New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway
<p>The antiaging effect of metformin. (Left panel) Metformin exerts an antiaging effect by modulating protein homeostasis. Metformin can suppress protein translation (e.g., progerin) and enhance autophagy to extend longevity via AMPK-induced inhibition of mTOR activity. It impedes the translation of aging-related proteins such as progerin through a decrease in the phosphorylation of ribosomal protein S6 (rsP6), S6 kinase (S6K) and eIF4E-binding protein 1 (eIF4E-BP1). In addition, metformin initiates the dephosphorylation of ULK1 and further results in the phosphorylation of Beclin-1, which triggers autophagy. (Right panel) Metformin exerts an antiaging effect by modulating ROS. ROS serve as a double-edged sword in the modulation of the aging process. On the one hand, AMPK-induced accumulation of ROS facilitates longevity via the PRDX-2/SKN-1 axis. On the other hand, AMPK alleviates ROS accumulation and increases longevity through the Nrf2/GPx7 axis of SIRT-3.</p> "> Figure 2
<p>Therapeutic effects against vascular abnormalities and the apoptosis of retinal cells.</p> "> Figure 3
<p>Necroptosis may be a double-edged sword in cancer progression. (<b>a</b>) In the CRPC cell line C4-2B, the combination of metformin and simvastatin upregulates RIPK1 and RIPK3, which further triggers necroptotic cell death. In the breast cancer cell line MCF-7, metformin promotes ROS generation and subsequently induces the autophosphorylation of RIPK1 at S161, leading to MLKL phosphorylation and necroptosis. (<b>b</b>) Metformin induces the AMPK-mediated phosphorylation of Parkin; activated Parkin blocks necroptosis and inflammation via the inhibition of RIPK3. This reduces the formation of polyps and suppresses the tumorigenesis of CRC.</p> "> Figure 4
<p>Metformin initiates canonical and noncanonical pyroptosis. Left panel: Canonical pyroptosis: metformin induces GSDMD-mediated pyroptotic cell death via the upregulation of miR-497 and the subsequent inhibition of FELP1. Right panel: Noncanonical pyroptosis: metformin triggers the activation of AMPK, which phosphorylates SIRT-1. This upregulates BAX and promotes the release of cytochrome C from mitochondria, which initiates caspase-3- and GSDME-mediated pyroptotic cell death.</p> "> Figure 5
<p>Metformin triggers ferroptosis. Metformin downregulates GPX4 by upregulating miR-324-3p; this contributes to the increased accumulation of lipid ROS and further promotes ferroptosis.</p> "> Figure 6
<p>Metformin and its role in suppressing metastasis.</p> "> Figure 7
<p>Metformin and its role in the modulation of cancer immunity.</p> ">
Abstract
:1. Introduction
2. Effect of Metformin on Aging
3. Metformin in Diabetes and DR
3.1. AMPK-Dependent Pathway
3.2. AMPK-Independent Pathways
3.2.1. Vascular Abnormalities
3.2.2. Apoptotic Cell Death
3.2.3. Cell Senescence
4. Metformin and Cancer
4.1. Induction of Nonapoptotic Cell Death by Metformin
4.2. Necroptosis
4.3. Pyroptosis
4.4. Ferroptosis
4.5. Metformin and Metastasis
4.6. Metformin and Immunosuppression
4.6.1. Hypoxia
4.6.2. PD-L1 & ICIs
4.6.3. Tumor-Associated Macrophages (TAMs)
4.6.4. Regulatory T Lymphocytes (Tregs)
4.6.5. Myeloid-Derived Suppressor Cells (MDSCs)
5. Ongoing Clinical Trials of Metformin Related to Aging, DR and Cancer
NCT Number | Status | Phase | Condition/Disease | Description |
Anti-aging | ||||
NCT02432287 | Completed | IV | Aging | Evaluate the effect of metformin on gene expression profiles in muscle and adipose tissue of older adults by RNA-Seq |
NCT04264897 | Recruiting | III | Aging | Assess changes in mitochondrial function and remodeling in skeletal muscle biopsies from patients treated with or without metformin |
NCT01765946 | Completed | IV | Aging | Evaluate longevity-related gene expression, including SIRT1, p66Shc, p53 and mTOR, in PBMCs |
Anti-DR | ||||
NCT02587741 | Recruiting | I | DR | Evaluate the efficacy of metformin on DR in comparison with Lantus and NovoMix30 |
Anti-cancer | ||||
NCT04559308 | Recruiting | II | Breast cancer (BC) | Ascertain the antitumor effect with neoadjuvant chemotherapy (e.g., paclitaxel and doxorubicin) |
NCT04387630 | Recruiting | II | Early BC | Evaluate the immunostimulatory effect on preoperative chemotherapy |
NCT02028221 | Active, not recruiting | II | BC | Investigate BC prevention and favorable changes in risk features, including breast density and hormone levels |
NCT02488564 | Completed | II | Operable and locally advanced HER-2-positive BC | Evaluate the antitumor effect of the combination of liposomal doxorubicin plus docetaxel, trastuzumab and metformin |
NCT02437656 | Completed | II | Locally advanced rectal cancer | Evaluate the antitumor effect of metformin with neoadjuvant radiochemotherapy |
NCT01941953 | Completed | II | Metastatic CRC | Evaluate the efficacy of metformin plus fluorouracil in patients refractory to oxaliplatin and irinotecan |
NCT02614339 | Recruiting | III | Non-DM stage II high-risk/stage III CRC | Determine the impact of additional metformin on CRC recurrence |
NCT01620593 | Completed | II | Advanced prostate cancer | Evaluate the inhibitory effect of metformin on castration-induced tumor growth mediated by hyperinsulinemia |
NCT02640534 | Active, not recruiting | II | Metastatic castration-resistant prostate cancer (mCRPC) | Determine the efficacy of metformin plus enzalutamide compared to enzalutamide alone in patients with mCRPC |
NCT02360618 | Unknown | II | Invasive bladder cancer | Determine the synergistic antitumor effect of metformin and simvastatin on aggressive cancer cells |
NCT02115464 | Terminated | II | Locally advanced NSCLC | Evaluate the influence of chemoradiotherapy plus metformin on progression-free survival |
NCT02019979 | Terminated | II | Stage IIIB/IV non-squamous NSCLC | Determine the effect of metformin combined with platinum-based chemotherapy in patients on a carbohydrate-restricted diet |
NCT01205672 | Completed | I | Endometrial cancer | Evaluate the efficacy of metformin in non-diabetic women with endometrial cancer and determine S6K expression after treatment |
NCT01529593 | Unknown | I | Advanced cancer | Evaluate the efficacy of metformin plus temsirolimus (both mTOR inhibitors) on tumor regression |
NCT03889795 | Recruiting | I | Advanced pancreatic cancer | Evaluate the response to and effects of C3 (simvastatin + digoxin + metformin) on disease progression |
NCT02143050 | Unknown | I/II | Metastatic melanoma | Assess the safety and efficacy of metformin + dabrafenib + trametinib in patients with stage IIIC/IV melanoma |
6. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Hsu, S.-K.; Cheng, K.-C.; Mgbeahuruike, M.O.; Lin, Y.-H.; Wu, C.-Y.; Wang, H.-M.D.; Yen, C.-H.; Chiu, C.-C.; Sheu, S.-J. New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway. Int. J. Mol. Sci. 2021, 22, 9453. https://doi.org/10.3390/ijms22179453
Hsu S-K, Cheng K-C, Mgbeahuruike MO, Lin Y-H, Wu C-Y, Wang H-MD, Yen C-H, Chiu C-C, Sheu S-J. New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway. International Journal of Molecular Sciences. 2021; 22(17):9453. https://doi.org/10.3390/ijms22179453
Chicago/Turabian StyleHsu, Sheng-Kai, Kai-Chun Cheng, Miracle Oluebube Mgbeahuruike, Yi-Hsiung Lin, Chang-Yi Wu, Hui-Min David Wang, Chia-Hung Yen, Chien-Chih Chiu, and Shwu-Jiuan Sheu. 2021. "New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway" International Journal of Molecular Sciences 22, no. 17: 9453. https://doi.org/10.3390/ijms22179453