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Review
. 2024 Jul;18(7):1719-1738.
doi: 10.1002/1878-0261.13583. Epub 2024 Jan 12.

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759

Marc Pujalte-Martin  1   2   3 , Amine Belaïd  1   2   3 , Simon Bost  2   3 , Michel Kahi  1   2   3 , Pascal Peraldi  1   2   3 , Matthieu Rouleau  2   3   4 , Nathalie M Mazure  1   2   3 , Frédéric Bost  1   2   3
Affiliations
Review

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759

Marc Pujalte-Martin et al. Mol Oncol. 2024 Jul.

Abstract

Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

Keywords: IACS‐010759; cancer; clinical trial; immunometabolism; metformin; microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Mitochondrion at the center of cell metabolism. In cancer cells, glycolysis is the first step in the energy‐producing process: it converts glucose, which has entered the cell via glucose transporters (GLUTs), into pyruvate. For some cancer cells, regulation of oxidative phosphorylation (OXPHOS) and pyruvate utilization in the tricarboxylic acid (TCA) cycle plays a crucial role in their unique metabolic adaptations. Pyruvate is imported into the mitochondria, where it is converted to acetyl‐CoA. It then enters the TCA cycle, fueling a series of metabolic reactions that generate reducing agents such as NADH and FADH2. The electron transport chain (ETC) is a critical component of cellular respiration. The ETC is in the inner mitochondrial membrane and consists of a series of protein complexes (I to IV) and electron carriers, including coenzyme Q and cytochrome c. During cellular respiration, the ETC transfers electrons derived from metabolic reactions, such as glycolysis and the citric acid cycle, from one protein complex to another. This flow of electrons creates an electron gradient, which drives the pumping of protons (H+) across the inner mitochondrial membrane from the matrix to the intermembrane space. However, most cancer cells will convert pyruvate into lactate (Warburg effect) irrespective of the oxygen concentration of the microenvironment. Lactate will then be released outside the cell via monocarboxylate transporters (MCTs) simultaneously with protons (H+). Cancer cells have a heightened dependence on glutamine, an essential amino acid, to support their rapid growth and proliferation. Glutaminolysis involves the conversion of glutamine into glutamate by the enzyme glutaminase. Glutamate can then enter the TCA cycle as α‐ketoglutarate, providing intermediates for the synthesis of lipids, nucleotides, and nonessential amino acids required for cell growth and proliferation. They can also utilize fatty acid oxidation (FAO) as a source of energy, particularly in nutrient‐poor environments. FAO involves the breakdown of fatty acids into acetyl‐CoA, which enters the citric acid cycle to generate adenosine triphosphate (ATP). (Figure done with BioRender).
Fig. 2
Fig. 2
Metformin and immune response. Comprehensive overview of the relationship between metformin and the immune system. This illustration encapsulates the multifaceted effects of metformin on immune cells, highlighting its potential to modulate memory CD8+ T cells, immunotherapy, regulatory T cells (Tregs), natural killer cells (NKs), tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs) and dendritic cells (DCs). (Figure done with Biorender).
Fig. 3
Fig. 3
Metformin and IACS‐010759 target oxidative phosphorylation (OXPHOS) vulnerability. Cells that rely on OXPHOS for their energetic needs are sensitive to metformin and IACS‐010759. Both metabolic disruptors inhibit complex I of the electron transport chain (ETC), leading to major energy stress (decrease in adenosine triphosphate (ATP) concentration) and increased glycolysis and glutaminolysis. The combination with other metabolic inhibitors (glycolysis, complex II, or glutaminolysis inhibitors) leads to apoptosis and increased energy stress. (Figure done with Biorender).
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