Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

Chen, Na; Zhou, Yuhui; Wang, Li-Cui; Huang, Jhin‐Fang

doi:10.3892/or.2022.8266

Cited by 16 publications

(9 citation statements)

References 119 publications

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“…The present review gives a more comprehensive overview of the mechanisms, in addition to the involvement of the AMPK signaling pathway and the AMPK-independent signaling pathway. In contrast to the review by Chen et al (164), the present review summarized other mechanisms. The mechanisms of metformin inhibiting complex I of the mitochondrial respiratory chain, regulating lung miRNAs, and affecting the tumor and its microenvironment were preliminarily reviewed.…”

Section: Limitations and Challenges Of Using Metformin In Lung Cancermentioning

confidence: 84%

“…Recently, the effects of metformin on lung cancer have gained the attention of a number of researchers, and numerous reviews have already been previously published. Li et al (163) and Chen et al (164) reviewed the effects of metformin on lung cancer. While the association between metformin and lung cancer was complex, the effects of metformin on lung cancer remained controversial and the mechanisms were intricate.…”

Section: Limitations and Challenges Of Using Metformin In Lung Cancermentioning

confidence: 99%

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Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

et al. 2022

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Lung cancer is the most common type of cancer and the leading cause of cancer-associated death worldwide. Despite the availability of various treatments such as surgery, chemoradiotherapy, targeted drugs and immunotherapy, treatment is expensive and the prognosis remains poor. At present, lung cancer drugs and treatment programs remain in a state of continuous exploration and research to improve the prognosis, and to reduce the pain and economic burden for the patients. Type 2 diabetes is a common chronic disease in middle-aged and elderly patients, leading to significantly increased complications of cardiovascular and cerebrovascular diseases. Epidemiology shows that type 2 diabetes also increases the incidence of malignant tumors, including lung, liver, colorectal and pancreatic cancer. Metformin is a biguanide, widely used as a first-line oral drug in treating type 2 diabetes. Metformin has a hypoglycemic effect and a biological antitumor impact, reducing the incidence of various tumors, including lung cancer, and improving the prognosis of patients with tumors. The anti-lung cancer effect of metformin involves a variety of mechanisms that can improve the therapeutic effect and prognosis of lung cancer, as a single drug or in combination with other therapies. The present study aims to review the associated literature and the therapeutic effects of metformin on lung cancer. Contents 1. Introduction 2. Mechanisms of metformin in the treatment of lung cancer 3. Application of metformin in lung cancer treatment 4. Limitations and challenges of using metformin in lung cancer 5. Conclusion

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Section: Limitations and Challenges Of Using Metformin In Lung Cancermentioning

confidence: 84%

Section: Limitations and Challenges Of Using Metformin In Lung Cancermentioning

confidence: 99%

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

et al. 2022

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“…It is also recognized that an additional barrier to treatment can occur when EGFR inhibitors induce a reverse Warburg effect whereby OXPHOS is upregulated as a favored bioenergetic survival strategy [ 44 ]. This observation has, in turn, raised the possibility that OXPHOS could be targeted in TKI-resistant NSCLC, which is proposed to be the mechanistic basis for the effectiveness of the mitochondrial complex I inhibitors metformin and phenformin in a variety of preclinical lung cancer models [ 45 , 46 , 47 ]. Phenformin was previously found to have superior efficacy against LKB1-deficient NSCLC cells [ 48 ], and thus our observation that the action of mandelalide A may be independent of LKB1 status provides a starting point for further investigation of ATP synthase inhibitors against TKI-resistant NSCLC cell types.…”

Section: Discussionmentioning

confidence: 99%

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

et al. 2022

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The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.

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“…Furthermore, it is reasonable to speculate that novel ICIs-combinations that specifically tackle tumor glycolysis in the specific scenario of high glycolysis – by means of baseline 18 F-FDG PET/CT parameters – might enhance the effectiveness of immunotherapies. 16 …”

Section: Discussionmentioning

confidence: 99%

Tumor glycolytic profiling through ¹⁸F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC

et al. 2022

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Background: A significant proportion of patients with non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICIs). Since metabolic reprogramming with increased glycolysis is a hallmark of cancer and is involved in immune evasion, we used 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) to evaluate the baseline glycolytic parameters of patients with advanced NSCLC submitted to ICIs, and assessed their predictive value. Methods: 18F-FDG PET/CT results in the 3 months before ICIs treatment were included. Maximum standardized uptake values, whole metabolic tumor volume (wMTV), and whole-body total lesion glycolysis (wTLG) were evaluated. Cutoff values for high or low glycolytic categories were determined using receiver-operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were evaluated. Patients with a complete response and a matching group with resistance to ICIs underwent immunohistochemistry analysis. An unsupervised k-means clustering model integrating programmed cell death ligand 1 (PD-L1) expression, glycolytic parameters, and ICIs therapy was performed. Results: In all, 98 patients were included. Lower baseline 18F-FDG PET/CT parameters were associated with responses to ICIs. Patients with low wMTV or wTLG had improved PFS and OS. High wTLG, strong tumor expression of glucose transporter-1, and lack of responses were significantly associated. Patients with low glycolytic parameters benefited from ICIs, regardless of chemotherapy. Conversely, those with high parameters benefited from the addition of chemotherapy. Patients with higher wTLG and lower PD-L1 were associated with progression and worse survival to ICIs monotherapy. Conclusions: Glycolytic metabolic profiles established through baseline 18F-FDG PET/CT are useful biomarkers for evaluating ICI therapy in advanced NSCLC.

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Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

Cited by 16 publications

References 119 publications

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

Tumor glycolytic profiling through ¹⁸F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC

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Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

Cited by 16 publications

References 119 publications

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK

Tumor glycolytic profiling through 18F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC

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Tumor glycolytic profiling through ¹⁸F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC