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Review
. 2020 Sep 1;12(9):2482.
doi: 10.3390/cancers12092482.

Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

Samson Mathews Samuel  1 , Elizabeth Varghese  1 , Lenka Koklesová  2 , Alena Líšková  2 , Peter Kubatka  3 , Dietrich Büsselberg  1
Affiliations
Review

"V体育安卓版" Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

V体育安卓版 - Samson Mathews Samuel et al. Cancers (Basel). .

V体育安卓版 - Abstract

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial-mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance VSports手机版. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting. .

Keywords: cancer; cancer stem cells; chemoresistance; metformin; multidrug resistance V体育安卓版. .

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Conflict of interest statement

The authors declare no conflict of interest V体育ios版. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the article.

Figures

Figure 1
Figure 1
Mechanisms of chemoresistance in breast cancers: In breast cancers, the factors that influence therapeutic resistance mainly include (illustrated clockwise); (1) the presence and influence of breast cancer stem cells (BCSCs) that can initiate and re-populate tumors, (2) epithelial–mesenchymal transition (EMT), (3) tumor heterogeneity and microenvironment (characterized by hypoxia, inflammation, autophagy, and presence of cancer-associated fibroblasts, immune cells such as tumor-associated macrophages, and tumor endothelial cells), (4) active DNA damage repair mechanisms, (5) altered/adaptive/aberrant metabolism (characterized by the Warburg effect, altered amino acid/protein/lipid and nucleotide metabolism, utilization of glutamine, and isoforms of metabolic enzymes that support cancer initiation, progression, and resistance to therapy), (6) variations in drug uptake and active drug efflux systems (ATP binding cassette; ABC/multidrug transporters), (7) activation of oncogenic, pro-survival and anti-apoptotic signaling pathways (the phosphatidylinositol-3-kinase; PI3K/protein kinase B; Akt/ mammalian target of rapamycin; mTOR, mitogen activated protein kinase; MAPK, nuclear factor-kappa B; NF-κB, Wnt/β-catenin, janus kinase; JAK/signal transducer and activator of transcription 3; STAT3 and hypoxia inducible factor 1; HIF1 pathways), and (8) active drug detoxification and target alteration systems.
Figure 2
Figure 2
The molecular mediators and ‘direct’ anti-cancer/anti-tumor effects of metformin in breast cancers: (A) Metformin treatment-mediated adenosine monophosphate-activated protein kinase (AMPK) activation subsequently involves ‘AMPK-dependent’ inhibition of mTORC1, cellular-Myc (c-Myc), acetyl–CoA carboxylase (ACC), and NF-κB and pathways and/or activation of p53 pathway and double-stranded RNA specific endoribonuclease (DICER)-dependent pathways. The ‘AMPK-independent’ anti-cancer or anti-tumor effects of metformin reportedly require the activation of regulated DNA damage-1 (REDD1) and/or the inhibition of Rag GTPases and signal transducer and activator of transcription 3 (STAT3)-dependent mechanisms. (B) Both AMPK-dependent and independent mechanisms ultimately account for the reported in vitro, in vivo, and clinical anti-cancer effects of metformin that involve translational inactivation, cell-cycle arrest, inhibition of cellular proliferation and migration, activation of apoptotic cell death, inhibition of epithelial–mesenchymal transition (EMT), suppression of cancer invasiveness and metastasis, and counteracting multidrug/therapy resistance in breast cancers.
Figure 3
Figure 3
Specialized capabilities of breast cancer stem cells (BCSCs) include the power to resist therapeutic strategies: The less abundant (when compared to the terminally differentiated breast cancer cells) BCSCs with an altered metabolism are highly capable of evading therapeutic intervention and causing a relapse of the disease by employing one or more of their capabilities such as the ability to self-renew and differentiate into tumor progenitor cells, to evade the immune system, to activate unique DNA repair systems, to utilize ABC transporters for multidrug resistance (MDR) and activate advanced detoxification processes and support epithelial–mesenchymal transition (EMT). The well-studied CD44+/CD24neg/low marker and other markers used in the identification of BCSCs are provided in the figure [157].
Figure 4
Figure 4
Known cellular anti-neoplastic and therapeutic resistance counteracting effects of metformin: (A) in breast cancer cells (figure adapted and modified from our published article Samuel, SM. et al. 2019 in Biomolecules [51] and (B) in breast cancer stem cells (BCSCs) (figure adapted and modified from Saini, N. et al. 2018 [202]. The hydrophilic and cationic metformin requires membrane-bound organic cation transporters (OCT) for intracellular transport and accumulation. In BCSCs, metformin treatment directly activates AMPK, and the ‘AMPK-dependent’ effects include NF-κB and DICER-mediated modulation of oncogenic and tumor-suppressor miRNA synthesis and expression. AMPK-independent metformin treatment-associated anti-cancer effects are mediated by the regulation of metabolism (inhibition of glycolysis) and transforming growth factor-beta (TGFβ), Wnt/β−catenin, and Sonic Hedgehog signaling mechanisms. Overall, metformin treatment in BCSCs causes BCSC growth inhibition, EMT marker suppression, and EMT inhibition, inhibits glycolysis, modulates miRNA expression and function, promotes BCSC senescence and apoptosis, and increases susceptibility to chemotherapeutic and radiotherapeutic intervention.
Figure 4
Figure 4
Known cellular anti-neoplastic and therapeutic resistance counteracting effects of metformin: (A) in breast cancer cells (figure adapted and modified from our published article Samuel, SM. et al. 2019 in Biomolecules [51] and (B) in breast cancer stem cells (BCSCs) (figure adapted and modified from Saini, N. et al. 2018 [202]. The hydrophilic and cationic metformin requires membrane-bound organic cation transporters (OCT) for intracellular transport and accumulation. In BCSCs, metformin treatment directly activates AMPK, and the ‘AMPK-dependent’ effects include NF-κB and DICER-mediated modulation of oncogenic and tumor-suppressor miRNA synthesis and expression. AMPK-independent metformin treatment-associated anti-cancer effects are mediated by the regulation of metabolism (inhibition of glycolysis) and transforming growth factor-beta (TGFβ), Wnt/β−catenin, and Sonic Hedgehog signaling mechanisms. Overall, metformin treatment in BCSCs causes BCSC growth inhibition, EMT marker suppression, and EMT inhibition, inhibits glycolysis, modulates miRNA expression and function, promotes BCSC senescence and apoptosis, and increases susceptibility to chemotherapeutic and radiotherapeutic intervention.
Figure 5
Figure 5
Efficacy of a combinatory metformin and breast cancer stem cell (BCSC) targeted therapy over conventional cancer cell-targeted therapy: A conventional anti-cancer therapy targeting terminally differentiated cancer cells (A) should efficiently inhibit cell proliferation and induce the apoptotic cell death of the cancer cells. However, the less abundant CSCs effectively evade therapeutic intervention. Then, the CSC through a process of self-renewal and generation of tumor progenitor cells and mutations mainly causes a relapse/recurrence of more aggressive, invasive, and metastatic forms of the neoplasm. Using metformin in combination with a cancer stem cell-targeted therapy (B) will effectively target and kill the CSCs, which then can be followed up with a combinatory treatment using metformin and the conventional anti-cancer therapy to cause tumor regression, effectively cure cancer, and avoid cancer relapse/recurrence.
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