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Review
. 2014:2014:132702.
doi: 10.1155/2014/132702. Epub 2014 Jun 24.

V体育官网 - Metformin against cancer stem cells through the modulation of energy metabolism: special considerations on ovarian cancer

Tae Hun Kim  1 , Dong Hoon Suh  2 , Mi-Kyung Kim  3 , Yong Sang Song  4
Affiliations
Review

Metformin against cancer stem cells through the modulation of energy metabolism: special considerations on ovarian cancer

Tae Hun Kim et al. Biomed Res Int. 2014.

Abstract

Ovarian cancer is the most lethal gynecologic malignancy among women worldwide and is presumed to result from the presence of ovarian cancer stem cells. To overcome the limitation of current anticancer agents, another anticancer strategy is necessary to effectively target cancer stem cells in ovarian cancer. In many types of malignancies, including ovarian cancer, metformin, one of the most popular antidiabetic drugs, has been demonstrated to exhibit chemopreventive and anticancer efficacy with respect to incidence and overall survival rates VSports手机版. Thus, the metabolic reprogramming of cancer and cancer stem cells driven by genetic alterations during carcinogenesis and cancer progression could be therapeutically targeted. In this review, the potential efficacy and anticancer mechanisms of metformin against ovarian cancer stem cells will be discussed. .

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"V体育ios版" Figures

Figure 1
Figure 1
Mechanism of action of metformin in the concept of dynamic cancer stem cells in ovarian cancer. In contrast to the hierarchically organized cancer stem cell (CSC) model, the dynamic CSC model represents bidirectional interconversion between CSC and differentiated non-CSC states. The acquisition and maintenance of CSC characteristics are affected by microenvironmental cues, including inflammation, stromal cells and hypoxia, and therapeutics, such as chemotherapy. These factors eventually constitute the CSC niche (gray field). Hypoxia, which causes glycolysis, maintains and upregulates ovarian CSCs characteristics. Chemotherapy kills rapidly proliferating nontumorigenic cells, sparing chemoresistant CSCs. Chemotherapy also induces the acquisition of stem cell characteristics via epithelial-mesenchymal transition. Many studies using embryonal stem cells and induced pluripotent stem cells have demonstrated that glycolysis plays a fundamental role in inducing stemness. It is hypothesized that glycolysis may have a critical role in acquiring the CSC phenotype. It remains to be elucidated whether the metabotype is different between tumorigenic CSCs and rapidly proliferating nontumorigenic cells. Assumptive mechanisms of metformin's synergic effect on chemotherapy and selective toxicity to CSCs are illustrated. Metabolic stress caused by metformin may inhibit the transition to the glycolytic phenotype, resulting in the prevention of the acquisition of stemness and dedifferentiation. Metformin may also target the inflammatory components present in the tumor microenvironment. Ovarian CSCs may lack the ability to cope with metabolic stress caused by metformin and glucose starvation.
Figure 2
Figure 2
Antineoplastic mechanisms of action of metformin. The mitochondria are the primary target of metformin. Metformin interferes with oxidative phosphorylation via interactions with respiratory complex I, resulting in reduced ATP production and metabolic stress. Metformin lowers plasma glucose levels by decreasing gluconeogenesis and glucose uptake, resulting in lower circulating insulin and IGF-1 levels. An energy compensation reaction occurring in tumor cells capable of responding to metabolic stress is shown in the left box. By activating the LKB1/AMPK pathway, metformin inhibits mTOR downstream signaling, ultimately causing downregulation of energy-consuming processes and an overall cytostatic effect. The antitumour effects of metformin are regulated by both AMPK-dependent and AMPK-independent mechanisms. If tumor cells lack ability to cope with energetic stress due to the loss of function of LKB1/AMPK or p53, they may undergo a metabolic crisis leading to death (middle box). The right box presents an assumptive mechanism of metformin's action against CSCs. Both inflammation and the glycolytic phenotype are likely to be associated with pluripotency and stemness. The activation of AMPK provides a metabolic barrier to reprogramming somatic cells into stem cells. Metformin has been demonstrated to inhibit dedifferentiation processes, tumor initiation, and malignant transformation. Anti-inflammatory effects, restoration from glycolysis, and reduced growth signals might explain the anti-CSC action of metformin.
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References (VSports)

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