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Viglianisi G, Polizzi A, Grippaudo C, Cocuzza S, Leonardi R, Isola G. Chemopreventive and Biological Strategies in the Management of Oral Potentially Malignant and Malignant Disorders. Bioengineering (Basel) 2024; 11:65. [PMID: 38247942 PMCID: PMC10813134 DOI: 10.3390/bioengineering11010065] [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: 11/21/2023] [Revised: 12/28/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
Oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) represent a significant global health burden due to their potential for malignant transformation and the challenges associated with their diagnosis and treatment. Chemoprevention, an innovative approach aimed at halting or reversing the neoplastic process before full malignancy, has emerged as a promising avenue for mitigating the impact of OPMD and OSCC. The pivotal role of chemopreventive strategies is underscored by the need for effective interventions that go beyond traditional therapies. In this regard, chemopreventive agents offer a unique opportunity to intercept disease progression by targeting the molecular pathways implicated in carcinogenesis. Natural compounds, such as curcumin, green tea polyphenols, and resveratrol, exhibit anti-inflammatory, antioxidant, and anti-cancer properties that could make them potential candidates for curtailing the transformation of OPMD to OSCC. Moreover, targeted therapies directed at specific molecular alterations hold promise in disrupting the signaling cascades driving OSCC growth. Immunomodulatory agents, like immune checkpoint inhibitors, are gaining attention for their potential to harness the body's immune response against early malignancies, thus impeding OSCC advancement. Additionally, nutritional interventions and topical formulations of chemopreventive agents offer localized strategies for preventing carcinogenesis in the oral cavity. The challenge lies in optimizing these strategies for efficacy, safety, and patient compliance. This review presents an up to date on the dynamic interplay between molecular insights, clinical interventions, and the broader goal of reducing the burden of oral malignancies. As research progresses, the synergy between early diagnosis, non-invasive biomarker identification, and chemopreventive therapy is poised to reshape the landscape of OPMD and OSCC management, offering a glimpse of a future where these diseases are no longer insurmountable challenges but rather preventable and manageable conditions.
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Affiliation(s)
- Gaia Viglianisi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Alessandro Polizzi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Cristina Grippaudo
- Head and Neck Department, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Salvatore Cocuzza
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia” ENT Section, University of Catania, Via S. Sofia 68, 95124 Catania, Italy;
| | - Rosalia Leonardi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
| | - Gaetano Isola
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 68, 95124 Catania, Italy; (G.V.); (A.P.); (R.L.); (G.I.)
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Sharma N, Dhingra R. Clinical potentials of metformin in cancer therapy. JOURNAL OF DIABETOLOGY 2023; 14:186-192. [DOI: 10.4103/jod.jod_84_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/28/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Diabetes is a prevalent metabolic disorder that results in several comorbidities including cancer. Cancer becomes the most severe complication of diabetes patients. Growing evidence proved that impaired glucose homeostasis is an independent risk factor for the occurrence of various types of cancers including liver, pancreatic, gastric (stomach), colorectal, kidney, and breast cancers, and influences cancer prognosis. Diabetes mellitus and cancer have a bidirectional relationship, thus there is a need to look for drugs that can be beneficial in treating both diseases. Therefore, more research is focusing on evaluating the role of antihyperglycemic agents in the treatment of various types of cancers. Metformin, an FDA-approved first-line antihyperglycemic agent can be used as a monotherapy or as an adjuvant to chemotherapeutic agents in the treatment of various types of cancer. However, the exact mechanism of metformin as an anticancer agent is still unknown, the majority of the described putative mechanisms focus on promoting the activity of the AMP-activated protein kinase (AMPK) pathway. This review article thus gives insights into the prognosis of cancer in diabetes patients and aims to explore the possible mechanism of action of metformin in the prevention and treatment of cancer.
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Affiliation(s)
- Nidhi Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
| | - Richa Dhingra
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Sohna, Haryana, India
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Bekezhankyzy Z, Nurzhan S, Berdigaliyev N, Sergazy S, Maulenkul T, Aljofan M. The antiproliferative potential and mechanism of action of metformin in MCF-7 cells. Future Sci OA 2023; 9:FSO859. [PMID: 37180606 PMCID: PMC10167719 DOI: 10.2144/fsoa-2022-0080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/03/2023] [Indexed: 05/16/2023] Open
Abstract
Aim The current study aimed to investigate the potential antiproliferative activity of metformin, the effective concentration range, and the mechanism of action. Materials & methods Human breast cancer cells, MCF-7 were treated with a serial dilution of metformin (10-150 μM) for 24 and 48 h. Potential antiproliferative activity of metformin and its ability in inducing cellular apoptosis and autophagy were also investigated. Results Metformin inhibited MCF-7 proliferation in a concentration and time dependent manner, with 80 μM as the most effective concentration. Compared with nontreated cells, metformin induced significant levels of autophagy and apoptosis, which were confirmed by the reduction of mTOR and BCL-2 protein expression. Conclusion The study confirms the antiproliferative activity of metformin, which may likely occur through AMPK signaling pathway.
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Affiliation(s)
- Zhibek Bekezhankyzy
- Department of Biomedical Sciences, School of Medicine, Nazarbayaev University, Astana, 010000, Kazakhstan
| | - Sholpan Nurzhan
- Department of Biomedical Sciences, School of Medicine, Nazarbayaev University, Astana, 010000, Kazakhstan
| | - Nurken Berdigaliyev
- Department of Biomedical Sciences, School of Medicine, Nazarbayaev University, Astana, 010000, Kazakhstan
| | - Shynggys Sergazy
- National Laboratory Astana, Nazarbayev University, Astana, 010000, Kazakhstan
| | - Tilektes Maulenkul
- Khoja Akhmet Yassawi International Kazakh-Turkish University, Turkistan, 161211, Turkistan, Kazakhstan
| | - Mohamad Aljofan
- Department of Biomedical Sciences, School of Medicine, Nazarbayaev University, Astana, 010000, Kazakhstan
- National Laboratory Astana, Nazarbayev University, Astana, 010000, Kazakhstan
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Efficient one-pot synthesis of arylated pyrazole-fused pyran analogs: as leads to treating diabetes and Alzheimer's disease. Future Med Chem 2022; 14:1507-1526. [PMID: 36268762 DOI: 10.4155/fmc-2022-0103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: To discover novel lead molecules against diabetes, Alzheimer's disease and oxidative stress, a library of arylated pyrazole-fused pyran derivatives, 1-20, were synthesized in a one-pot reaction. Materials & methods:1H-NMR spectroscopic and electron ionization mass spectrometry techniques were used to characterize the synthetic hybrid molecules 1-20. Analogs were screened against four indispensable therapeutic targets, including α-amylase, α-glucosidase, acetylcholinesterase and butyrylcholinesterase enzymes. Results: Except for derivatives 17 and 18, all other compounds exhibited varying degrees of inhibitory activities against target enzymes. The kinetic studies revealed that the synthetic molecules followed a competitive-type mode of inhibition for α-amylase and acetylcholinesterase enzymes, as well as a non-competitive mode of inhibition for α-glucosidase and butyrylcholinesterase enzymes. In addition, molecular docking studies identified crucial binding interactions of ligands with the enzyme's active site. Conclusion: These molecules may serve as a potential drug candidate to cure diabetes, Alzheimer's disease and oxidative stress in the future.
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Zhao W, Chen C, Zhou J, Chen X, Cai K, Shen M, Chen X, Jiang L, Wang G. Inhibition of Autophagy Promotes the Anti-Tumor Effect of Metformin in Oral Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14174185. [PMID: 36077722 PMCID: PMC9454503 DOI: 10.3390/cancers14174185] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022] Open
Abstract
Oral Squamous Cell Carcinoma (OSCC) is the most common malignant tumor in the head and neck. Due to its high malignancy and easy recurrence, the five-year survival rate is only 50–60%. Currently, commonly used chemotherapy drugs for OSCC include cisplatin, paclitaxel, and fluorouracil, which are highly cytotoxic and cause drug resistance in patients. Therefore, a safe and effective treatment strategy for OSCC is urgent. To address this issue, our study investigated the anti-tumor activity of metformin (the first-line diabetes drug) in OSCC. We found that metformin could inhibit OSCC cell proliferation by promoting apoptosis and blocking the cell cycle in G1 phase. Additionally, we also found that metformin could induce protective autophagy of OSCC cells. After inhibiting autophagy with hydroxychloroquine (HCQ), the metformin-induced apoptosis was enhanced. In vitro, metformin inhibited the growth of subcutaneous xenograft tumor in nude mice and HCQ enhanced this effect of metformin. Therefore, metformin combined with HCQ may become a safe and effective treatment strategy for OSCC.
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Affiliation(s)
- Wei Zhao
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Chen Chen
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jianjun Zhou
- Department of Stomatology, 900 Hospital of the Joint Logistics Team, Fuzhou 350025, China
| | - Xiaoqing Chen
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Kuan Cai
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Miaomiao Shen
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xuan Chen
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Lei Jiang
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Guodong Wang
- Department of Stomatology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
- Correspondence:
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The insulin sensitivity Mcauley index (MCAi) is associated with 40-year cancer mortality in a cohort of men and women free of diabetes at baseline. PLoS One 2022; 17:e0272437. [PMID: 35921366 PMCID: PMC9348742 DOI: 10.1371/journal.pone.0272437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 07/19/2022] [Indexed: 12/24/2022] Open
Abstract
Background The association between insulin resistance and cancer-mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer-mortality over 3.5 decades in a cohort of adult men and women. We hypothesized that higher insulin resistance will be associated with greater cancer-mortality risk. Methods A cohort of 1,612 men and women free of diabetes during baseline were followed since 1979 through 2016 according to level of insulin resistance (IR) for cause specific mortality, as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). IR was defined according to the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, the Homeostatic Model Assessment (HOMA), the Matsuda Insulin Sensitivity Index (MISI), and the Quantitative Insulin Sensitivity Check Index (QUICKI), calculated by plasma glucose and insulin. Results Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status, revealed an increased risk for cancer-mortality, HR = 1.5 (95% CI: 1.1–2.0, p = 0.005) for the MCAi Q1 compared with Q2-4. No statistically significant associations were observed between the other ISIs and cancer-mortality. Conclusion The MCAi was independently associated with an increased risk for cancer-mortality in adult men and women free of diabetes and should be further studied as an early biomarker for cancer risk.
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The effect of metformin on the survival of colorectal cancer patients with type 2 diabetes mellitus. Sci Rep 2022; 12:12374. [PMID: 35859114 PMCID: PMC9300732 DOI: 10.1038/s41598-022-16677-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 07/13/2022] [Indexed: 11/23/2022] Open
Abstract
Evidence from previous studies suggests a protective effect of metformin in patients with colorectal cancer (CRC). The aim of this study was to examine the associations between metformin use and overall survival (OS) and disease-free survival (DFS) in CRC patients with type 2 diabetes mellitus (DM). We retrospectively included patients who underwent surgery for CRC at Limoges’ University Hospital between 2005 and 2019 and diagnosed with type 2 DM. Data on the characteristics of patients, CRC, comorbidities and drug exposure were collected from the electronic medical records. The exposure was the use of metformin and the outcomes were OS and DFS. We identified 290 CRC patients with type 2 DM. A total of 144 (49.7%) of them were treated with metformin. Metformin users were significantly younger, with higher body mass index and less diabetes-related complications compared to non-users. The 2-year OS was significantly higher in metformin users than in non-users (86.9 ± 2.9% vs. 71.0 ± 4.0%, p = 0.001). In multivariate analysis, metformin use was associated with better OS (adjusted hazard ratios [aHR] = 0.45 95% confidence interval [95% CI]: 0.21–0.96) and better DFS (aHR = 0.31; 95% CI: 0.18–0.54). In conclusion, the use of metformin may improve OS and DFS in CRC patients with type 2 DM.
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Barakat HE, Hussein RRS, Elberry AA, Zaki MA, Elsherbiny Ramadan M. Factors influencing the anticancer effects of metformin on breast cancer outcomes: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2022; 22:415-436. [PMID: 35259320 DOI: 10.1080/14737140.2022.2051482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Several clinical trials have attempted to find evidence that supports the use of metformin as an anticancer treatment. However, the observed effects on various breast cancer (BC) outcomes have been heterogeneous. AREAS COVERED Based on the outcomes of previous clinical trials, this review discusses the patients' characteristics, cancer intrinsic subtypes, cancer stage, and anticancer treatments that may influence the anticancer effect of metformin on BC outcomes. Additionally, the safety and tolerability of metformin addition to various anticancer regimens are reviewed. EXPERT OPINION Metformin is a challenging anticancer agent in BC cohorts, besides being safe and well-tolerated at antidiabetic doses. Survival benefits of metformin have been observed in BC patients with: hormone receptor-positive, human epidermal growth factor receptor-2 overexpression, and high insulin like growth factor-1 receptor expression on the tumor surface. Moreover, patients with diabetes receiving metformin experienced better survival outcomes compared to diabetic patients not receiving metformin. Additionally, metformin has anti-proliferative activity in patients with BC who have high insulin resistance and high body mass index. Besides, metformin has been shown to decrease metastatic events, and enhance the level of metabolic- and insulin-related biomarkers associated with carcinogenesis. Finally, most adverse events following metformin treatment were low-grade GIT toxicities.
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Kushchayeva Y, Kushchayev S, Jensen K, Brown RJ. Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer. Cancers (Basel) 2022; 14:cancers14030555. [PMID: 35158824 PMCID: PMC8833385 DOI: 10.3390/cancers14030555] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary An epidemiologic link exists between obesity, insulin resistance, diabetes, and some cancers, such as breast cancer and colon cancer. The prevalence of obesity and diabetes is increasing, and additional epidemiologic data suggest that there may be a link between obesity and risk of thyroid abnormalities. Factors that may link obesity and diabetes with thyroid proliferative disorders include elevated circulating levels of insulin, increased body fat, high blood sugars, and exogenous insulin use. However, mechanisms underlying associations of obesity, diabetes, and thyroid proliferative disorders are not yet fully understood. The present manuscript reviews and summarizes current evidence of mechanisms and epidemiologic associations of obesity, insulin resistance, and use of anti-diabetes medications with benign and malignant proliferative disorders of the thyroid. Abstract The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.
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Affiliation(s)
- Yevgeniya Kushchayeva
- Diabetes and Endocrinology Center, University of South Florida, Tampa, FL 33612, USA
- Correspondence:
| | - Sergiy Kushchayev
- Department of Radiology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Kirk Jensen
- F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA;
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;
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Sumbly V, Landry I. Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer. Cureus 2022; 14:e21078. [PMID: 35165542 PMCID: PMC8826623 DOI: 10.7759/cureus.21078] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 12/25/2022] Open
Abstract
There are two major groups of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLCs can be further separated into three different categories: lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Pulmonary adenocarcinomas represent nearly half of all lung cancer cases and are known to be caused by smoking, certain occupational exposures, and specific genetic mutations. Scientists have noticed that most NSCLCs are driven by defects in the following genes: EGFR, BRAF, ALK, MET, and HER. Abnormalities in the STK11/LKB1 gene have also been shown to induce lung adenocarcinoma. LKB1-deficient cancer cells contain an overactive AMPK “energy sensor,” which inhibits cellular death and promotes glucose, lipid, and protein synthesis via the mTOR protein complex. Studies have also discovered that the loss of STK11/LKB1 favors oncogenesis by creating an immunosuppressive environment for tumors to grow and accelerate events such as angiogenesis, epithelial-mesenchymal transition (EMT), and cell polarity destabilization. STK11/LKB1-mutant lung cancers are currently treated with radiotherapy with or without chemotherapy. Recent clinical trials studying the effects of glutaminase inhibitors, mTOR inhibitors, and anti-PD-L1 therapy in lung cancer patients have yielded promising results. This narrative review provides an overview of the STK11/LKB1 gene and its role in cancer development. Additionally, a summary of the LKB1/APMK/mTOR is provided.
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Affiliation(s)
- Vikram Sumbly
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals/Queens, Jamaica, USA
| | - Ian Landry
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals/Queens, Jamaica, USA
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Meerson A, Khatib S, Mahajna J. Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics. Int J Mol Sci 2021; 22:ijms222313044. [PMID: 34884848 PMCID: PMC8657727 DOI: 10.3390/ijms222313044] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/28/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor's resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.
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Affiliation(s)
- Ari Meerson
- Department of Natural Products and Nutrition, MIGAL—Galilee Research Institute, Kiryat Shmona 11016, Israel; (A.M.); (S.K.)
- Faculty of Sciences, Tel Hai Academic College, Qiryat Shemona 12208, Israel
| | - Soliman Khatib
- Department of Natural Products and Nutrition, MIGAL—Galilee Research Institute, Kiryat Shmona 11016, Israel; (A.M.); (S.K.)
- Faculty of Sciences, Tel Hai Academic College, Qiryat Shemona 12208, Israel
| | - Jamal Mahajna
- Department of Natural Products and Nutrition, MIGAL—Galilee Research Institute, Kiryat Shmona 11016, Israel; (A.M.); (S.K.)
- Faculty of Sciences, Tel Hai Academic College, Qiryat Shemona 12208, Israel
- Correspondence:
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Fontana F, Limonta P. The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer. Free Radic Biol Med 2021; 176:203-221. [PMID: 34597798 DOI: 10.1016/j.freeradbiomed.2021.09.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 12/15/2022]
Abstract
Mitochondria are the cytoplasmic organelles mostly known as the "electric engine" of the cells; however, they also play pivotal roles in different biological processes, such as cell growth/apoptosis, Ca2+ and redox homeostasis, and cell stemness. In cancer cells, mitochondria undergo peculiar functional and structural dynamics involved in the survival/death fate of the cell. Cancer cells use glycolysis to support macromolecular biosynthesis and energy production ("Warburg effect"); however, mitochondrial OXPHOS has been shown to be still active during carcinogenesis and even exacerbated in drug-resistant and stem cancer cells. This metabolic rewiring is associated with mutations in genes encoding mitochondrial metabolic enzymes ("oncometabolites"), alterations of ROS production and redox biology, and a fine-tuned balance between anti-/proapoptotic proteins. In cancer cells, mitochondria also experience dynamic alterations from the structural point of view undergoing coordinated cycles of biogenesis, fusion/fission and mitophagy, and physically communicating with the endoplasmic reticulum (ER), through the Ca2+ flux, at the MAM (mitochondria-associated membranes) levels. This review addresses the peculiar mitochondrial metabolic and structural dynamics occurring in cancer cells and their role in coordinating the balance between cell survival and death. The role of mitochondrial dynamics as effective biomarkers of tumor progression and promising targets for anticancer strategies is also discussed.
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Affiliation(s)
- Fabrizio Fontana
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milano, Italy.
| | - Patrizia Limonta
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milano, Italy.
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Tully E, Bharti S, Woo J, Bhujwalla Z, Gabrielson E. Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells. Cancer Biol Ther 2021; 22:579-586. [PMID: 34720054 DOI: 10.1080/15384047.2021.1982599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Biguanide drugs (metformin and phenformin) have drawn interest for potential cancer treatments, and laboratory studies show that some cancer cells are selectively sensitive to growth-inhibitory effects of biguanides. Examining metabolic pathways affected by biguanide treatments in cancer cells that are highly sensitive to biguanides, we found that biguanide treatment depletes cellular levels of both aspartate and NAD+. Experiments to replenish these metabolites or block steps of the aspartate-malate shuttle suggest that depletion of both metabolites, rather than either aspartate of NAD+ individually, is critical for growth-inhibitory effects of biguanide exposure. Even in sensitive cancer cells, though, biguanide treatment alone over a broad range of doses only inhibits cell replication without significantly affecting cell viability. Noting that clinical observations of biguanide efficacy have used combinations of agents that typically include cisplatin, we found that biguanide treatment at a cytostatic level substantially decreases survival of lung cancer and breast cancer cells when co-treated with cisplatin at doses that alone are also non-cytotoxic. This striking enhancement of cisplatin toxicity by biguanides depends on reductions of levels of NAD+ and aspartate, since addition of either of these metabolites prevented this potentiation of cisplatin cytotoxicity. Thus, biguanide drugs can have cytotoxic effects when used in combination with other cancer drugs, such as cisplatin, and depleting cellular levels of NAD+ and aspartate is critical for enhancing the cytotoxicity of cisplatin by biguanide drugs in sensitive cancer cells.
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Affiliation(s)
- Ellen Tully
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Santosh Bharti
- The Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Juhyung Woo
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zaver Bhujwalla
- The Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Department of Oncology and the Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward Gabrielson
- The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Department of Oncology and the Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Kumar Das B, Gadad PC. Impact of diabetes on the increased risk of hepatic cancer: An updated review of biological aspects. DIABETES EPIDEMIOLOGY AND MANAGEMENT 2021; 4:100025. [DOI: 10.1016/j.deman.2021.100025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Roque DR, Zhang L, Wysham WZ, Han J, Sun W, Yin Y, Livingston JN, Batchelor KW, Zhou C, Bae-Jump VL. The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth. Front Oncol 2021; 11:690435. [PMID: 34422646 PMCID: PMC8377676 DOI: 10.3389/fonc.2021.690435] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/19/2021] [Indexed: 01/14/2023] Open
Abstract
Objectives Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model. Methods Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks. Results NT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 μM for Ishikawa; 87 μM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice. Conclusions NT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.
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Affiliation(s)
- Dario R Roque
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Lu Zhang
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Weiya Z Wysham
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jianjun Han
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wenchuan Sun
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Yajie Yin
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - James N Livingston
- NovaTarg Therapeutics, First Flight Venture Center, Durham, NC, United States
| | - Ken W Batchelor
- NovaTarg Therapeutics, First Flight Venture Center, Durham, NC, United States
| | - Chunxiao Zhou
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Victoria L Bae-Jump
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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16
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Liao YP, Kung PT, Wang YH, Chu YR, Kao ST, Tsai WC. Effects and Relative Factors of Adjunctive Chinese Medicine Therapy on Survival of Hepatocellular Carcinoma Patients: A Retrospective Cohort Study in Taiwan. Integr Cancer Ther 2021; 19:1534735420915275. [PMID: 32552053 PMCID: PMC7307484 DOI: 10.1177/1534735420915275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Some patients with cancer use adjunctive Chinese medicine, which might improve
the quality of life. This study aims to investigate the effects and relative
factors of adjunctive Chinese medicine on survival of hepatocellular carcinoma
patients at different stages. The study population was 23 581 newly diagnosed
hepatocellular carcinoma patients and received surgery from 2004 to 2010 in
Taiwan. After propensity score matching with a ratio of 1:10, this study
included 1339 hepatocellular carcinoma patients who used adjunctive Chinese
medicine and 13 390 hepatocellular carcinoma patients who used only Western
medicine treatment. All patients were observed until the end of 2012.
Kaplan-Meier method and Cox proportional hazards model was applied to find the
relative risk of death between these 2 groups. The study results show that the
relative risk of death was lower for patients with adjunctive Chinese medicine
treatment than patients with only Western medicine treatment (hazard ratio =
0.68; 95% confidence interval = 0.62-0.74). The survival rates of patients with
adjunctive Chinese medicine or Western medicine treatment were as follows:
1-year survival rate: 83% versus 72%; 3-year survival rate: 53% versus 44%; and
5-year survival rate: 40% versus 31%. The factors associated with survival of
hepatocellular carcinoma patients included treatment, demographic
characteristics, cancer stage, health status, physician characteristics, and
characteristics of primary medical institution. Moreover, stage I and stage II
hepatocellular carcinoma patients had better survival outcome than stage III
patients by using adjunctive Chinese medicine therapy. The effect of adjunctive
Chinese medicine was better on early-stage disease.
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Affiliation(s)
- Yu-Pei Liao
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Pei-Tseng Kung
- Department of Healthcare Administration, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yueh-Hsin Wang
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Yeong-Ruey Chu
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Shung-Te Kao
- Department of Chinese Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Wen-Chen Tsai
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
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17
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The relationship between rice consumption and glioma: a case-control study in adults. Sci Rep 2021; 11:6073. [PMID: 33727597 PMCID: PMC7971041 DOI: 10.1038/s41598-021-85562-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 03/03/2021] [Indexed: 12/07/2022] Open
Abstract
Previous studies have shown the effect of refined grains on various cancers; however, data on the link between rice consumption and brain cancer are scarce. We aimed to investigate the relationship between rice consumption and glioma in Iranian adults. Current hospital-based case–control study was done in Tehran between 2009 and 2011. Cases were individuals with pathologically confirmed glioma in a maximally 1 month of the disease diagnosis (n = 128). Controls were individuals, aged between 20 and 75 years, who were hospitalized or were outpatients referred to other wards of the same hospital (n = 256). Cases and controls were frequently matched in terms of age and gender. Usual dietary intakes of participants, including rice consumption, during the preceding year were examined using a Block-format validated semi-quantitative 126-item food frequency questionnaire. Compared with participants in the lowest tertile of rice consumption (< 181 g/day), those in the highest tertile (≥ 279 g/day) had 2.47 times greater chance for having glioma (OR: 2.47, 95% CI 1.44–4.23). This relationship was also seen when potential confounders including demographic variables, energy and dietary intakes as well as body mass index were taking into account; such that individuals in the top tertile of rice consumption had 2.46 times greater odds of glioma compared with those in the bottom tertile (OR: 2.46, 95% CI 1.01–5.97). We found that rice consumption was positively associated with risk of glioma in adults. Further prospective studies are required to confirm this finding.
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18
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Babatunde O, Hameed S, Salar U, Chigurupati S, Wadood A, Rehman AU, Venugopal V, Khan KM, Taha M, Perveen S. Dihydroquinazolin-4(1H)-one derivatives as novel and potential leads for diabetic management. Mol Divers 2021; 26:849-868. [PMID: 33650031 DOI: 10.1007/s11030-021-10196-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 02/05/2021] [Indexed: 11/25/2022]
Abstract
A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 μM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 μM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 μM for α-amylase and IC50 = 17.67 ± 0.09 μM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.
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Affiliation(s)
- Oluwatoyin Babatunde
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
- Department of Chemical Sciences, Ajayi Crowther University, Oyo, P.M.B 1066, Nigeria
| | - Shehryar Hameed
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Uzma Salar
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah, 52571, Saudi Arabia
| | - Abdul Wadood
- Department of Biochemistry, Computational Medicinal Chemistry Laboratory, UCSS, Abdul Wali Khan University, Mardan, Pakistan
| | - Ashfaq Ur Rehman
- Department of Biochemistry, Computational Medicinal Chemistry Laboratory, UCSS, Abdul Wali Khan University, Mardan, Pakistan
| | | | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
- Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia.
| | - Muhammad Taha
- Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia
| | - Shahnaz Perveen
- PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, 75280, Pakistan
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Durrer C, McKelvey S, Singer J, Batterham AM, Johnson JD, Wortman J, Little JP. Pharmacist-led therapeutic carbohydrate restriction as a treatment strategy for type 2 diabetes: the Pharm-TCR randomized controlled trial protocol. Trials 2019; 20:781. [PMID: 31881991 PMCID: PMC6935079 DOI: 10.1186/s13063-019-3873-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/02/2019] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND The current treatment paradigm for type 2 diabetes mellitus (T2D) typically involves use of multiple medications to lower glucose levels in hope of reducing long-term complications. However, such treatment does not necessarily address the underlying pathophysiology of the disease and very few patients achieve partial, complete, or prolonged remission of T2D after diagnosis. The therapeutic potential of nutrition has been highlighted recently based on results of clinical trials reporting remission of T2D with targeted dietary approaches. During the initial phase of such interventions that restrict carbohydrates and/or induce rapid weight loss, hypoglycemia presents a notable risk to patients. We therefore hypothesized that delivering very low-carbohydrate, low-calorie therapeutic nutrition through community pharmacies would be an innovative strategy to facilitate lowering of glycated hemoglobin (A1C) while safely reducing the use of glucose-lowering medications in T2D. METHODS A community-based randomized controlled trial that is pragmatic in nature, following a parallel-group design will be conducted (N = 200). Participants will have an equal chance of being randomized to either a pharmacist-led, therapeutic carbohydrate restricted (Pharm-TCR) diet or guideline-based treatment as usual (TAU). Pharm-TCR involves a 12-week very low carbohydrate, calorie-restricted commercial diet plan led by pharmacists and lifestyle coaches with pharmacists responsible for managing medications in collaboration with the participants' family physicians. Main inclusion criteria are diagnosis of T2D, currently treated with glucose-lowering medications, age 30-75 years, and body mass index ≥ 30. The primary outcome is a binary measure of use of glucose-lowering medication. Secondary outcomes include A1C, anthropometrics and clinical blood markers. DISCUSSION There are inherent risks involved if patients with T2D who take glucose-lowering medications follow very low carbohydrate diets. This randomized controlled trial aims to determine whether engaging community pharmacists is a safe and effective way to deliver therapeutic carbohydrate restriction and reduce/eliminate the need for glucose-lowering medications in people with T2D. TRIAL REGISTRATION ClinicalTrials.gov, NCT03181165. Registered on 8 June 2017.
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Affiliation(s)
- Cody Durrer
- School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, V1V 1V7, Canada
| | - Sean McKelvey
- Institute for Personalized Therapeutic Nutrition, Vancouver, BC, Canada
| | - Joel Singer
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Alan M Batterham
- Centre for Rehabilitation, Exercise and Sports Science, Teesside University, Middlesbrough, UK
| | - James D Johnson
- Diabetes Research Group, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jay Wortman
- Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Jonathan P Little
- School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, V1V 1V7, Canada.
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20
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Mejia JF, Hirschi KM, Tsai KYF, Long MG, Tullis BC, Bitter EEK, Bikman BT, Reynolds PR, Arroyo JA. Differential placental ceramide levels during gestational diabetes mellitus (GDM). Reprod Biol Endocrinol 2019; 17:81. [PMID: 31647034 PMCID: PMC6813062 DOI: 10.1186/s12958-019-0523-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 09/10/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is associated with important factors that influence fetal development. Sphingolipids are known to be associated with the development of diabetes. Our objective was to examine ceramide, a key sphingolipid, hyperosmolarity, and apoptosis in placentas from GDM patients treated with insulin or diet. METHODS Ceramide levels were assessed in placental tissues using immunohistochemistry. Immunoblot was performed to quantify serine palmitoyltransferase (SPT), the rate-limiting enzyme in ceramide biosynthesis, NFAT5, SMIT, AR, caspase 3 and the X-linked inhibitor of apoptosis. Trophoblast cells were treated with insulin or ceramide and assessments for mitochondrial respiration, caspase 3 and XIAP were also performed. RESULTS Immunohistochemistry showed increased ceramides in the placental villous trophoblasts of the insulin-treated GDM patients. Nuclear SPT was upregulated only in the insulin-treated GDM placenta when compared to controls. Nuclear NFAT5 was also increased in the GDM placenta. Active caspase 3 was elevated in placentas from both insulin- and diet-treated GDM patients. Mitochondrial respiration was decreased in trophoblasts treated with ceramide. Active caspase was not changed while XIAP protein was increased in trophoblasts treated with ceramide. CONCLUSIONS Our findings confirm the presence of ceramide in the human placenta of control and GDM patients. Furthermore, we conclude that ceramide is increased in the placental trophoblast during insulin treatment and that its upregulation correlates with elevated NFAT5, SMIT, increased apoptosis and decreased trophoblast mitochondrial respiration.
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Affiliation(s)
- Juan F Mejia
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Kelsey M Hirschi
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Kary Y F Tsai
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Matthew G Long
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Benton C Tullis
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Eliza E K Bitter
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA
| | - Benjamin T Bikman
- Department of Physiology and Developmental Biology, Metabolism Research Laboratory, Brigham Young University, Provo, UT, USA
| | - Paul R Reynolds
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA
| | - Juan A Arroyo
- Department of Physiology and Developmental Biology, Lung and Placenta Research Laboratory, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA.
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Yang C, Zhao N, Li D, Zou G, Chen Y. Metformin improves the sensitivity of ovarian cancer cells to chemotherapeutic agents. Oncol Lett 2019; 18:2404-2411. [PMID: 31402943 PMCID: PMC6676676 DOI: 10.3892/ol.2019.10564] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 06/11/2019] [Indexed: 01/22/2023] Open
Abstract
Ovarian cancer is a common tumor of the reproductive system, and primarily responds to cytoreductive surgery and cisplatin (DDP)-based chemotherapy. However, chemoresistance results in high ovarian cancer mortality. Therefore, the aim of the present study was to investigate the effects of metformin on the apoptosis and autophagy of ovarian cancer drug-resistant SKOV3/DDP cells. To do so, MTT assay, flow cytometry, electron microscopy and western blotting were used in the present study. Metformin could inhibit the growth of SKOV3 and SKOV3/DDP cells in a concentration- and time-dependent manner (P<0.05). The half-inhibitory concentration (IC50) values of DDP and methotrexate (MTX) were 14.35 and 4.21 µg/ml for SKOV3 cells, and 70.26 and 15.27 µg/ml for SKOV3/DDP cells, respectively. In addition, the resistance index of SKOV3/DDP for DDP and MTX was 4.89 and 3.62, respectively. After combining metformin with DDP and MTX, the IC50 values for SKOV3 cells were 11.20 and 2.80 µg/ml, and 6.21 and 2.74 µg/ml for SKOV3/DDP cells, respectively. Metformin decreased the IC50 of DDP and MTX in drug-resistant cancer cells SKOV3/DDP by 11.31- and 6.18-fold. This indicated that cell proliferation was inhibited when treated with the combination of metformin and chemotherapeutic agents, compared with chemotherapeutic agents alone. In addition, autophagy was not observed in SKOV3 and SKOV3/DDP cells; however, it was observed in SKOV3/DDP cells following incubation with 10 mmol/l metformin for 48 h. Furthermore, the expression levels of microtubule-associated protein 1 light chain 3-II protein in SKOV3/DDP cells were upregulated compared with in SKOV3 cells (P<0.05). These results demonstrated that metformin can sensitize drug-resistant ovarian cancer cells to chemotherapeutic agents, and that it may be associated with the induction of autophagy.
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Affiliation(s)
- Chen Yang
- School of Medicine, Tsinghua University, Beijing 100084, P.R. China
| | - Nanan Zhao
- Department of Obstetrics and Gynecology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Dandan Li
- Department of Obstetrics and Gynecology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Ge Zou
- Department of Obstetrics and Gynecology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
| | - Yan Chen
- Department of Obstetrics and Gynecology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China
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23
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Parikh AB, Marrone KA, Becker DJ, Brahmer JR, Ettinger DS, Levy BP. A pooled analysis of two phase II trials evaluating metformin plus platinum-based chemotherapy in advanced non-small cell lung cancer. Cancer Treat Res Commun 2019; 20:100150. [PMID: 31102920 DOI: 10.1016/j.ctarc.2019.100150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Despite a wealth of preclinical and observational data, prospective data regarding the use of metformin in lung cancer is extremely limited. METHODS We pooled individualized data from two prospective trials evaluating metformin plus platinum-based chemotherapy, with or without bevacizumab, in non-diabetic patients with untreated advanced NSCLC. In addition to reporting on clinical efficacy and safety endpoints, we also explored metformin's activity in key molecular cohorts. RESULTS 33 patients were included in the pooled analysis, of whom 70% were current or previous smokers. 82% had standard tissue molecular testing results available. KRAS, EGFR, and LKB1 mutation prevalence was 48%, 26%, and 8.3%, respectively. Composite median PFS was 6 months for all patients (95% CI: [1.36, 7.96]), 7.2 months for KRAS mutants (95% CI: [1.18, 9.21]), and 6.6 months for EGFR mutants (95% CI: [1.18, 15.29]). Composite median OS was 14.8 months for all patients (95% CI: [8.25, 19.99]), 17.5 months for KRAS mutants (95% CI: [8.86, 26.96]), and 13.3 months for EGFR mutants (95% CI: [2.60, 25.86]). Lymphopenia was the most common grade 3 AE (12%), followed by leukopenia, nausea, vomiting, and hypertension (9% each). There were 2 grade 4 AEs, neutropenia (21%) and sepsis (3%), and 1 grade 5 AE (colonic perforation) attributed to bevacizumab. CONCLUSION Our results confirm the previously shown efficacy and tolerability of metformin in combination with chemotherapy and highlight encouraging activity in key molecular cohorts. Future efforts should build on this work by prospectively studying metformin in these molecular subgroups.
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Affiliation(s)
- Anish B Parikh
- Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY, USA.
| | - Kristen A Marrone
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Daniel J Becker
- Manhattan Veterans Association Hospital, NYU Langone Perlmutter Cancer Center, New York, NY, USA
| | - Julie R Brahmer
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - David S Ettinger
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Benjamin P Levy
- Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, Washington, DC, USA
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Shafaee A, Pirayesh Islamian J, Zarei D, Mohammadi M, Nejati-Koshki K, Farajollahi A, Aghamiri SMR, Rahmati Yamchi M, Baradaran B, Asghari Jafarabadi M. Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism. IRANIAN JOURNAL OF MEDICAL SCIENCES 2019; 44:99-107. [PMID: 30936596 PMCID: PMC6423430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND Both mitochondrial dysfunction and aerobic glycolysis are signs of growing aggressive cancer. If altered metabolism of cancer cell is intended, using the glycolysis inhibitor (2-deoxyglucose (2DG)) would be a viable therapeutic method. The AMP-activated protein kinase (AMPK), as a metabolic sensor, could be activated with metformin and it can also launch a p53-dependent metabolic checkpoint and might inhibit cancer cell growth. METHODS After treatment with 5 mM metformin and/or 500 µM 2DG, the TE1, TE8, and TE11 cellular viability and apoptosis were assessed by MTT, TUNEL, and ELISA methods. The changes in p53 and Bcl-2 genes expression levels were examined using real-time PCR method. Data were analyzed by Kruskal-Wallis test using the SPSS 17.0 software. RESULTS Metformin and 2DG, alone and in combination, induced apoptosis in the cell lines. Real-time PCR revealed that metformin induced apoptosis in TE8 and TE11 cells by activating p53, down-regulating Bcl-2 expression. The induced apoptosis by 2DG raised by metformin and the combination modulated the expression of Bcl-2 protein in all cell lines and it was more effective in TE11 cell line. CONCLUSION Metformin induced apoptosis in ESCC by down-regulating Bcl-2 expression, and up-regulating p53 and induced apoptosis increased by 2-deoxy-d-glucose. Thus, the combination therapy is an effective therapeutic strategy for esophageal squamous cell carcinoma.
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Affiliation(s)
- Abbas Shafaee
- Department of Radiology-Faculty of Paramedicine- Tabriz University of Medical Sciences, Tabriz, Iran;
| | - Jalil Pirayesh Islamian
- Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;
| | - Davoud Zarei
- Department of Medical Radiation Science, School of Paramedicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Mohsen Mohammadi
- Department of Medical Radiation Science, School of Paramedicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Kazem Nejati-Koshki
- Department of Medical Biotechnology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran;
| | - Alireza Farajollahi
- Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;
| | - Seyed Mahmoud Reza Aghamiri
- Department of Radiation Medicine, Faculty of Nuclear Engineering, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Mohammad Rahmati Yamchi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;
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Kwon YS, Chun SY, Nan HY, Nam KS, Lee C, Kim S. Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways. Oncol Lett 2018; 17:2523-2530. [PMID: 30675314 DOI: 10.3892/ol.2018.9827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023] Open
Abstract
Recent studies have reported that metformin (Met), the first-line medication for the treatment of type 2 diabetes, exhibited anticancer and chemoprotective effects in diverse cancer cells. In this study, we investigated the effects of Met on the drug-resistance of 4T1 murine breast cancer tumorspheres (TS) and the mechanism responsible for its drug-resistance. 4T1 TS exhibited accumulations of cells at the G0/G1 phase compared with cells in monolayer culture, which suggested the majority of cells in TS were quiescent. Furthermore, it was identified that activations of the signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT) signaling pathways in 4T1 TS conferred drug-resistance to doxorubicin (Dox) and lapatinib (Lapa). However, Met selectively targeted TS rather than cells in monolayer culture and increased the cytotoxic effect of Dox on TS by inhibiting activations of the STAT3 and AKT signaling pathways. These observations suggested that inhibitions of STAT3 and AKT underlie the selective cytotoxic effects of Met on TS. In addition, Met exhibited synergistic antitumor effects with Dox on 4T1 tumor-bearing BALB/c mice. Our findings suggest that combinations of Met and cytotoxic anticancer drugs may offer an advantage for treating drug-resistant breast cancer.
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Affiliation(s)
- Yun-Suk Kwon
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - So-Young Chun
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - Hong-Yan Nan
- Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Kyung-Soo Nam
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
| | - Chuhee Lee
- Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Soyoung Kim
- Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk University, Gyeongju, Gyeongsangbuk-do 380660, Republic of Korea
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Kellam H, Yim KL. Exploring the bi-directional relationship between pancreatic cancer and diabetes mellitus: a retrospective study. J Diabetes Metab Disord 2018; 17:247-252. [PMID: 30918860 DOI: 10.1007/s40200-018-0366-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/01/2018] [Indexed: 12/16/2022]
Abstract
Objective To explore the bi-directional between pancreatic cancer (PC) and diabetes mellitus (DM); focusing on the prevalence, temporal association and impact on survival outcomes. Methods A retrospective audit of pancreatic cancer patients from the institutional clinical database (CaNISC) between January 2012 and April 2018. Results A total of 131 patients were analysed, 58 patients carried a diagnosis of diabetes mellitus. The median overall survival for diabetes mellitus patients was 12.0 months (95 CI, 5.9 to 18.1 months) in comparison to 13.0 months (95% CI, 8.6 to 17.3 months) in non-diabetes mellitus patients (p = 0.334). Conclusion There was no significant difference in the overall survival between DM and non-DM patients.
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Amin S, Lux A, O'Callaghan F. The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth. Br J Clin Pharmacol 2018; 85:37-46. [PMID: 30290005 DOI: 10.1111/bcp.13780] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 09/26/2018] [Accepted: 10/01/2018] [Indexed: 12/19/2022] Open
Abstract
Our knowledge of the effect of metformin on human health is increasing. In addition to its ability to improve the control of hyperglycaemia, metformin has been shown to reduce the burden o,f ageing via effects on damaged DNA and the process of apoptosis. Studies have shown that metformin may reduce the risk of cardiovascular disease through influences on body weight, blood pressure, cholesterol levels and the progression of atherosclerosis. Studies also suggest that metformin may be beneficial for neuro-psychiatric disorders, cognitive impairment and in reducing the risk of dementia, erectile dysfunction and Duchenne muscular dystrophy. In vivo and in vitro studies have shown that metformin has anti-cancer properties, and population studies have suggested that metformin may reduce the risk of cancer or improve cancer prognosis. It is thought that it exerts its anti-cancer effect through the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. Because of its effect on the mTOR pathway, there may be a role for metformin in slowing or reversing growth of life-threatening hamartomas in tuberous sclerosis complex.
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Affiliation(s)
- Sam Amin
- Paediatric Neurologist, University Hospitals Bristol, Upper Maudlin Street Centre Level 6, Bristol, BS28AE, UK
| | - Andrew Lux
- Paediatric Neurologist, University Hospitals Bristol, Upper Maudlin Street Centre Level 6, Bristol, BS28AE, UK
| | - Finbar O'Callaghan
- Institute of Child Health, University College London, London, WC1N 1EH, UK
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Chittepu VCSR, Kalhotra P, Gallardo-Velázquez T, Robles-de la Torre RR, Osorio-Revilla G. Designed Functional Dispersion for Insulin Protection from Pepsin Degradation and Skeletal Muscle Cell Proliferation: In Silico and In Vitro Study. NANOMATERIALS (BASEL, SWITZERLAND) 2018; 8:E852. [PMID: 30347680 PMCID: PMC6215209 DOI: 10.3390/nano8100852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/12/2018] [Accepted: 10/17/2018] [Indexed: 12/25/2022]
Abstract
Functionalized single-walled carbon nanotubes with polyethylene glycol (PEGylated SWCNTs) are a promising nanomaterial that recently has emerged as the most attractive "cargo" to deliver chemicals, peptides, DNA and RNAs into cells. Insulin therapy is a recommended therapy to treat diabetes mellitus despite its side effects. Recently, functional dispersion made up of bioactive peptides, bioactive compounds and functionalized carbon nanomaterials such as PEGylated SWCNTs have proved to possess promising applications in nanomedicine. In the present study, molecular modeling simulations are utilized to assist in designing insulin hormone-PEGylated SWCNT composites, also called functional dispersion; to achieve this experimentally, an ultrasonication tool was utilized. Enzymatic degradation assay revealed that the designed functional dispersion protects about 70% of free insulin from pepsin. In addition, sulforhodamine B (SRB) assay, the quantification of insulin and glucose levels in differentiated skeletal muscle cell supernatants, reveals that functional dispersion regulates glucose and insulin levels to promote skeletal muscle cell proliferation. These findings offer new perspectives for designed functional dispersion, as potential pharmaceutical preparations to improve insulin therapy and promote skeletal muscle cell health.
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Affiliation(s)
- Veera C S R Chittepu
- Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu S/N, Col. Unidad Profesional Adolfo López Mateos, Zacatenco, CP. Ciudad de Mexico 07738, Mexico.
| | - Poonam Kalhotra
- Departamento de Biofísica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, CP. Ciudad de Mexico 11340, Mexico.
| | - Tzayhri Gallardo-Velázquez
- Departamento de Biofísica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, CP. Ciudad de Mexico 11340, Mexico.
| | - Raúl René Robles-de la Torre
- Centro de Investigación en Biotecnología Aplicada CIBA, Instituto Politécnico Nacional, Carretera Estatal, Tecuexcomac-Tepetitla, Km 1.5, CP. Tlaxcala 90700, Mexico.
| | - Guillermo Osorio-Revilla
- Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu S/N, Col. Unidad Profesional Adolfo López Mateos, Zacatenco, CP. Ciudad de Mexico 07738, Mexico.
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Li X, Xu H, Gao P. Diabetes Mellitus is a Risk Factor for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection in China. Med Sci Monit 2018; 24:6729-6734. [PMID: 30245503 PMCID: PMC6178879 DOI: 10.12659/msm.911702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND This study aimed to investigate whether diabetes mellitus (DM) increased the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. MATERIAL AND METHODS Individuals with a confirmed diagnosis of HCC and chronic HBV infection (n=112), and non-diabetic individuals with both chronic HBV infection and HCC (n=210), were matched by age, sex, and degree of liver cirrhosis. Demographic, lifestyle, and clinical data were reviewed. Data were analyzed by univariate and multiple logistic regression analysis to identify the risk factors for HCC. RESULTS Of the 112 patients with HCC (median age, 52.0 years; range, 46.3-56.0 years), 18.8% were men, and the prevalence of cirrhosis was 90.2%. Of the 210 patients without HCC (median age, 51.0 years; range, 47.0-58.0 years), 26.2% were men, and the prevalence of cirrhosis was 91.9%. Diabetes mellitus was more prevalent among individuals with HCC (16.1%) compared with those without HCC (7.6%) and increased the risk for HCC by two-fold to three-fold (adjusted odds ratio [AOR]: 2.402; 95% confidence interval [CI], 1.150-5.018). Multivariate analysis showed that cigarette smoking significantly increased the risk of HBV-related HCC (AOR: 1.665; 95% CI, 1.031-2.690), as did increased levels of HBV DNA (≥10³ IU/mL) (AOR: 1.753; 95% CI, 1.079-2.849). CONCLUSIONS In a Chinese population with chronic HBV infection, DM increased the risk of HCC, as did cigarette smoking and high levels of HBV DNA. Screening patients with known risk factors for HCC might improve early detection rates and treatment to prevent tumor progression.
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Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland).,Jilin Province Key Laboratory of Infectious Disease, Laboratory of Molecular Virology, Changchun, Jilin, China (mainland)
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
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Juárez-Vázquez CI, Gurrola-Díaz CM, Vargas-Guerrero B, Domínguez-Rosales JA, Rodriguez-Ortiz JF, Barros-Núñez P, Flores-Martínez SE, Sánchez-Corona J, Rosales-Reynoso MA. Insulin glargine affects the expression of Igf-1r, Insr, and Igf-1 genes in colon and liver of diabetic rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2018; 21:489-494. [PMID: 29922429 PMCID: PMC6000212 DOI: 10.22038/ijbms.2018.24867.6185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objective(s): The mitogenic effect of the analogous insulin glargine is currently under debate since several clinical studies have raised the possibility that insulin glargine treatment has a carcinogenic potential in different tissues. This study aimed to evaluate the Igf-1r, Insr, and Igf-1 gene expression in colon and liver of streptozotocin-induced diabetic rats in response to insulin glargine, neutral protamine Hagedorn (NPH) insulin, and metformin treatments. Materials and Methods: Male Wistar rats were induced during one week with streptozotocin to develop Type 2 Diabetes (T2D) and then randomly distributed into four groups. T2D rats included in the first group received insulin glargine, the second group received NPH insulin, the third group received metformin; finally, untreated T2D rats were included as the control group. All groups were treated for seven days; after the treatment, tissue samples of liver and colon were obtained. Quantitative PCR (qPCR) was performed to analyze the Igf-1r, Insr and Igf-1 gene expression in each tissue sample. Results: The liver tissue showed overexpression of the Insr and Igf-1r genes (P>0.001) in rats treated with insulin glargine in comparison with the control group. Similar results were observed for the Insr gene (P>0.011) in colonic tissue of rats treated with insulin glargine. Conclusion: These observations demonstrate that insulin glargine promote an excess of insulin and IGF-1 receptors in STZ-induced diabetic rats, which could overstimulate the mitogenic signaling pathways.
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Affiliation(s)
- Clara I Juárez-Vázquez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Carmen M Gurrola-Díaz
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - Belinda Vargas-Guerrero
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - José A Domínguez-Rosales
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - Jessica F Rodriguez-Ortiz
- División de Genética, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Patricio Barros-Núñez
- División de Genética, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Silvia E Flores-Martínez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - José Sánchez-Corona
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Mónica A Rosales-Reynoso
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
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31
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Collins G, Mesiano S, DiFeo A. Effects of Metformin on Cellular Proliferation and Steroid Hormone Receptors in Patient-Derived, Low-Grade Endometrial Cancer Cell Lines. Reprod Sci 2018; 26:609-618. [PMID: 29848180 DOI: 10.1177/1933719118779734] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy and is the result of disruption of the balance between estrogen-stimulated growth and progesterone-induced growth modulation. Metformin has been shown to inhibit EC proliferation; however, its role in early-stage EC and its effects on steroid hormone receptors have not been adequately explored. Our aim was to examine the effects of metformin on cellular proliferation in patient-derived, low-grade EC cell lines and to determine whether it directly modulates steroid hormone receptor expression. Two novel EC cell lines were produced (EM2 and 3) from endometrial tumor tissue obtained from women undergoing surgery. Cellular proliferation was determined by the 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay, and in both cell lines, metformin decreased cell proliferation in a dose-dependent (10-200 µmol/L) manner and induced apoptosis as measured by cleaved PARP. Furthermore, metformin abrogated the effects of E2 on cell proliferation. Using quantitative real-time polymerase chain reaction and Western immunoblotting, metformin significantly decreased estrogen receptor (ER) α messenger RNA abundance but did not consistently affect the expression of progesterone receptor. Estrogen receptor α protein levels significantly decreased across all metformin doses tested, which resulted in a significant decrease in the expression of the ER targets genes Keratin-19 and Wnt-1 inducible signaling pathway 2. In addition, metformin increased phosphorylation of AMPK in a dose-dependent manner (10-200 µmol/L) indicating an effect on mammalian target of rapamycin (mTOR) signaling. Our data suggest that metformin therapy represents a potential fertility-sparing option for women with early-stage EC, given its capacity to inhibit EC cell proliferation, ERα expression, and the mTOR cell proliferation pathway.
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Affiliation(s)
- Gretchen Collins
- 1 Department of Reproductive Endocrinology & Infertility, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Sam Mesiano
- 2 Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Analisa DiFeo
- 3 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
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32
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Xin WX, Fang L, Fang QL, Zheng XW, Ding HY, Huang P. Effect of hypoglycemic agents on survival outcomes of lung cancer patients with diabetes mellitus: A meta-analysis. Medicine (Baltimore) 2018; 97:e0035. [PMID: 29489653 PMCID: PMC5851744 DOI: 10.1097/md.0000000000010035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND To assess the association between hypoglycemic agents and prognosis of lung cancer patients with diabetes. METHODS A comprehensive literature search was performed in PubMed, Web of Science, Embase, and Cochrane Library until May 2017. The search yielded 2593 unique citations, of which 18 articles met inclusion criteria. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated by a fixed-effects or random-effects model. RESULTS The pooled HRs favoring metformin users were 0.77 for overall survival (OS) (n = 15, 95% CI: 0.68-0.86) and 0.50 for disease-free survival (n = 5, 95% CI: 0.39-0.64). One study assessed the relationship between metformin and cancer-specific survival (CSS), reporting no significant results. No significant association between insulin and OS (n = 2, HR: 0.95, 95% CI: 0.79-1.13) or CSS (n = 2, HR: 1.03, 95% CI: 0.76-1.41) was noted. One study evaluated association of sulfonylureas with lung cancer survival and reported no clinical benefit (HR: 1.10, 95% CI: 0.87-1.40). One study reported no association of thiazolidinediones with lung cancer survival (HR: 1.04, 95% CI: 0.65-1.66). CONCLUSIONS This meta-analysis demonstrated that metformin exposure might improve survival outcomes in lung cancer patients with diabetes.
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Affiliation(s)
- Wen-Xiu Xin
- Laboratory of Clinical Pharmacy
- Key Laboratory of Head and Neck Translational Research of Zhejiang Province
| | - Luo Fang
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, P.R. China
| | | | | | | | - Ping Huang
- Laboratory of Clinical Pharmacy
- Key Laboratory of Head and Neck Translational Research of Zhejiang Province
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Sormendi S, Wielockx B. Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Microenvironment. Front Immunol 2018; 9:40. [PMID: 29434587 PMCID: PMC5796897 DOI: 10.3389/fimmu.2018.00040] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 01/05/2018] [Indexed: 12/24/2022] Open
Abstract
Low oxygen tension or hypoxia is a determining factor in the course of many different processes in animals, including when tissue expansion and cellular metabolism result in high oxygen demands that exceed its supply. This is mainly happening when cells actively proliferate and the proliferating mass becomes distant from the blood vessels, such as in growing tumors. Metabolic alterations in response to hypoxia can be triggered in a direct manner, such as the switch from oxidative phosphorylation to glycolysis or inhibition of fatty acid desaturation. However, as the modulated action of hypoxia-inducible factors or the oxygen sensors (prolyl hydroxylase domain-containing enzymes) can also lead to changes in enzyme expression, these metabolic changes can also be indirect. With this review, we want to summarize our current knowledge of the hypoxia-induced changes in metabolism during cancer development, how they are affected in the tumor cells and in the cells of the microenvironment, most prominently in immune cells.
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Affiliation(s)
- Sundary Sormendi
- Heisenberg Research Group, Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Ben Wielockx
- Heisenberg Research Group, Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
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Zi F, Zi H, Li Y, He J, Shi Q, Cai Z. Metformin and cancer: An existing drug for cancer prevention and therapy. Oncol Lett 2018; 15:683-690. [PMID: 29422962 PMCID: PMC5772929 DOI: 10.3892/ol.2017.7412] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 09/22/2017] [Indexed: 12/17/2022] Open
Abstract
Metformin is a standard clinical drug used to treat type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Recently, epidemiological studies and meta-analyses have revealed that patients with T2DM have a lower incidence of tumor development than healthy controls and that patients diagnosed with cancer have a lower risk of mortality when treated with metformin, demonstrating an association between metformin and tumorigenesis. In vivo and in vitro studies have revealed that metformin has a direct antitumor effect, which may depress tumor proliferation and induce the apoptosis, autophagy and cell cycle arrest of tumor cells. The mechanism underpinning the antitumor effect of metformin has not been well established. Studies have demonstrated that reducing insulin and insulin-like growth factor levels in the peripheral blood circulation may lead to the inhibition of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin (mTOR) signaling or activation of AMP-activated protein kinase, which inhibits mTOR signaling, a process that may be associated with the antitumor effect of metformin. The present review primarily focuses on the recent progress in understanding the function of metformin in tumor development.
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Affiliation(s)
- Fuming Zi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Huapu Zi
- Department of Oncology, Rizhao Traditional Chinese Medicine Hospital of Shandong Traditional Chinese Medicine University, Rizhao, Shandong 276800, P.R. China
| | - Yi Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Qingzhi Shi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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Diabetes Mellitus and Risk of Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5202684. [PMID: 29379799 PMCID: PMC5742888 DOI: 10.1155/2017/5202684] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is two to three times higher in patients with diabetes mellitus (DM), the prevalence of which is increasing sharply worldwide. The purpose of this review was to describe clinical links between DM and HCC and potential biological mechanisms that may account for this association. We evaluated the role of potential pathways that could account for the development of HCC with different etiologies in the presence of DM. In addition, we also briefly discuss the potential effect of other factors such as type and dosage of antidiabetic medicines and duration of DM on HCC risk.
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Kim YJ, Park HB, Kim PH, Park JS, Kim KS. Enhanced Anti-cancer Efficacy in MCF-7 Breast Cancer Cells by Combined Drugs of Metformin and Sodium Salicylate. ACTA ACUST UNITED AC 2017. [DOI: 10.15616/bsl.2017.23.3.290] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Yun-Ji Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Korea
| | - Hee-Bin Park
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Korea
| | - Pyung-Hwan Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Korea
| | - James S. Park
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
| | - Keun-Sik Kim
- Department of Biomedical Laboratory Science, Konyang University, Daejeon 35365, Korea
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Parikh AB, Kozuch P, Rohs N, Becker DJ, Levy BP. Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial. Invest New Drugs 2017; 35:813-819. [DOI: 10.1007/s10637-017-0511-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Accepted: 09/14/2017] [Indexed: 11/24/2022]
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Zhao Y, Gong C, Wang Z, Zhang J, Wang L, Zhang S, Cao J, Tao Z, Li T, Wang B, Hu X. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget 2017; 8:84224-84236. [PMID: 29137418 PMCID: PMC5663590 DOI: 10.18632/oncotarget.20478] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022] Open
Abstract
Background Everolimus significantly improves progression-free survival (PFS) and has been approved to use in aromatase inhibitor pretreated patients with hormone receptor positive advanced breast cancer. Metformin has been shown to inhibit mTOR pathway, with more favorable safety profile, leading to this hypothesis-generating trial to assess whether metformin enhances the efficacy of aromatase inhibitors. Methods 60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer were randomly assigned 1:1 to aromatase inhibitor (exemestane 25mg/d or letrozole 2.5mg/d depending on the most recent treatment) plus metformin (0.5g bid, orally) or placebo. The primary endpoint was PFS, and secondary endpoints were objective response rate, clinical benefit rate, overall survival and safety. Results Median PFS was 4.7 months in the combination group and 6.0 months in the control group (hazard ratio, 1.2; 95% confidence interval [CI], 0.7 to 2.1; P =0.48). ORR was 6.7% in the combination group and 0% in the control group (odds ratio for ORR not available; P =0.99), and CBR was 33.3% and 50.0%, respectively (OR for CBR 0.5; 95% CI, 0.2 to 1.4; P=0.15). No significant difference in overall survival was observed between the combination and control groups (median OS, 30.9 vs. 32.4 months; P = 0.81). Subgroup analyses didn't find any specific population favoring the combination treatment. No substantial difference in incidence or severity of adverse events was seen between the two treatment groups. Conclusion This randomized phase II clinical trial failed to show an improved efficacy with the addition of metformin to endocrine therapy, although with excellent tolerability.
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Affiliation(s)
- Yannan Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chengcheng Gong
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhonghua Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jian Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Leiping Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Sheng Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jun Cao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhonghua Tao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ting Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Biyun Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xichun Hu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Zhang Y, Feng X, Li T, Yi E, Li Y. Metformin synergistic pemetrexed suppresses non-small-cell lung cancer cell proliferation and invasion in vitro. Cancer Med 2017; 6:1965-1975. [PMID: 28719077 PMCID: PMC5548881 DOI: 10.1002/cam4.1133] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 05/03/2017] [Accepted: 05/26/2017] [Indexed: 01/14/2023] Open
Abstract
The aim of this study was to investigate whether metformin in combination with pemetrexed has an effect on the treatment of non-small-cell lung cancer (NSCLC) models and to explore the related molecular mechanism. The half maximal inhibitory concentration (IC50) and combination index (CI) of metformin and pemetrexed were detected by the CCK8 assay to assess the antiproliferative and therapeutic effects of the two-drug combination. Flow cytometry (FCM) and invasion assays were used to estimate the variation in apoptosis rate and invasion ability of the differently treated NSCLC cell lines. Apoptotic markers were detected by western blotting to validate the data related to the antiproliferation and proapoptosis effects. Metformin monotherapy inhibited the growth of NSCLC cell lines and reduced the invasion ability to different degrees compared with the control groups (P < 0.05). Metformin in combination with pemetrexed produced a synergistic effect (CI < 0.90) compared with the two drugs in monotherapy in the three tested NSCLC cell lines. Metformin in combination with pemetrexed significantly increased the cell numbers of HCC827 cells at S phase (P < 0.001), and the combination therapy had no influence on the A549 and H1975 cell lines. We found that combining metformin with pemetrexed induced more cell apoptosis than metformin or pemetrexed used alone (P < 0.05), which was validated by the apoptotic markers. These results demonstrate that the combination of metformin and pemetrexed has a synergistic effect on the treatment of NSCLC cell lines by inducing apoptosis or blocking the cell cycle. Our data indicate that the combination of metformin and pemetrexed could have beneficial antitumor effects on NSCLC cells in vitro.
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Affiliation(s)
- Yan Zhang
- Departments of Respiratory MedicineQilu hospital of Shandong UniversityJinanShandongChina
| | - Xiuli Feng
- Departments of Respiratory MedicineQilu hospital of Shandong UniversityJinanShandongChina
- Departments of Respiratory MedicinePeople's Hospital of QingzhouWeifangShandongChina
| | - Tao Li
- Departments of Respiratory MedicineQilu hospital of Shandong UniversityJinanShandongChina
| | - Erpan Yi
- Departments of Respiratory MedicineQilu hospital of Shandong UniversityJinanShandongChina
| | - Yu Li
- Departments of Respiratory MedicineQilu hospital of Shandong UniversityJinanShandongChina
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Guo X, Guo N, Zhao J, Cai Y. Active targeting co-delivery system based on hollow mesoporous silica nanoparticles for antitumor therapy in ovarian cancer stem-like cells. Oncol Rep 2017; 38:1442-1450. [PMID: 28731164 PMCID: PMC5549023 DOI: 10.3892/or.2017.5829] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/21/2017] [Indexed: 01/01/2023] Open
Abstract
The combination of nanocarriers and chemotherapy drugs can release the chemotherapy drugs to the tumor tissue, which can enhance the antitumor effect and reduce the adverse reactions at the same time. In this study, a co-delivery system based on hollow mesoporous silica nanoparticles (HMSN) was developed and characterized. We also investigated the in vitro effect of this system on CD117+CD44+A2780 cell line. HMSN was selected as the nanocarrier, with -COOH modified on the surface and doxorubicin (DOX), NVP-AEW 541 (NVP) loaded inside. IGF‑1R was chosen as the drug target, apoptosis rate and expression of cyclin B1, Bax, Bcl-xl, p-Akt were used to evaluate the antitumor effect of HMSN‑COOH@DOX fluorescence NVP. The HMSN co-delivery system was successfully synthesized with encapsulation efficiency of 37% (DOX) and 44% (NVP), and high PH-sensitive property was observed. The apoptosis rate of CD117+CD44+A2780 ovarian cancer stem-like cells treated by HMSN co-delivery system were almost 3 times higher than those of the free drugs group. The expression of Bax was significantly increased while Bcl-xl, and p-Akt reduced (P≤0.05). These data indicate that the co-delivery system demonstrated a high efficiency in promoting apoptosis in ovarian cancer stem-like cells by targeting IGF‑1R, but further study is still needed.
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Affiliation(s)
- Xin Guo
- Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Nan Guo
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jianwen Zhao
- Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Yunlang Cai
- Department of Gynaecology and Obstetrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Sulfonylureas (not metformin) improve survival of patients with diabetes and resectable pancreatic adenocarcinoma. INTERNATIONAL JOURNAL OF SURGERY-ONCOLOGY 2017; 2:e15. [PMID: 29177213 PMCID: PMC5673127 DOI: 10.1097/ij9.0000000000000015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Patients with pancreatic adenocarcinoma have an increased propensity for diabetes. Recent studies suggest patients with diabetes and pancreatic adenocarcinoma treated with metformin have increased survival. This study was undertaken to determine whether metformin use is associated with increased survival in patients with pancreatic adenocarcinoma.
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Li X, Xu H, Gao Y, Pan M, Wang L, Gao P. Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China. Medicine (Baltimore) 2017; 96:e6508. [PMID: 28353605 PMCID: PMC5380289 DOI: 10.1097/md.0000000000006508] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naïve chronic hepatitis C (CHC) patients in China.To examine the association between DM and HCC, we conducted a case-control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC.We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17-2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31-6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25-13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89-0.99]).DM was associated with an increased risk for HCC development in treatment-naïve CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM.
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Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
- Jilin Province Key Laboratory of Infectious Disease, Laboratory of Molecular Virology
| | - Yang Gao
- Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Meng Pan
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Le Wang
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
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Biswal BN, Das SN, Das BK, Rath R. Alteration of cellular metabolism in cancer cells and its therapeutic prospects. J Oral Maxillofac Pathol 2017; 21:244-251. [PMID: 28932034 PMCID: PMC5596675 DOI: 10.4103/jomfp.jomfp_60_17] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Transformation of a normal cell into a cancerous phenotype is essentially backed by genetic mutations that trigger several oncogenic signaling pathways. These signaling pathways rewire the cellular metabolism to meet the bioenergetic and biomass requirement of proliferating cell, which is different from a quiescent cell. Although the change of metabolism in a cancer cell was observed and studied in the mid-20th century, it was not adequate to explain oncogenesis. Now, equipped with a revolution of oncogenes, we have a genetic basis to explain the transformation. Through several studies, it is clear now that such metabolic alterations not only promote cancer progression but also contribute to the chemoresistance of cancer. Targeting specific enzymes and combinations of enzymes can improve the efficacy of cancer therapy and help to overcome the therapeutic resistance.
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Affiliation(s)
- Biranchi Narayan Biswal
- Department of Oral Pathology and Microbiology, S.C.B. Dental College and Hospital, Cuttack, Odisha, India
| | - Surya Narayan Das
- Department of Oral Pathology and Microbiology, S.C.B. Dental College and Hospital, Cuttack, Odisha, India
| | - Bijoy Kumar Das
- Department of Oral Pathology and Microbiology, S.C.B. Dental College and Hospital, Cuttack, Odisha, India
| | - Rachna Rath
- Department of Oral Pathology and Microbiology, S.C.B. Dental College and Hospital, Cuttack, Odisha, India
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Malaguarnera R, Vella V, Nicolosi ML, Belfiore A. Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer? Front Endocrinol (Lausanne) 2017; 8:314. [PMID: 29184536 PMCID: PMC5694441 DOI: 10.3389/fendo.2017.00314] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 10/30/2017] [Indexed: 12/13/2022] Open
Abstract
In the past few decades, the incidence of thyroid cancer (TC), namely of its papillary hystotype (PTC), has shown a steady increase worldwide, which has been attributed at least in part to the increasing diagnosis of early stage tumors. However, some evidence suggests that environmental and lifestyle factors can also play a role. Among the potential risk factors involved in the changing epidemiology of TC, particular attention has been drawn to insulin-resistance and related metabolic disorders, such as obesity, type 2 diabetes, and metabolic syndrome, which have been also rapidly increasing worldwide due to widespread dietary and lifestyle changes. In accordance with this possibility, various epidemiological studies have indeed gathered substantial evidence that insulin resistance-related metabolic disorders might be associated with an increased TC risk either through hyperinsulinemia or by affecting other TC risk factors including iodine deficiency, elevated thyroid stimulating hormone, estrogen-dependent signaling, chronic autoimmune thyroiditis, and others. This review summarizes the current literature evaluating the relationship between metabolic disorders characterized by insulin resistance and the risk for TC as well as the possible underlying mechanisms. The potential implications of such association in TC prevention and therapy are discussed.
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Affiliation(s)
- Roberta Malaguarnera
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Veronica Vella
- School of Human and Social Sciences, “Kore” University of Enna, Enna, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Veronica Vella, ; Antonino Belfiore,
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Abstract
PURPOSE OF REVIEW Prostate cancer (PCa) demonstrates characteristic changes in metabolism and bioenergetics in the transition from benign to malignant tissue. It is feasible that some of these changes may be targetable for therapeutic purposes. This review will highlight some of the current metabolically targeted therapies being investigated for the treatment of prostate cancer. RECENT FINDINGS The transition from benign to malignant prostate cells is characterized by decreased intracellular zinc concentration and subsequent release of inhibition of the tricarboxylic acid cycle enzyme m-aconitase, which leads to the decrease in citrate concentration within the cancer tissue. Instead of the largely glycolytic phenotype exhibited by most cancers, PCa relies on glutamine and lipids for survival and proliferation. Early studies are beginning to demonstrate that targeting some of the upregulated pathways with inhibitors of key enzymes, such as glutaminase, fatty acid synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, hexokinase, zinc transport, or complex I in the mitochondria may have significant metabolic effects and therapeutic potential. SUMMARY The unique metabolic profile of PCa allows for many potential avenues of treatment. Future studies will continue to test if the metabolic characterization and treatment of PCa could be an important approach to provide personalized treatment for the disease.
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Zhao W, Zhang X, Liu J, Sun B, Tang H, Zhang H. miR-27a-mediated antiproliferative effects of metformin on the breast cancer cell line MCF-7. Oncol Rep 2016; 36:3691-3699. [DOI: 10.3892/or.2016.5199] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 06/21/2016] [Indexed: 11/06/2022] Open
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Zhou JY, Xu B, Li L. A New Role for an Old Drug: Metformin Targets MicroRNAs in Treating Diabetes and Cancer. Drug Dev Res 2016; 76:263-9. [PMID: 26936407 DOI: 10.1002/ddr.21265] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
MicroRNAs (miRNAs) are a family of short, noncoding, 19-23 base pair RNA molecules. Due to their unique role in gene regulation in various tissues, miRNAs play important roles in regulating insulin secretion, metabolic disease, and cancer biology. Emerging evidence demonstrates that miRNAs could also be novel diagnostic markers for a variety of disease states. Additionally, miRNAs have been found to function either as oncogenes, or tumor suppressor genes in cerian cancers. An increasing number of studies have been conducted investigating new drugs targeting miRNAs as a potential anticancer therapy. Metformin is the most widely prescribed medication for treating Type 2 diabetes (T2D). Recent clinical data suggests that metformin impacts the miRNA profile in T2D subjects. Most excitingly, studies have found that metformin is protective against cancer. The anticancer activity of metformin is mediated through a direct regulation of miRNAs, which further modulates several downstream genes in metabolic or preoncogenic pathways. These miRNAs are, therefore, prospective therapeutic targets for treating diabetes and cancer which is the topic of this review. Further study on the regulation of miRNAs by metformin could result in novel therapeutic strategies for recurrent or drug-esistant cancer, and as part of combinatorial approaches with conventional anticancer therapies.
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Affiliation(s)
- Joseph Yi Zhou
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada, H3A 0G4
| | - Biao Xu
- Department of Cardiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lixin Li
- Department of Physician Assistant, College of Health Professions, Central Michigan University, Mount Pleasant, MI, 48859, USA
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Zaorsky NG, Shaikh T, Ruth K, Sharda P, Hayes SB, Sobczak ML, Hallman MA, Smaldone MC, Chen DYT, Horwitz EM. Prostate Cancer Patients With Unmanaged Diabetes or Receiving Insulin Experience Inferior Outcomes and Toxicities After Treatment With Radiation Therapy. Clin Genitourin Cancer 2016; 15:326-335.e3. [PMID: 27789181 DOI: 10.1016/j.clgc.2016.08.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/22/2016] [Accepted: 08/26/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The purpose of the study was to determine the effect of type 2 diabetes mellitus (T2DM) on outcomes and toxicities among men with localized prostate cancer receiving definitive radiation therapy. PATIENTS AND METHODS We performed a retrospective review of 3217 patients, from 1998 to 2013, subdivided into 5 subgroups: (I) no T2DM; (II) T2DM receiving oral antihyperglycemic agent that contains metformin, no insulin; (III) T2DM receiving nonmetformin oral agent alone, no insulin; (IV) T2DM receiving any insulin; and (V) T2DM not receiving medication. Outcome measures were overall survival, freedom from biochemical failure (BF), freedom from distant metastasis, cancer-specific survival, and toxicities. Kaplan-Meier analysis, log rank tests, Fine and Gray competing risk regression (to adjust for patient and lifestyle factors), Cox models, and subdistribution hazard ratios (sHRs) were used. RESULTS Of the 3217 patients, 1295 (40%) were low-risk, 1192 (37%) were intermediate-risk, and 652 (20%) were high risk. The group I to V distribution was 81%, 8%, 5%, 3%, and 4%. The median dose was 78 Gy, and the median follow-up time was 50 (range, 1-190) months. Group V had increased mortality (sHR, 2.1; 95% confidence interval [CI], 0.66-1.54), BF (sHR, 2.14; 0.88-1.83), and cause-specific mortality (sHR, 3.87; 95% CI, 1.31-11). Acute toxicities were higher in group IV versus group I (genitourinary: 38% vs. 26%; P = .01; gastrointestinal: 21% vs. 5%; P = 001). Late toxicities were higher in groups IV and V versus group I (12%-14% vs. 2%-6%; P < .01). CONCLUSION Men with T2DM not receiving medication and men with T2DM receiving insulin had worse outcomes and toxicities compared to other patients.
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Affiliation(s)
- Nicholas G Zaorsky
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA.
| | - Talha Shaikh
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Karen Ruth
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA
| | - Pankaj Sharda
- Department of Endocrinology, Fox Chase Cancer Center, Philadelphia, PA
| | - Shelly B Hayes
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Mark L Sobczak
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Mark A Hallman
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Marc C Smaldone
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - David Y T Chen
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Eric M Horwitz
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
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Bansal N, Mishra PJ, Stein M, DiPaola RS, Bertino JR. Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells. Oncotarget 2016; 6:15321-31. [PMID: 26036314 PMCID: PMC4558154 DOI: 10.18632/oncotarget.4148] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 03/10/2015] [Indexed: 01/09/2023] Open
Abstract
Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl.
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Affiliation(s)
- Nitu Bansal
- Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, New Brunswick, NJ, USA
| | - Prasun J Mishra
- Department of Biochemical and Cellular Pharmacology, Genentech, South San Fransisco, CA, USA
| | - Mark Stein
- Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, New Brunswick, NJ, USA
| | - Robert S DiPaola
- Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, New Brunswick, NJ, USA
| | - Joseph R Bertino
- Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, New Brunswick, NJ, USA
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