB activation in erlotinib-resistant NSCLC cells. In erlotinib-resistant NSCLC cells, treatment with combination of curcumin and erlotinib displayed the same effects on apoptosis as the combination of curcumin and cisplatin [60]. Treatment with curcumin (50–100 μM) induced autophagy in the human lung adenocarcinoma cells and increased the phosphorylation of AMP-activated protein kinase (AMPKα) and acetylCoA carboxylase.…”

“…It also caused significant decrease in the tumor growth of orthotopic human NSCLC xenografts and increased survival of athymic nude mice [66]. Treatment with combination of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in-vivo, suggesting that curcumin might be a prospective adjuvant for NSCLC patients during treatment with erlotinib [60]. Co-administration of phospho-sulindac (200 mg/kg/day) and curcumin (500 mg/kg/body/day) synergistically inhibited the growth of human lung cancer xenografts in nude mice, which was credited to the inhibition of efflux transporters by curcumin, leading to improved bioavailability of phospho-sulindac [67].…”

Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems

“…The MTT-bioassay data unambiguously showed that the pH-sensitive liposomal formulation of curcumin proved to significantly outclass the free drug in terms of The established high efficacy of formulated curcumin in resistant cells is of special interest, since this compound has been shown to restore the responsiveness to anticancer drugs and is considered as a potential multidrug-resistance reversal agent (Li et al, 2013;Li et al, 2011;Misra and Sahoo, 2011;Rao et al, 2014;Roy and Mukherjee, 2014;Sreekanth et al, 2011;Sreenivasan et al, 2012). The apoptosis assay firmly demonstrated that liposomal curcumin is a potent inducer of apoptotic DNA-fragmentation in HL-60, in compliance to preceding reports (Alaikov et al, 2007;Liao et al, 2008;Tan et al, 2006) and especially in HL-60/CDDP cells which proved to be more sensitive to the apoptogenic effects of equieffective levels of curcumin.…”

Translating Curcumin to the Clinic for Lung Cancer Prevention: Evaluation of the Preclinical Evidence for Its Utility in Primary, Secondary, and Tertiary Prevention Strategies

“…However, some cell lines (PC9, H1975, H1650) become resistant to targeted drugs such as the tyrosine kinase inhibitors (e.g., erlotinib, gefitinib) and have thus been used to expand the potential utility of curcumin to lung cancers harboring/gaining specific mutations. Cotreatment using standard chemotherapy drugs in combination with curcumin enhanced antitumor efficacy of erlotinib (Yamauchi et al, 2014;Li et al, 2014a), cisplatin (Chanvorachote et al, 2009;Ye et al, 2012;Zhou et al, 2013a), and vinorelbine (Chen et al, 2004) by sensitizing cells to drug-induced apoptosis.…”