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Naeimzadeh Y, Tajbakhsh A, Nemati M, Fallahi J. Exploring the anti-cancer potential of SGLT2 inhibitors in breast cancer treatment in pre-clinical and clinical studies. Eur J Pharmacol 2024; 978:176803. [PMID: 38950839 DOI: 10.1016/j.ejphar.2024.176803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/03/2024]
Abstract
The link between type 2 diabetes mellitus (T2DM) and an increased risk of breast cancer (BC) has prompted the exploration of novel therapeutic strategies targeting shared metabolic pathways. This review focuses on the emerging evidence surrounding the potential anti-cancer effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the context of BC. Preclinical studies have demonstrated that various SGLT2 inhibitors, such as canagliflozin, dapagliflozin, ipragliflozin, and empagliflozin, can inhibit the proliferation of BC cells, induce apoptosis, and modulate key cellular signaling pathways. These mechanisms include the activation of AMP-activated protein kinase (AMPK), suppression of mammalian target of rapamycin (mTOR) signaling, and regulation of lipid metabolism and inflammatory mediators. The combination of SGLT2 inhibitors with conventional treatments, including chemotherapy and radiotherapy, as well as targeted therapies like phosphoinositide 3-kinases (PI3K) inhibitors, has shown promising results in enhancing the anti-cancer efficacy and potentially reducing treatment-related toxicities. The identification of specific biomarkers or genetic signatures that predict responsiveness to SGLT2 inhibitor therapy could enable more personalized treatment selection and optimization, particularly for challenging BC subtypes [e, g., triple negative BC (TNBC)]. Ongoing and future clinical trials investigating the use of SGLT2 inhibitors, both as monotherapy and in combination with other agents, will be crucial in elucidating their translational potential and guiding their integration into comprehensive BC care. Overall, SGLT2 inhibitors represent a novel and promising therapeutic approach with the potential to improve clinical outcomes for patients with various subtypes of BC, including the aggressive and chemo-resistant TNBC.
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Affiliation(s)
- Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, 7133654361, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mahnaz Nemati
- Amir Oncology Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, 7133654361, Iran.
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2
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Bastos-Silva VJ, Spineli H, Guimarães JC, Borbely KSC, Ursulino JS, Aquino TM, Bento ES, Scariot PPM, Sousa FAB, Araujo GGD. Effects of long-term metformin administration associated with high-intensity interval training on physical performance, glycogen concentration, GLUT-4 content, and NMR-based metabolomics in healthy rats. Braz J Med Biol Res 2024; 57:e13276. [PMID: 39194030 DOI: 10.1590/1414-431x2024e13276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/22/2024] [Indexed: 08/29/2024] Open
Abstract
The aim was to investigate the long-term effects of metformin ingestion on high-intensity interval training on performance, glycogen concentration (GC), GLUT-4 content, and metabolomics outcomes in rats. Fifty male Wistar rats were randomly divided into baseline, metformin (500 mg daily), and control groups. Training consisted of 4 sets of 10 jumps with 30 s of passive recovery per day, 5 days/week for 8 weeks. The intensity equivalent was 50% of body mass (BM) in the first four weeks and 70% of BM in the last four weeks. The animals were submitted to a weekly jump test until exhaustion at 50% of BM. Serum and tissues were collected at baseline and after 4 and 8 weeks for biochemical and metabolomics analysis. The number of jumps increased in the Control group without a significant difference between groups at 4 and 8 weeks. GLUT4 was lower in the gastrocnemius muscle in the Metformin at the fourth week compared to Control (P=0.03) and compared to Metformin (P=0.02) and Control (P=0.01) at eight weeks. Hepatic and soleus GC were not altered by metformin. Gastrocnemius GC was lower after 8 weeks in the Metformin group compared to Control (P=0.01). Significantly lower levels of pyruvate and phenylalanine and higher levels of ethanol, formate, betaine, very low-density lipoprotein, low-density lipoprotein, and creatine were found in the Metformin compared to the Control. Although chronic administration of metformin decreased food intake and negatively influenced the synthesis of muscle glycogen, it did not significantly change physical performance compared to the Control.
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Affiliation(s)
- V J Bastos-Silva
- Laboratório de Ciências Aplicadas ao Esporte, Instituto de Educação Física e Esporte, Universidade Federal de Alagoas, Maceió, AL, Brasil
- Grupo de Pesquisa Aplicada ao Desempenho e Saúde, Centro Universitário CESMAC, Maceió, AL, Brasil
| | - H Spineli
- Laboratório de Ciências Aplicadas ao Esporte, Instituto de Educação Física e Esporte, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - J C Guimarães
- Laboratório de Ciências Aplicadas ao Esporte, Instituto de Educação Física e Esporte, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - K S C Borbely
- Laboratório de Biologia Celular, Instituto de Biologia e Ciências da Saúde, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - J S Ursulino
- Núcleo de Análise e Pesquisa em Ressonância Magnética Nuclear, Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - T M Aquino
- Núcleo de Análise e Pesquisa em Ressonância Magnética Nuclear, Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - E S Bento
- Núcleo de Análise e Pesquisa em Ressonância Magnética Nuclear, Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - P P M Scariot
- Laboratório de Fisiologia Aplicada ao Esporte, Faculdade de Ciências Aplicadas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - F A B Sousa
- Laboratório de Ciências Aplicadas ao Esporte, Instituto de Educação Física e Esporte, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - G G de Araujo
- Laboratório de Ciências Aplicadas ao Esporte, Instituto de Educação Física e Esporte, Universidade Federal de Alagoas, Maceió, AL, Brasil
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Sun M, Sun J, Sun W, Li X, Wang Z, Sun L, Wang Y. Unveiling the anticancer effects of SGLT-2i: mechanisms and therapeutic potential. Front Pharmacol 2024; 15:1369352. [PMID: 38595915 PMCID: PMC11002155 DOI: 10.3389/fphar.2024.1369352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 03/14/2024] [Indexed: 04/11/2024] Open
Abstract
Cancer and diabetes are significant diseases that pose a threat to human health. Their interconnection is complex, particularly when they coexist, often necessitating multiple therapeutic approaches to attain remission. Sodium-glucose cotransporter protein two inhibitors (SGLT-2i) emerged as a treatment for hyperglycemia, but subsequently exhibited noteworthy extra-glycemic properties, such as being registered for the treatment of heart failure and chronic kidney disease, especially with co-existing albuminuria, prompting its assessment as a potential treatment for various non-metabolic diseases. Considering its overall tolerability and established use in diabetes management, SGLT-2i may be a promising candidate for cancer therapy and as a supplementary component to conventional treatments. This narrative review aimed to examine the potential roles and mechanisms of SGLT-2i in the management of diverse types of cancer. Future investigations should focus on elucidating the antitumor efficacy of individual SGLT-2i in different cancer types and exploring the underlying mechanisms. Additionally, clinical trials to evaluate the safety and feasibility of incorporating SGLT-2i into the treatment regimen of specific cancer patients and determining appropriate dosage combinations with established antitumor agents would be of significant interest.
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Affiliation(s)
- Min Sun
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Jilei Sun
- Changchun Traditional Chinese Medicine Hospital, Changchun, China
| | - Wei Sun
- First Affiliated Hospital of Jilin University, Changchun, China
| | - Xiaonan Li
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Zhe Wang
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
| | - Liwei Sun
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Yuehui Wang
- Department of Geriatrics, First Hospital, Jilin University, Changchun, China
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Ando K, Suenaga Y, Kamijo T. DNA Ligase 4 Contributes to Cell Proliferation against DNA-PK Inhibition in MYCN-Amplified Neuroblastoma IMR32 Cells. Int J Mol Sci 2023; 24:ijms24109012. [PMID: 37240360 DOI: 10.3390/ijms24109012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/12/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Identifying the vulnerability of altered DNA repair machinery that displays synthetic lethality with MYCN amplification is a therapeutic rationale in unfavourable neuroblastoma. However, none of the inhibitors for DNA repair proteins are established as standard therapy in neuroblastoma. Here, we investigated whether DNA-PK inhibitor (DNA-PKi) could inhibit the proliferation of spheroids derived from neuroblastomas of MYCN transgenic mice and MYCN-amplified neuroblastoma cell lines. DNA-PKi exhibited an inhibitory effect on the proliferation of MYCN-driven neuroblastoma spheroids, whereas variable sensitivity was observed in those cell lines. Among them, the accelerated proliferation of IMR32 cells was dependent on DNA ligase 4 (LIG4), which comprises the canonical non-homologous end-joining pathway of DNA repair. Notably, LIG4 was identified as one of the worst prognostic factors in patients with MYCN-amplified neuroblastomas. It may play complementary roles in DNA-PK deficiency, suggesting the therapeutic potential of LIG4 inhibition in combination with DNA-PKi for MYCN-amplified neuroblastomas to overcome resistance to multimodal therapy.
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Affiliation(s)
- Kiyohiro Ando
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Yusuke Suenaga
- Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
| | - Takehiko Kamijo
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
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Bobiński R, Dutka M, Pizon M, Waksmańska W, Pielesz A. Ferroptosis, Acyl Starvation, and Breast Cancer. Mol Pharmacol 2023; 103:132-144. [PMID: 36750321 DOI: 10.1124/molpharm.122.000607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022] Open
Abstract
To maintain their growth rate, cancer cells must secure a supply of fatty acids, which are necessary for building cell membranes and maintaining energy processes. This is one of the reasons why tissues with intensive fatty acid metabolism, such as the mammary gland, are more likely to develop tumors. One natural or induced defense process against cancer is ferroptosis, which interferes with normal fatty acid metabolism. This leads to the oxidation of polyunsaturated fatty acids, which causes a rearrangement of the metabolism and damages cell membranes. As a consequence of this oxidation, there is a shortage of normal polyunsaturated fatty acids, which disturbs the complicated metabolism of fatty acids. This imbalance in metabolism, resulting from the deficiency of properly structured fatty acids, is called, by these authors, "acyl starvation." When cancer cells are exposed to alternating hypoxia and reoxygenation, they often develop resistance to neoadjuvant therapies. Blocking the stearoyl-CoA desaturase - fatty acid-binding protein 4 - fatty acid translocase axis appears to be a promising pathway in the treatment of breast cancer. On the one hand, the inhibition of desaturase leads to the formation of toxic phospholipid hydroperoxides in ferroptosis, whereas on the other hand, the inhibition of fatty acid-binding protein 4 and translocase leads to a reduced uptake of fatty acids and disruption of the cellular transport of fatty acids, resulting in intracellular acyl starvation. The disruption in the metabolism of fatty acids in cancer cells may augment the effectiveness of neoadjuvant therapy. SIGNIFICANCE STATEMENT: Regulation of the metabolism of fatty acids in cancer cells seems to be a promising therapeutic direction. Studies show that the induction of ferroptosis in cancer cells, combined with use of neoadjuvant therapies, effectively inhibits the proliferation of these cells. We link the process of ferroptosis with apoptosis and SCD1-FABP4-CD36 axis and propose the term "acyl starvation" for the processes leading to FA deficiency, dysregulation of FA metabolism in cancer cells, and, most importantly, the appearance of incorrect proportions FAs.
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Affiliation(s)
- Rafał Bobiński
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Mieczysław Dutka
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Monika Pizon
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Wioletta Waksmańska
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Anna Pielesz
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
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A Triphenylphosphonium-Functionalized Delivery System for an ATM Kinase Inhibitor That Ameliorates Doxorubicin Resistance in Breast Carcinoma Mammospheres. Cancers (Basel) 2023; 15:cancers15051474. [PMID: 36900267 PMCID: PMC10000448 DOI: 10.3390/cancers15051474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/20/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023] Open
Abstract
The enzyme ataxia-telangiectasia mutated (ATM) kinase is a pluripotent signaling mediator which activates cellular responses to genotoxic and metabolic stress. It has been shown that ATM enables the growth of mammalian adenocarcinoma stem cells, and therefore the potential benefits in cancer chemotherapy of a number of ATM inhibitors, such as KU-55933 (KU), are currently being investigated. We assayed the effects of utilizing a triphenylphosphonium-functionalized nanocarrier delivery system for KU on breast cancer cells grown either as a monolayer or in three-dimensional mammospheres. We observed that the encapsulated KU was effective against chemotherapy-resistant mammospheres of breast cancer cells, while having comparably lower cytotoxicity against adherent cells grown as monolayers. We also noted that the encapsulated KU sensitized the mammospheres to the anthracycline drug doxorubicin significantly, while having only a weak effect on adherent breast cancer cells. Our results suggest that triphenylphosphonium-functionalized drug delivery systems that contain encapsulated KU, or compounds with a similar impact, are a useful addition to chemotherapeutic treatment schemes that target proliferating cancers.
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Li L, Huang J, Huang T, Yao J, Zhang Y, Chen M, Shentu H, Lou H. Effect of Metformin on the Prognosis of Gastric Cancer Patients with Type 2 Diabetes Mellitus: A Meta-Analysis Based on Retrospective Cohort Studies. Int J Endocrinol 2023; 2023:5892731. [PMID: 36915376 PMCID: PMC10008112 DOI: 10.1155/2023/5892731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Metformin is one of the most common drugs for type 2 diabetes mellitus (T2DM) treatment. In addition, metformin intends to have a positive effect on the prognosis of several cancers. However, the therapeutic effect of metformin on gastric cancer (GC) remains controversial. This study explores and updates the therapeutic effect of metformin in GC patients with T2DM. METHODS We searched through PubMed, Embase, Web of Science, and the Cochrane Library for relevant articles by July 2022. The relationship between metformin therapy and the prognosis of GC patients with T2DM was evaluated based on the hazard ratio (HR) at a 95% confidence interval (95% CI). Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were the primary outcomes analyzed. RESULTS Seven retrospective cohort studies with a combined 2,858 patients met the inclusion criteria. OS and CSS were reported in six studies, and PFS was reported in four studies. Pooled results showed that, compared to the nonmetformin group, the prolonged OS (HR = 0.72, p = 0.001), CSS (HR = 0.81, p = 0.001), and PFS (HR = 0.70, p = 0.008) of the experimental group may be associated with the exposure to metformin. CONCLUSION Metformin may have a beneficial effect on the prognosis of GC patients with T2DM.
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Affiliation(s)
- Lingna Li
- Pharmacy Department, The Affiliated Hospital of Ningbo University, Li Huili Hospital, Ningbo, China
| | - Jianing Huang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tongmin Huang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jie Yao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yeyuan Zhang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Meiling Chen
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Haojie Shentu
- School of Medical Imaging, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Haiying Lou
- Department of Endocrinology, Zhuji People's Hospital, Shaoxing, Zhejiang, China
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Cunha Júnior AD, Bragagnoli AC, Costa FO, Carvalheira JBC. Repurposing metformin for the treatment of gastrointestinal cancer. World J Gastroenterol 2021; 27:1883-1904. [PMID: 34007128 PMCID: PMC8108031 DOI: 10.3748/wjg.v27.i17.1883] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/13/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus type 2 and cancer share many risk factors. The pleiotropic insulin-dependent and insulin-independent effects of metformin might inhibit pathways that are frequently amplified in neoplastic tissue. Particularly, modulation of inflammation, metabolism, and cell cycle arrest are potential therapeutic cancer targets utilized by metformin to boost the anti-cancer effects of chemotherapy. Studies in vitro and in vivo models have demonstrated the potential of metformin as a chemo- and radiosensitizer, besides its chemopreventive and direct therapeutic activity in digestive system (DS) tumors. Hence, these aspects have been considered in many cancer clinical trials. Case-control and cohort studies and associated meta-analyses have evaluated DS cancer risk and metformin usage, especially in colorectal cancer, pancreatic cancer, and hepatocellular carcinoma. Most clinical studies have demonstrated the protective role of metformin in the risk for DS cancers and survival rates. On the other hand, the ability of metformin to enhance the actions of chemotherapy for gastric and biliary cancers is yet to be investigated. This article reviews the current findings on the anti-cancer mechanisms of metformin and its apparatus from pre-clinical and ongoing studies in DS malignancies.
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Affiliation(s)
- Ademar Dantas Cunha Júnior
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Felipe Osório Costa
- Department of Internal Medicine, Division of Oncology, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
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Wu T, Zhou S, Qin M, Tang J, Yan X, Huang L, Huang M, Deng J, Xiao D, Hu X, Wu J, Yang X, Li G. Phenformin and ataxia-telangiectasia mutated inhibitors synergistically co-suppress liver cancer cell growth by damaging mitochondria. FEBS Open Bio 2021; 11:1440-1451. [PMID: 33742560 PMCID: PMC8091576 DOI: 10.1002/2211-5463.13152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/08/2021] [Accepted: 03/18/2021] [Indexed: 12/18/2022] Open
Abstract
Inhibitors of ataxia–telangiectasia mutated (ATM), such as KU‐55933 (Ku), represent a promising class of novel anticancer drugs. In addition, the biguanide derivative phenformin exhibits antitumor activity superior to that of the AMPK activator metformin. Herein, we assessed the potential combinatorial therapeutic efficacy of phenformin and Ku when used to inhibit the growth of liver cancer cells, and we assessed the mechanisms underlying such efficacy. The Hep‐G2 and SMMC‐7721 liver cancer cell lines were treated with phenformin and Ku either alone or in combination, after which the impact of these drugs on cellular proliferation was assessed via 3‐(4,5‐dimethylthiazol) 2, 5‐diphenyltetrazolium and colony formation assays, whereas Transwell assays were used to gauge cell migratory activity. The potential synergy between these two drugs was assessed using the compusyn software, while flow cytometry was employed to evaluate cellular apoptosis. In addition, western blotting was utilized to measure p‐ATM, p‐AMPK, p‐mTOR, and p‐p70s6k expression, while mitochondrial functionality was monitored via morphological analyses, JC‐1 staining, and measurements of ATP levels. Phenformin and Ku synergistically impacted the proliferation, migration, and apoptotic death of liver cancer cells. Together, these compounds were able to enhance AMPK phosphorylation while inhibiting the phosphorylation of mTOR and p70s6k. These data also revealed that phenformin and Ku induced mitochondrial dysfunction as evidenced by impaired ATP synthesis, mitochondrial membrane potential, and abnormal mitochondrial morphology. These findings suggest that combination treatment with phenformin and Ku may be an effective approach to treating liver cancer via damaging mitochondria within these tumor cells.
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Affiliation(s)
- Tianyu Wu
- Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Sichun Zhou
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Mei Qin
- Department of Gynecologists, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jing Tang
- Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xinjian Yan
- Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Lingli Huang
- Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Meiyuan Huang
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jun Deng
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Di Xiao
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Xin Hu
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Jingtao Wu
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Xiaoping Yang
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy School of Medicine, Hunan Normal University, Changsha, China
| | - Gaofeng Li
- Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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10
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Bhalla K, Jaber S, Reagan K, Hamburg A, Underwood KF, Jhajharia A, Singh M, Bhandary B, Bhat S, Nanaji NM, Hisa R, McCracken C, Creasy HH, Lapidus RG, Kingsbury T, Mayer D, Polster B, Gartenhaus RB. SIRT3, a metabolic target linked to ataxia-telangiectasia mutated (ATM) gene deficiency in diffuse large B-cell lymphoma. Sci Rep 2020; 10:21159. [PMID: 33273545 PMCID: PMC7712916 DOI: 10.1038/s41598-020-78193-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 11/10/2020] [Indexed: 12/16/2022] Open
Abstract
Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells. ATM-/- DLBCL cells have decreased apoptosis in contrast to radiosensitive non-cancerous A-T cells. In vivo studies using gain and loss of SIRT3 expression showed that SIRT3 promotes growth of ATM CRISPR knockout DLBCL xenografts compared to wild-type ATM control xenografts. Importantly, screening of DLBCL patient samples identified SIRT3 as a putative therapeutic target, and validated an inverse relationship between ATM and SIRT3 expression. Our data predicts SIRT3 as an important therapeutic target for DLBCL patients with ATM null phenotype.
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Affiliation(s)
- Kavita Bhalla
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
| | - Sausan Jaber
- Department of Anesthesiology, University of Maryland, Baltimore, MD, 21201, USA
| | - Kayla Reagan
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Arielle Hamburg
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Karen F Underwood
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Aditya Jhajharia
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
| | - Maninder Singh
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
| | - Binny Bhandary
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Shambhu Bhat
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Nahid M Nanaji
- Veterans Administration Medical Center, Baltimore, MD, 21201, USA
| | - Ruching Hisa
- Electron Microscopy Core Imaging Facility, Department of Medicine, University of Maryland, Baltimore, USA
| | - Carrie McCracken
- Institute of Genome Sciences, University of Maryland, Baltimore, MD, 21201, USA
| | - Heather Huot Creasy
- Institute of Genome Sciences, University of Maryland, Baltimore, MD, 21201, USA
| | - Rena G Lapidus
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Tami Kingsbury
- Department of Physiology, The Center for Stem Cell Biology and Regenerative Medicine, Baltimore, MD, 21201, USA
| | - Dirk Mayer
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
| | - Brian Polster
- Department of Anesthesiology, University of Maryland, Baltimore, MD, 21201, USA
| | - Ronald B Gartenhaus
- Hunter Holmes McGuire Veterans Administration Medical Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
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11
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Zhou J, Zhu J, Yu SJ, Ma HL, Chen J, Ding XF, Chen G, Liang Y, Zhang Q. Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Biomed Pharmacother 2020; 132:110821. [PMID: 33068934 DOI: 10.1016/j.biopha.2020.110821] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/14/2020] [Accepted: 09/25/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate the potential ability of SGLT2 inhibitors to attenuate cancer growth of SGLT2-expressing cancer cells, but there is little known about the effects of SGLT2 inhibitors on breast cancer. The goal in this research was to assess the anticancer activity of SGLT2 inhibitors in breast cancerin vitro and in vivo. METHODS We test the SGLT2 expression in breast cancer using immunohistochemistry and immunoblot assay. MTT cytotoxicity assay, colony formation assay and human breast cancer cells nude mice xenograft model were performed to detect the effects of SGLT2 inhibitors on cancer cell proliferation and growth. Flow Cytometry assay was performed to determine if the SGLT2 inhibitors induced cell cycle arrest and apoptosis. RESULTS We proved that SGLT2 expresses in breast cancer cell lines and human breast tumor tissue samples. SGLT2 inhibitors Dapagliflozin and Canagliflozin exhibited a potent anti-proliferative effect in breast cancer cells as demonstrated by MTT, clonogenic survival assay in vitro and xenograft growth model in vivo. Furthermore, we found that SGLT2 inhibitors arrested cell cycle in G1/G0 phase and induced cell apoptosis. Western blot analysis demonstrated that treatment with SGLT2 inhibitors increased the phosphorylation of Amp-activated protein kinase (AMPK) and decreased the phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (p70S6K1) in breast cancer cells. CONCLUSIONS These findings indicate that SGLT2 inhibitor-therapy induced AMPK-mediated cell cycle arrest and apoptosis, which is a potential novel strategy for the treatment of breast cancer.
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Affiliation(s)
- Jun Zhou
- Department of Rehabilitation Medicine, School of Clinical Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Jin Zhu
- Department of Breast Surgical Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330046, China
| | - Sheng-Jian Yu
- Institute of Tumor, Taizhou University, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Huai-Lu Ma
- Institute of Tumor, Taizhou University, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Jie Chen
- Department of Experimental and Clinical Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Xiao-Fei Ding
- Department of Experimental and Clinical Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China
| | - Guang Chen
- Department of Pharmacology, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China; Department of Experimental and Clinical Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China.
| | - Yong Liang
- Institute of Tumor, Taizhou University, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China; Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, Zhejiang, 318000, China.
| | - Qiang Zhang
- Department of Surgical Oncology, Taizhou Municipal Hospital, Taizhou University, Taizhou, Zhejiang, 318000, China.
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12
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Chen CW, Buj R, Dahl ES, Leon KE, Aird KM. ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells. Heliyon 2020; 6:e05097. [PMID: 33024871 PMCID: PMC7527645 DOI: 10.1016/j.heliyon.2020.e05097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/04/2020] [Accepted: 09/24/2020] [Indexed: 11/09/2022] Open
Abstract
While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for high grade serous ovarian cancer (HGSOC) patients, this strategy is limited to the ~50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies. We found that the HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype and its activity is upregulated in HGSOC compared to normal fallopian tube tissue. Interestingly, multiple pathways related to metabolism are inversely correlated with ATM expression in HGSOC specimens, suggesting that combining ATM inhibition with metabolic drugs would be effective. Analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM-low cells are more sensitive to fenofibrate, a PPARα agonist that affects multiple cellular metabolic pathways. Consistently, PPARα signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Together, our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment of HGSOC.
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13
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Chow HM, Cheng A, Song X, Swerdel MR, Hart RP, Herrup K. ATM is activated by ATP depletion and modulates mitochondrial function through NRF1. J Cell Biol 2019; 218:909-928. [PMID: 30642892 PMCID: PMC6400560 DOI: 10.1083/jcb.201806197] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/27/2018] [Accepted: 12/26/2018] [Indexed: 12/19/2022] Open
Abstract
Oxidative stress, resulting from neuronal activity and depleted ATP levels, activates ATM, which phosphorylates NRF1, causing nuclear translocation and up regulation of mitochondrial gene expression. In ATM deficiency, ATP levels recover more slowly, particularly in active neurons with high energy demands. Ataxia-telangiectasia (A-T) is an autosomal recessive disease caused by mutation of the ATM gene and is characterized by loss of cerebellar Purkinje cells, neurons with high physiological activity and dynamic ATP demands. Here, we show that depletion of ATP generates reactive oxygen species that activate ATM. We find that when ATM is activated by oxidative stress, but not by DNA damage, ATM phosphorylates NRF1. This leads to NRF1 dimerization, nuclear translocation, and the up-regulation of nuclear-encoded mitochondrial genes, thus enhancing the capacity of the electron transport chain (ETC) and restoring mitochondrial function. In cells lacking ATM, cells replenish ATP poorly following surges in energy demand, and chronic ATP insufficiency endangers cell survival. We propose that in the absence of ATM, cerebellar Purkinje cells cannot respond adequately to the increase in energy demands of neuronal activity. Our findings identify ATM as a guardian of mitochondrial output, as well as genomic integrity, and suggest that alternative fuel sources may ameliorate A-T disease symptoms.
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Affiliation(s)
- Hei-Man Chow
- Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong .,Institute for Advanced Study, Hong Kong University of Science and Technology, Hong Kong
| | - Aifang Cheng
- Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong
| | - Xuan Song
- Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong
| | - Mavis R Swerdel
- Department of Cell Biology and Neuroscience, Rutgers University, New Brunswick, NJ
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers University, New Brunswick, NJ
| | - Karl Herrup
- Division of Life Science and The State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong
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14
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Xu L, Ma E, Zeng T, Zhao R, Tao Y, Chen X, Groth J, Liang C, Hu H, Huang J. ATM deficiency promotes progression of CRPC by enhancing Warburg effect. Endocr Relat Cancer 2019; 26:59-71. [PMID: 30400006 PMCID: PMC6226046 DOI: 10.1530/erc-18-0196] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/07/2018] [Indexed: 12/16/2022]
Abstract
ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.
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Affiliation(s)
- Lingfan Xu
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, China, 230022
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
| | - Enze Ma
- Depaertment of Neuroscience, Duke University, Durham, NC, USA, 27710
| | - Tao Zeng
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
- Department of Urology, Jiangxi Province People’s Hospital, Nanchang, China
| | - Ruya Zhao
- Department of Dermatology, Duke School of Medicine, Durham, NC, USA, 27710
| | - Yulei Tao
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
| | - Xufeng Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
| | - Jeff Groth
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
| | - Chaozhao Liang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, China, 230022
| | - Hailiang Hu
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, 27710
| | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA, 27710
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA, 27710
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA, 27710
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15
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Abstract
Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.
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16
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Yu X, Mao W, Zhai Y, Tong C, Liu M, Ma L, Yu X, Li S. Anti-tumor activity of metformin: from metabolic and epigenetic perspectives. Oncotarget 2018; 8:5619-5628. [PMID: 27902459 PMCID: PMC5354934 DOI: 10.18632/oncotarget.13639] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/03/2016] [Indexed: 12/30/2022] Open
Abstract
Metformin has been used to treat type 2 diabetes for over 50 years. Epidemiological, preclinical and clinical studies suggest that metformin treatment reduces cancer incidence in diabetes patients. Due to its potential as an anti-cancer agent and its low cost, metformin has gained intense research interest. Its traditional anti-cancer mechanisms involve both indirect and direct insulin-dependent pathways. Here, we discussed the anti-tumor mechanism of metformin from the aspects of cell metabolism and epigenetic modifications. The effects of metformin on anti-cancer immunity and apoptosis were also described. Understanding these mechanisms will shed lights on application of metformin in clinical trials and development of anti-cancer therapy.
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Affiliation(s)
- Xilan Yu
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Wuxiang Mao
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Yansheng Zhai
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Chong Tong
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Min Liu
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Lixin Ma
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Xiaolan Yu
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Shanshan Li
- Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, College of Life Sciences, Hubei University, Wuhan, Hubei, China
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17
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Najafi M, Cheki M, Rezapoor S, Geraily G, Motevaseli E, Carnovale C, Clementi E, Shirazi A. Metformin: Prevention of genomic instability and cancer: A review. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2018; 827:1-8. [PMID: 29502733 DOI: 10.1016/j.mrgentox.2018.01.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 12/28/2017] [Accepted: 01/15/2018] [Indexed: 12/21/2022]
Abstract
The diabetes drug metformin can mitigate the genotoxic effects of cytotoxic agents and has been proposed to prevent or even cure certain cancers. Metformin reduces DNA damage by mechanisms that are only incompletely understood. Metformin scavenges free radicals, including reactive oxygen species and nitric oxide, which are produced by genotoxicants such as ionizing or non-ionizing radiation, heavy metals, and chemotherapeutic agents. The drug may also increase the activities of antioxidant enzymes and inhibit NADPH oxidase, cyclooxygenase-2, and inducible nitric oxide synthase, thereby limiting macrophage recruitment and inflammatory responses. Metformin stimulates the DNA damage response (DDR) in the homologous end-joining, homologous recombination, and nucleotide excision repair pathways. This review focuses on the protective properties of metformin against genomic instability.
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Affiliation(s)
- Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Science, Kermanshah, Iran
| | - Mohsen Cheki
- Department of Radiologic Technology, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Saeed Rezapoor
- Department of Radiology, Faculty of Paramedical, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazale Geraily
- Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Carla Carnovale
- Department of Biomedical and Clinical Sciences L. Sacco, Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, Università di Milano, Milan, Italy
| | - Emilio Clementi
- Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco, Italy; Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, L. Sacco University Hospital, Università di Milano, Milan, Italy
| | - Alireza Shirazi
- Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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18
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Ogrodzinski MP, Bernard JJ, Lunt SY. Deciphering metabolic rewiring in breast cancer subtypes. Transl Res 2017; 189:105-122. [PMID: 28774752 DOI: 10.1016/j.trsl.2017.07.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 06/02/2017] [Accepted: 07/11/2017] [Indexed: 02/07/2023]
Abstract
Metabolic reprogramming, an emerging hallmark of cancer, is observed in breast cancer. Breast cancer cells rewire their cellular metabolism to meet the demands of survival, proliferation, and invasion. However, breast cancer is a heterogeneous disease, and metabolic rewiring is not uniform. Each subtype of breast cancer displays distinct metabolic alterations. Here, we focus on unique metabolic reprogramming associated with subtypes of breast cancer, as well as common features. Therapeutic opportunities based on subtype-specific metabolic alterations are also discussed. Through this discussion, we aim to provide insight into subtype-specific metabolic rewiring and vulnerabilities that have the potential to better guide therapy and improve outcomes for patients.
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Affiliation(s)
- Martin P Ogrodzinski
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Mich; Department of Physiology, Michigan State University, East Lansing, Mich
| | - Jamie J Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Mich
| | - Sophia Y Lunt
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Mich; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Mich.
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19
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Ravindran G, Chakrabarty D, Sarkar A. Cell specific stress responses of cadmium-induced cytotoxicity. Anim Cells Syst (Seoul) 2016; 21:23-30. [PMID: 30460048 DOI: 10.1080/19768354.2016.1267041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 11/02/2016] [Accepted: 11/14/2016] [Indexed: 01/23/2023] Open
Abstract
Cadmium is one of the age old toxic heavy metal, detrimental to the biological system. In this study, we explored the cellular and molecular mechanisms induced on exposure to different concentrations of cadmium chloride (CdCl2), on three different human cell lines with wild type p53, viz., A549, HEK293 and HCT116. We investigated whether the cellular responses followed, displayed any specific pattern related to their viability, mitochondrial respiration, DNA damage and apoptotic gene expression. All the cell lines showed decrease in viability following exposure to CdCl2. p53 was transcriptionally down regulated in all the three cell lines, but with different extents, in response to increasing concentration of cadmium. The cellular responses of the three cell lines were compared with that of a p53 knock out cell line (HCT116p53-/-). The p53 knock out cell line was highly sensitive to cadmium-induced toxicity; so was the cell line in which p53 mRNA expression was highly down regulated. This might implicate an unknown protective role of p53 signaling during heavy metal toxicity and that one of the possible mechanisms by which cadmium manifests its cytotoxic effect is through the transcriptional down regulation of p53 gene.
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Affiliation(s)
- Geethanjali Ravindran
- CMBL, Department of Biological Sciences, BITS Pilani K K Birla Goa Campus, Zuarinagar, Goa, India
| | - Dibakar Chakrabarty
- CMBL, Department of Biological Sciences, BITS Pilani K K Birla Goa Campus, Zuarinagar, Goa, India
| | - Angshuman Sarkar
- CMBL, Department of Biological Sciences, BITS Pilani K K Birla Goa Campus, Zuarinagar, Goa, India
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20
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Smith TAD, Phyu SM. Metformin Decouples Phospholipid Metabolism in Breast Cancer Cells. PLoS One 2016; 11:e0151179. [PMID: 26959405 PMCID: PMC4784930 DOI: 10.1371/journal.pone.0151179] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/24/2016] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION The antidiabetic drug metformin, currently undergoing trials for cancer treatment, modulates lipid and glucose metabolism both crucial in phospholipid synthesis. Here the effect of treatment of breast tumour cells with metformin on phosphatidylcholine (PtdCho) metabolism which plays a key role in membrane synthesis and intracellular signalling has been examined. METHODS MDA-MB-468, BT474 and SKBr3 breast cancer cell lines were treated with metformin and [3H-methyl]choline and [14C(U)]glucose incorporation and lipid accumulation determined in the presence and absence of lipase inhibitors. Activities of choline kinase (CK), CTP:phosphocholine cytidylyl transferase (CCT) and PtdCho-phospholipase C (PLC) were also measured. [3H] Radiolabelled metabolites were determined using thin layer chromatography. RESULTS Metformin-treated cells exhibited decreased formation of [3H]phosphocholine but increased accumulation of [3H]choline by PtdCho. CK and PLC activities were decreased and CCT activity increased by metformin-treatment. [14C] incorporation into fatty acids was decreased and into glycerol was increased in breast cancer cells treated with metformin incubated with [14C(U)]glucose. CONCLUSION This is the first study to show that treatment of breast cancer cells with metformin induces profound changes in phospholipid metabolism.
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Affiliation(s)
- Tim A. D. Smith
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
| | - Su M. Phyu
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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21
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Silvestri A, Palumbo F, Rasi I, Posca D, Pavlidou T, Paoluzi S, Castagnoli L, Cesareni G. Metformin Induces Apoptosis and Downregulates Pyruvate Kinase M2 in Breast Cancer Cells Only When Grown in Nutrient-Poor Conditions. PLoS One 2015; 10:e0136250. [PMID: 26291325 PMCID: PMC4546379 DOI: 10.1371/journal.pone.0136250] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 08/03/2015] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Metformin is proposed as adjuvant therapy in cancer treatment because of its ability to limit cancer incidence by negatively modulating the PI3K/AKT/mTOR pathway. In vitro, in addition to inhibiting cancer cell proliferation, metformin can also induce apoptosis. The molecular mechanism underlying this second effect is still poorly characterized and published data are often contrasting. We investigated how nutrient availability can modulate metformin-induced apoptosis in three breast cancer cell lines. MATERIAL AND METHODS MCF7, SKBR3 and MDA-MB-231 cells were plated in MEM medium supplemented with increasing glucose concentrations or in DMEM medium and treated with 10 mM metformin. Cell viability was monitored by Trypan Blue assay and treatment effects on Akt/mTOR pathway and on apoptosis were analysed by Western Blot. Moreover, we determined the level of expression of pyruvate kinase M2 (PKM2), a well-known glycolytic enzyme expressed in cancer cells. RESULTS Our results showed that metformin can induce apoptosis in breast cancer cells when cultured at physiological glucose concentrations and that the pro-apoptotic effect was completely abolished when cells were grown in high glucose/high amino acid medium. Induction of apoptosis was found to be dependent on AMPK activation but, at least partially, independent of TORC1 inactivation. Finally, we showed that, in nutrient-poor conditions, metformin was able to modulate the intracellular glycolytic equilibrium by downregulating PKM2 expression and that this mechanism was mediated by AMPK activation. CONCLUSION We demonstrated that metformin induces breast cancer cell apoptosis and PKM2 downregulation only in nutrient-poor conditions. Not only glucose levels but also amino acid concentration can influence the observed metformin inhibitory effect on the mTOR pathway as well as its pro-apoptotic effect. These data demonstrate that the reduction of nutrient supply in tumors can increase metformin efficacy and that modulation of PKM2 expression/activity could be a promising strategy to boost metformin anti-cancer effect.
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Affiliation(s)
- Alessandra Silvestri
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
- * E-mail:
| | - Francesco Palumbo
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Ignazio Rasi
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Daniela Posca
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Theodora Pavlidou
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Serena Paoluzi
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Luisa Castagnoli
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
| | - Giovanni Cesareni
- Laboratory of Molecular Genetics, Department of Biology, Tor Vergata University, Rome, Italy
- IRCCS, Fondazione Santa Lucia, Rome, Italy
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22
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Diaz-Muñoz MD, Bell SE, Fairfax K, Monzon-Casanova E, Cunningham AF, Gonzalez-Porta M, Andrews SR, Bunik VI, Zarnack K, Curk T, Heggermont WA, Heymans S, Gibson GE, Kontoyiannis DL, Ule J, Turner M. The RNA-binding protein HuR is essential for the B cell antibody response. Nat Immunol 2015; 16:415-25. [PMID: 25706746 PMCID: PMC4479220 DOI: 10.1038/ni.3115] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 01/28/2015] [Indexed: 12/26/2022]
Abstract
Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.
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Affiliation(s)
- Manuel D Diaz-Muñoz
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
| | - Sarah E Bell
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
| | - Kirsten Fairfax
- 1] Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK. [2] The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | - Elisa Monzon-Casanova
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
| | - Adam F Cunningham
- MRC Centre for Immune Regulation, Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, UK
| | - Mar Gonzalez-Porta
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge, UK
| | | | - Victoria I Bunik
- A. N. Belozersky Institute of PhysicoChemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Kathi Zarnack
- Buchmann Institute for Molecular Life Sciences, Frankfurt, Germany
| | - Tomaž Curk
- University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, Slovenia
| | | | - Stephane Heymans
- 1] Center for Molecular and Vascular Biology, KU Leuven, Belgium. [2] Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
| | - Gary E Gibson
- Weill Cornell Medical College, Brain and Mind Research Institute, Burke Medical Research Institute, White Plains, New York, USA
| | - Dimitris L Kontoyiannis
- Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece
| | - Jernej Ule
- UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK
| | - Martin Turner
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
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23
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Lea MA, Pourat J, Patel R, desBordes C. Growth inhibition of colon cancer cells by compounds affecting AMPK activity. World J Gastrointest Oncol 2014; 6:244-252. [PMID: 25024815 PMCID: PMC4092340 DOI: 10.4251/wjgo.v6.i7.244] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 04/16/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To determine if other molecules reported to modulate AMP-dependent protein kinase (AMPK) activity would have effects resembling those of metformin and phenformin on colon cancer cell proliferation and metabolism.
METHODS: Studies were performed with four human colon cancer cell lines, Caco-2, HCT116, HT29 and SW1116. The compounds that were studied included A-769662, 5-aminoimidazole-4-carboxamide-1-ribofuranoside, butyrate, (-)-epigallocatechin gallate (EGCG), KU-55933, quercetin, resveratrol and salicylates. The parameters that were measured were cell proliferation and viability, glucose uptake, lactate production and acidification of the incubation medium.
RESULTS: Investigations with several molecules that have been reported to be associated with AMPK activation (A-769662, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside, EGCG, KU-55933, quercetin, resveratrol and salicylates) or AMPK inhibition (compound C) failed to reveal increased medium acidification and increased glucose uptake in colon cancer cells as previously established with metformin and phenformin. The only exception was 5-aminosalicylic acid with which there were apparently lower glucose levels in the medium after incubation for 72 h. Further study in the absence of cells revealed that the effect was an artifact due to inhibition of the enzyme-linked glucose assay. The compounds were studied at concentrations that inhibited cell proliferation.
CONCLUSION: It was concluded that treatment with several agents that can affect AMPK activity resulted in the inhibition of the proliferation of colon cancer cells under conditions in which glucose metabolism is not enhanced, in contrast to the effect of biguanides.
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Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A 2014; 111:10574-9. [PMID: 25002509 DOI: 10.1073/pnas.1409844111] [Citation(s) in RCA: 220] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Metformin, a first-line diabetes drug linked to cancer prevention in retrospective clinical analyses, inhibits cellular transformation and selectively kills breast cancer stem cells (CSCs). Although a few metabolic effects of metformin and the related biguanide phenformin have been investigated in established cancer cell lines, the global metabolic impact of biguanides during the process of neoplastic transformation and in CSCs is unknown. Here, we use LC/MS/MS metabolomics (>200 metabolites) to assess metabolic changes induced by metformin and phenformin in an Src-inducible model of cellular transformation and in mammosphere-derived breast CSCs. Although phenformin is the more potent biguanide in both systems, the metabolic profiles of these drugs are remarkably similar, although not identical. During the process of cellular transformation, biguanide treatment prevents the boost in glycolytic intermediates at a specific stage of the pathway and coordinately decreases tricarboxylic acid (TCA) cycle intermediates. In contrast, in breast CSCs, biguanides have a modest effect on glycolytic and TCA cycle intermediates, but they strongly deplete nucleotide triphosphates and may impede nucleotide synthesis. These metabolic profiles are consistent with the idea that biguanides inhibit mitochondrial complex 1, but they indicate that their metabolic effects differ depending on the stage of cellular transformation.
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25
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Bonini MG, Gantner BN. The multifaceted activities of AMPK in tumor progression--why the "one size fits all" definition does not fit at all? IUBMB Life 2014; 65:889-96. [PMID: 24265196 DOI: 10.1002/iub.1213] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/27/2013] [Indexed: 12/19/2022]
Abstract
AMP-activated kinase (AMPK) is a central cellular energetic biosensor and regulator of a broad array of cellular metabolic routes activated by nutrient deprivation, mitochondrial dysfunction, oxidative stress, and cytokines. The activation of AMPK maintains ATP levels in response to hypoxia, mitochondrial dysfunction, and shortage of essential metabolic fuels. Activated AMPK turns on energy sparing pathways and promotes antiapoptotic functions thereby permitting cells to survive extremely hostile conditions for prolonged periods of time. Cancer cells in solid tumors are generally subjected to such harsh conditions; however, they manage to efficiently survive and proliferate. This is likely due, in great part, to a peculiar form of metabolism that is heavily reliant on glycolysis and which promotes cancer cell adaptation and tumor progression. AMPK controls the influx and utilization of glucose by cancer cells and therefore has emerged as an attractive target to treat cancer. Investigations exploring this possibility demonstrated that activators or inhibitors of AMPK impact cancer cell viability and possibly cancer progression. For example, the AMPK activator metformin induces apoptosis in a variety of cancer cell lines and models. A major problem with many of the studies on metformin is that little effort has been invested in unraveling how metformin activates AMPK in the many contexts it has been tested. This is significant because many AMPK-independent effects of metformin have been documented. The notion that AMPK acts solely as a tumor suppressor also conflicts with findings that it confers resistance to nutrient deprivation, sustains NADPH levels in cancer cells, facilitates stress-induced gene transcription, promotes cell survival via antiapoptotic function upregulation, intermediates epithelial-to-mesenchymal transition, and increases malignant transformation. These are all recognized steps necessary for the successful evolution of tumors. This review highlights some of these findings and proposes that the role of AMPK in cancer should be reconsidered in light of the complex roles of AMPK under different metabolic conditions.
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Affiliation(s)
- Marcelo G Bonini
- Department of Medicine, University of Illinois at Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, IL, USA; Department of Pathology, University of Illinois at Chicago, IL, USA
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26
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Glossmann H, Reider N. A marriage of two "Methusalem" drugs for the treatment of psoriasis?: Arguments for a pilot trial with metformin as add-on for methotrexate. DERMATO-ENDOCRINOLOGY 2014; 5:252-63. [PMID: 24194965 PMCID: PMC3772913 DOI: 10.4161/derm.23874] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 02/04/2013] [Indexed: 02/06/2023]
Abstract
In this article we present arguments that the “antidiabetic” drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.g., important for cellular growth or function in many tissues including T-lymphocytes. Clinical observations as well as experimental results argue for anti-inflammatory, antineoplastic and antiproliferative activities of metformin and a case-control study suggests that the drug reduces the risk for psoriasis.
Patients with psoriasis have higher risk of metabolic syndrome, type 2 diabetes and cardiovascular mortality. Metformin has proven efficacy in the treatment of prediabetes and leads to a pronounced and sustained weight loss in overweight individuals. We expect that addition of metformin to methotrexate can lead to positive effects with respect to the PASI score, reduction of the weekly methotrexate dose and of elevated cardiovascular risk factors in patients with metabolic syndrome and psoriasis. For reasons explained later we suggest that only male, overweight patients are to be included in a pilot trial. On the other side of the coin are concerns that the gastrointestinal side effects of metformin are intolerable for patients under low dose, intermittent methotrexate therapy. Metformin has another side effect, namely interference with vitamin B12 and folate metabolism, leading to elevated homocysteine serum levels. As patients must receive folate supplementation and will be controlled with respect to their B12 status increased hematological toxicity is unlikely to result.
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Affiliation(s)
- Hartmut Glossmann
- Institute for Biochemical Pharmacology; Department of Dermatology; Medical University of Innsbruck; Innsbruck, Austria
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27
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UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc Natl Acad Sci U S A 2014; 111:960-5. [PMID: 24395786 DOI: 10.1073/pnas.1317400111] [Citation(s) in RCA: 313] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties.
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28
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Foster CR, Daniel LL, Daniels CR, Dalal S, Singh M, Singh K. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis. PLoS One 2013; 8:e83513. [PMID: 24358288 PMCID: PMC3865210 DOI: 10.1371/journal.pone.0083513] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 11/05/2013] [Indexed: 12/19/2022] Open
Abstract
Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and Results: Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.
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Affiliation(s)
- Cerrone R. Foster
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Laura L. Daniel
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Christopher R. Daniels
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Suman Dalal
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Mahipal Singh
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
| | - Krishna Singh
- Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America
- * E-mail:
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Sanli T, Steinberg GR, Singh G, Tsakiridis T. AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 2013; 15:156-69. [PMID: 24100703 DOI: 10.4161/cbt.26726] [Citation(s) in RCA: 161] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AMP-activated protein kinase (AMPK), an established metabolic stress sensor, has gained popularity in cancer biology due to its ability to control cellular growth and mediate cell cycle checkpoints in cancer cells in response to low energy levels. AMPK is a key effector of the tumor suppressor liver kinase B 1 (LKB1) which inhibits the cellular growth mediator mammalian target of rapamycin (mTOR) and activates checkpoint mediators such as p53 and the cyclin dependent kinase inhibitors p21(cip1) and p27(kip1). However, recent work describes a novel function for AMPK as a sensor of genomic stress and a participant of the DNA damage response (DDR) pathway. Ionizing radiation and chemotherapy activate AMPK in cancer cells to mediate signal transduction downstream of ataxia telangiectasia mutated (ATM) to activate p53- p21(cip1)/p27(kip1) and inhibit mTOR. We discuss evidence on the transcriptional and post-translational regulation of AMPK by ionizing radiation and the role of the enzyme as a mediator of chemo- and radiation sensitivity in epithelial cancer cells. Furthermore, we review data on the participation of AMPK in cytokinesis and observations suggesting a physical association of this enzyme with the mitotic apparatus. The evidence available to date suggests that AMPK is a point of convergence of metabolic and genomic stress signals, which (1) control the activity of growth mediators, (2) propagate DDR, and (3) mediate the anti-proliferative effects of common cytotoxic cancer therapy such as radiation and chemotherapy. This highlights the importance of targeting AMPK with novel cancer therapeutics.
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Affiliation(s)
- Toran Sanli
- Translational Radiation Biology Laboratory; Juravinski Cancer Center; Hamilton, ON Canada; Department of Oncology; McMaster University; Hamilton, ON Canada
| | | | - Gurmit Singh
- Department of Pathology and Molecular Medicine; McMaster University; Hamilton, ON Canada
| | - Theodoros Tsakiridis
- Translational Radiation Biology Laboratory; Juravinski Cancer Center; Hamilton, ON Canada; Department of Oncology; McMaster University; Hamilton, ON Canada
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Salomäki H, Vähätalo LH, Laurila K, Jäppinen NT, Penttinen AM, Ailanen L, Ilyasizadeh J, Pesonen U, Koulu M. Prenatal metformin exposure in mice programs the metabolic phenotype of the offspring during a high fat diet at adulthood. PLoS One 2013; 8:e56594. [PMID: 23457588 PMCID: PMC3574083 DOI: 10.1371/journal.pone.0056594] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 01/11/2013] [Indexed: 01/15/2023] Open
Abstract
AIMS The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice. METHODS Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR. RESULTS Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice. CONCLUSIONS The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.
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Affiliation(s)
- Henriikka Salomäki
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Laura H. Vähätalo
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Kirsti Laurila
- Department of Information and Service Economy, Aalto University School of Economics, Helsinki, Finland
- Department of Information and Computer Science, Aalto University School of Science, Helsinki, Finland
| | - Norma T. Jäppinen
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Anna-Maija Penttinen
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Liisa Ailanen
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Juan Ilyasizadeh
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Ullamari Pesonen
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Markku Koulu
- Institute of Biomedicine, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
- * E-mail:
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