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

Abstract

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

Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp

“…Metformin, combined with tyrosine kinase inhibitors, is in Phase III trials evaluation against NSCLC with EGFR ( Figure 2 ) and Phase II trials as a single treatment or combined with sintilimab ( Figure 5 A). Metformin’s effects, as a single drug or combined with other therapies, against lung cancer involve a variety of mechanisms that can improve the therapeutic effect and prognosis of lung cancer [ 146 ]. Such mechanisms include LKB1-dependent AMPK kinase pathways, AMPK-dependent p53 activation, downregulation of the GRB/IRS-1/PI3K/AKT/mTOR pathway, inhibition of mTORC1 to regulate glucose and amino acid concentration, inhibition of complex I of the mitochondrial respiratory chain, regulation of lung miRNA, modulation of the tumor and its microenvironment (enhanced CD8+ T cell memory), and sensitization of radiotherapeutic agents [ 140 , 146 , 147 , 148 , 149 ].…”

“…In addition, the pathways modulated repeatedly by metformin are the STAT pathway (breast [ 103 , 138 ]), and the mTOR pathway (breast [ 104 , 166 ], prostate [ 120 ], kidney [ 191 ], and myeloma [ 228 , 229 ]). Nevertheless, the striking effect of metformin is inducing its effect by activation of AMPK (AMPK dependent), the same on-target in diabetes, in the lung [ 140 , 146 , 147 , 148 , 149 ], glioblastoma [ 177 ], skin [ 217 ], and myeloma [ 229 ]. Therefore, it is no wonder that metformin is in 37 trials due to its pleiotropic effects.…”

Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core–Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation

“…However, a large amount of oxygen is consumed by the abnormal proliferation of solid tumors, leading to serious hypoxia in the TME and severe limitation in oxygen-dependent therapeutics, typically for RT. Current tumor oxygenation strategies include two main approaches: one is to increase oxygen supply by increasing blood supply (e.g., erlotinib and nitric oxide), , carrying oxygen (e.g., fluorocarbon and metal–organic frameworks), , and generating oxygen in situ (e.g., catalase and catalase-like nanozymes); the other is to reduce oxygen consumption by inhibiting cellular respiration (e.g., atovaquone and metformin). , Nonetheless, strategies to increase oxygen supply may be hindered by low vascular remodeling efficiency, oxygen transport capacity, and intrinsic hydrogen peroxide (H 2 O 2 ) content . In contrast, inhibition of oxygen consumption can be more efficient in improving tumor oxygenation and can benefit oxygen-dependent RT.…”

Addition of metformin for non-small cell lung cancer patients receiving antineoplastic agents

“…Metformin (1,1-dimethylbiguanide) is the most commonly used drug for treating type 2 diabetes mellitus. In recent decades, substantial evidence has suggested that there is a clear beneficial effect of metformin in cases of malignancies, and that metformin plays a significant role in reducing cancer risk and improving outcomes for cancer patients (Mu et al, 2022;Yao et al, 2022;Zhang Q. et al, 2022;Han et al, 2023). A number of studies have found that metformin could reduce cancer morbidity and mortality rates in diabetic patients (Brancher et al, 2021;Kang et al, 2021).…”

“…A number of studies have found that metformin could reduce cancer morbidity and mortality rates in diabetic patients (Brancher et al, 2021;Kang et al, 2021). The underlying mechanisms are complicated and involve numerous pathways, such as the liver kinase B1 (LKB1)dependent AMPK pathway and the GRB/IRS-1/PI3K/AKT/mTOR pathway, and the regulation of certain targets, such as the silent information regulator T1 (SIRT1) and YAP (Han et al, 2023).…”