Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density

Takenaka, Tomoya; Katayama, M.; Sugiyama, Akihisa; Hagiwara, Masatoshi; Fujii, Ikuo; Takatani‐Nakase, Tomoka; Kobayashi, Susumu; Nakase, Ikuhiko

doi:10.21873/anticanres.11884

Cited by 2 publications

(2 citation statements)

References 16 publications

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“…Among them, ATP production was significantly increased after EGF treatment ( Figure 3G). A recent study showed that gefitinib treatment enhanced the mitochondrial membrane potential (MMP) and mitochondrial dehydrogenase activity of gefitinib-resistant NSCLC, but those were decreased in gefitinib-sensitive NSCLC [39]. In contrast, in the present study, gefitinib downregulated the mitochondrial function in gefitinib-sensitive PE089 cells.…”

Section: Discussioncontrasting

confidence: 77%

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

Huang

Hsu

Chen

et al. 2020

Cancers

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Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and –resistant non-small cell lung cancer.

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Section: Discussioncontrasting

confidence: 77%

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

Huang

Hsu

Chen

et al. 2020

Cancers

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“…Mutations in the subunit gene, Smarca4, of the SWI/SNF chromatin remodeling complex led to dependence of Smarca4deficient lung tumors on elevated oxidative phosphorylation (47,48). Kinase inhibitors, such the EGFR inhibitor, gefitinib, and the BRAF V600E inhibitor, vemurafenib, induced enhanced mitochondrial metabolism and drug resistance (49)(50)(51). These drug resistance cases highlight the potential use of ISQs for targeting oxidative phosphorylation as a therapeutic opportunity in multiple well-defined refractory cancers and provides an approach for overcoming certain types of drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor

Xie

Zhang

Guo

et al. 2021

Molecular Cancer Therapeutics

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Developing effective treatments for colorectal cancers through combinations of small-molecule approaches and immunotherapies present intriguing possibilities for managing these otherwise intractable cancers. During a broad-based, screening effort against multiple colorectal cancer cell lines, we identified indole-substituted quinolines (ISQ), such as N7,N7-dimethyl-3-(1-methyl-1H-indol-3-yl)quinoline-2,7-diamine (ISQ-1), as potent in vitro inhibitors of several cancer cell lines. We found that ISQ-1 inhibited Wnt signaling, a main driver in the pathway governing colorectal cancer development, and ISQ-1 also activated adenosine monophosphate kinase (AMPK), a cellular energy–homeostasis master regulator. We explored the effect of ISQs on cell metabolism. Seahorse assays measuring oxygen consumption rate (OCR) indicated that ISQ-1 inhibited complex I (i.e., NADH ubiquinone oxidoreductase) in the mitochondrial, electron transport chain (ETC). In addition, ISQ-1 treatment showed remarkable synergistic depletion of oncogenic c-Myc protein level in vitro and induced strong tumor remission in vivo when administered together with BI2536, a polo-like kinase-1 (Plk1) inhibitor. These studies point toward the potential value of dual drug therapies targeting the ETC and Plk-1 for the treatment of c-Myc–driven cancers.

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Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density

Abstract: Our results indicate that gefitinib may work as a mitochondrial protector against combinational treatment with mitochondria-dependent anticancer agents in high-cell-density.

Cited by 2 publications

References 16 publications

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

Potent Synergistic Effect on C-Myc–Driven Colorectal Cancers Using a Novel Indole-Substituted Quinoline with a Plk1 Inhibitor

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