Obesity is a complex multifactorial disease with detrimental effects on health. This disease induces a pro-inflammatory state, innate and adaptative i

Obesity paradox and lung cancer, metformin-based therapeutic opportunity?

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2023-11-20 12:00:03

Obesity is a complex multifactorial disease with detrimental effects on health. This disease induces a pro-inflammatory state, innate and adaptative immune system dysfunction, and immune exhaustion, which in conjunction promote cancer growth. Although obesity and type 2 diabetes mellitus (T2DM) have been associated with lung cancer (LC) development, several confounding factors, such as chronic inflammation, high insulin levels, microbiome, as well as the oncogenic potential of growth and sexual hormones, have introduced uncertainty and avoid the fully recognition of this relationship [1, 2]. Thus, therapies that can bring potential therapeutic effects to both comorbidities are being tested globally and their effect on cancer cells.

In detail, this biguanide has been related to several metabolic mechanisms, signaling pathways, and glucose uptake in concomitant use with standard anticancer therapies, such as radiotherapy (RT), chemotherapy, tyrosine-kinase inhibitors (TKIs), and immunotherapy [3]. Moreover, metformin acts over cell metabolism inhibiting complex I of the electron transport chain, and cell metabolic stress through AMPK pathway activation, which subsequently inhibits the mammalian target of rapamycin (mTOR) and its downstream effectors. Through this mechanism, metformin reduce protein synthesis, anabolic processes and proliferation [4]. In cancer cells, metformin has been shown to modify tumor metastatic properties by cell migration inhibition and suppressing epithelial-mesenchymal transition (EMT). Similarly, positive immunogenic properties have been associated with metformin through the activation of cytotoxic T- cells and enhancement of oxidative metabolism, which promotes an antitumor immune response [3, 5].

Metformin in combination with antineoplastic therapies has been tested in lung cancer models, promoting apoptosis, autophagy, and cell cycle arrest [3]. Therefore, lately has raised a particular interest in emerging metabolic-modifying therapies such as metformin, seeking to defeat cancer-promoting conditions caused by obesity. In one clinical study, patients with non-small cell lung cancer and early-stage disease who underwent lobectomy showed a higher disease-specific survival (DSS) and overall survival (OS) in patients with a body mass index (BMI)≥24 and metformin intake. Conversely, no survival benefits have been reported in patients with a BMI<24, which contributes to the formulation of the “obesity paradox” [6]. Yendamuri and colleagues also underscore about the positive interaction of obesity and metformin, in which those patients with a BMI>30 kg/m2 reported even a more prolonged OS and DSS. Of interest, in a separate cohort of advanced-stage LC tumors, downregulation of immune checkpoint gene expression (PD-L1, CTLA4, LAG3) was withheld in metformin users and high BMI, reinforcing the potential implication of leptin as a mediator of obesity associated immune disfunction and its restoration with metformin [7].

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