Abstract
Cancer cells are characterized by abnormally increased glucose uptake and active bio-energy and biosynthesis to support the proliferation, metastasis, and drug resistant survival. We examined the therapeutic value of the combination of apigenin (a natural small-molecule inhibitor of Glut1 belonging to the flavonoid family) and gefitinib on epidermal growth factor receptor (EGFR)-resistant mutant non-small cell lung cancer, to notably damage glucose utilization and thus suppress cell growth and malignant behavior. Here, we demonstrate that apigenin combined with gefitinib inhibits multiple oncogenic drivers such as c-Myc, HIF-1α, and EGFR, reduces Gluts and MCT1 protein expression, and inactivates the 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling, which regulates glucose uptake and maintains energy metabolism, leading to impaired energy utilization in EGFR L858R-T790M-mutated H1975 lung cancer cells. H1975 cells exhibit dysregulated metabolism and apoptotic cell death following treatment with apigenin + gefitinib. Therefore, the combined apigenin + gefitinib treatment presents an attractive strategy as alternative treatment for the acquired resistance to EGFR-TKIs in NSCLC.
Highlights
Due to the high number of tobacco consumers in China, i.e., over 300 million male smokers and more than 740 million people exposed to second-hand smoke (Yang et al, 2015)
We found that gefitinib and the combination markedly downregulated the expression of glucose uptake-associated proteins such as glucose transporter 1 (Glut1), Glut3, Glut4, PDK1, and lactate exportassociated protein MCT1, but the treatments did not alter lactate production kinase LDHA expression (Figure 4E)
We investigated the mechanism of apoptosis in each treatment group of H1975 cells and found that combination therapy induced apoptosis by FIGURE 6 | Targeting of multiple oncogenes and glycolysis increases H1975 apoptotic cell death. (A) The morphology of the H1975 cells is shown for the vehicle and following compound treatment at the indicated concentrations of 10058-F4, STF-31 (D), and KC7F2 (G) for 24 h under inverted phase contrast microscope. (B,E,H,J,K) H1975 cells were treated with different conditions, and cell lysates were used to test protein expression using specific antibodies. (C,F,I) Cell viability recordings for the indicated protocols for 36 h as quantified using Cell Counting Kit-8 (CCK-8) assay
Summary
Due to the high number of tobacco consumers in China, i.e., over 300 million male smokers and more than 740 million people exposed to second-hand smoke (Yang et al, 2015). The mutation rate of epidermal growth factor receptor (EGFR) in mainland China population has reached 50.2%, and the activating mutation rate is 48.0% (Shi et al, 2015). In all EGFR mutations of NSCLC patients, deletion of EGFR exon 19 and mutation of EGFR L858R exon 21 account for 85–90%. NSCLC patients have high response rates to EGFR tyrosine kinase inhibitors (EGFR-TKIs) (Rotow and Bivona, 2017). Acquired resistance to these EGFR-TKIs frequently develops after 9–13 months exposure, and mutation of EGFR T790M accounts for 60% of this acquired resistance associated with progressive disease after first response to TKIs (Janne et al, 2015).
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