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Doxorubicin and metformin

Yun-Suk Kwon, So-Young Chun, Hong-Yan Nan, Kyung-Soo Nam, Chuhee Lee, Soyoung Kim
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...
February 2019: Oncology Letters
O Nanni, D Amadori, A De Censi, A Rocca, A Freschi, A Bologna, L Gianni, F Rosetti, L Amaducci, L Cavanna, F Foca, S Sarti, P Serra, L Valmorri, P Bruzzi, D Corradengo, A Gennari
PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2  + cyclophosphamide (C) 600 mg/m2  × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS...
December 7, 2018: Breast Cancer Research and Treatment
Maryam Hoseini Shafa, Razieh Jalal, Negin Kosari, Farzad Rahmani
The clinical use of doxorubicin (DOX) is limited due to its systemic side effects and drug resistance. Recent evidence suggests that metformin prevents and controls certain but not all types of cancer. The beneficial use of metformin in combination with some chemotherapeutic agents has been reported. The aim of this study is to investigate the influence of metformin on DOX-induced effects in human prostate DU145 cancer cells and clarify its molecular mechanisms. For this purpose, DU145 cells were treated with DOX or metformin, either alone or in combination with each other...
November 2018: Regulatory Toxicology and Pharmacology: RTP
Edson A de Lima, Luís G O de Sousa, Alexandre Abilio de S Teixeira, Andrea G Marshall, Nelo E Zanchi, José C Rosa Neto
Doxorubicin (DOX) is a chemotherapy agent widely used in clinical practice, and it is very efficient in tumor suppression, but the use of DOX is limited by a strong association with the development of severe muscle atrophy and cardiotoxicity effects. Reversion or neutralization of the muscular atrophy can lead to a better prognosis. Recent studies have proposed that the negative effect of DOX on skeletal muscle is linked to its inhibition of AMP-activated protein kinase (AMPk), a key mediator of cellular metabolism...
December 2018: Journal of Cellular Physiology
Sandhiya Ramachandran, Swetha Loganathan, Vinnie Cheeran, Soniya Charles, Ganesh Munuswamy-Ramanujan, Mohankumar Ramasamy, Vijay Raj, Kanchana Mala
Doxorubicin (DOX) is an antitumor drug, associated with cardiomyopathy. Strategies to address DOX-cardiomyopathy are scarce. Here, we identify the effect of forskolin (FSK) on DOX-induced-asymmetric-dimethylarginine (ADMA) accumulation in monocytoid cells. DOX-challenge led to i) augmented cytotoxicity, reactive-oxygen-species (ROS) production and methyltransferase-enzyme-activity identified as ADMA and s-adenosylhomocysteine (SAH) accumulation (SAH-A). However, except cytotoxicity, other DOX effects were decreased by metformin and FSK...
2018: Leukemia Research Reports
Luana A Biondo, Helena A Batatinha, Camila O Souza, Alexandre A S Teixeira, Loreana S Silveira, Maria I Alonso-Vale, Lila M Oyama, Michele J Alves, Marilia Seelaender, José C R Neto
Doxorubicin (DX) is a chemotherapeutic drug that is used in clinical practice that promotes deleterious side effects in non-tumor tissues such as adipose tissue. We showed that DX leads to extensive damage in adipose tissue via a disruption in 5'-adenosine monophosphate-activated protein kinase (AMPK) and PPAR-gamma signaling. Thus, we investigated whether co-treatment with the biguanide drug metformin (MET) could prevent the side effects of DX through the activation of AMPK in adipose tissue. The goal of the present study was to verify the effects of DX and adjuvant MET treatment in subcutaneous adipose tissue (SAT) and to determine whether MET could protect against chemotherapy-induced side effects...
2018: Frontiers in Pharmacology
Zhengze Lu, Yang Long, Xingli Cun, Xuhui Wang, Jianping Li, Ling Mei, Yiliang Yang, Man Li, Zhirong Zhang, Qin He
Cancer-related inflammation can promote tumorigenesis, tumor growth and tumor metastasis in many types of cancers. Therefore, inhibiting cancer-related inflammation significantly improves cancer therapy. It has been reported that metformin (MET) inhibits the nuclear translocation of nuclear factor-κB (NF-κB), a key factor in cancer-related inflammation. However, the short half-life and the lack of tumor targeting limit the anti-inflammatory efficacy of MET in vivo. Herein, using pH-sensitive imine bonds, MET and the chemotherapy drug doxorubicin (DOX) were loaded onto size-shrinkable RGD-DGL-GNP nanoparticles (RDG NPs) for combination therapy...
May 31, 2018: Nanoscale
Rita Zilinyi, Attila Czompa, Andras Czegledi, Andrea Gajtko, Dora Pituk, Istvan Lekli, Arpad Tosaki
The molecular mechanisms underlying doxorubicin-induced cardiotoxicity are still being investigated, but are known to involve oxidative stress, mitochondrial dysfunction, and the dysregulation of autophagy. The objective of the current study was to examine the protective role of metformin and its effect on autophagy in doxorubicin-induced cardiotoxicity. Sprague⁻Dawley rats were divided into four groups at random. The doxorubicin-treated group received doxorubicin (3 mg/kg every second day) intraperitoneally...
May 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Vahid Shafiei-Irannejad, Nasser Samadi, Roya Salehi, Bahman Yousefi, Mahdi Rahimi, Abolfazl Akbarzadeh, Nosratollah Zarghami
PURPOSE: P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been recognized as the main obstacle against successful cancer treatment. To address this problem, co-encapsulated doxorubicin (DOX) and metformin (Met) in a biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared. We reported in our previous study that Met inhibits P-gp in DOX resistant breast cancer (MCF-7/DOX) cells. TPGS is a bioactive compound which has also been shown to inhibit P-gp, further to its pharmaceutical advantages...
April 18, 2018: Pharmaceutical Research
Balraj Singh, Vanessa N Sarli, Laura J Washburn, Milan R Raythatha, Anthony Lucci
We previously described a strategy for selecting highly adaptable rare triple-negative breast cancer (TNBC) cells based on their ability to survive a severe and prolonged metabolic challenge, e.g., a lack of glutamine. We hypothesized that metabolically adaptable (MA) cancer cells selected from the SUM149 cell line in this manner have the capacity to survive a variety of challenges that postulated "decathlon winner" cancer cells must survive to succeed in metastasis. These MA cells were resistant to glutaminase inhibitor CB-839, as predicted from their ability to proliferate without exogenous glutamine...
February 16, 2018: Oncotarget
Saverio Candido, Stephen L Abrams, Linda Steelman, Kvin Lertpiriyapong, Alberto M Martelli, Lucio Cocco, Stefano Ratti, Matilde Y Follo, Ramiro M Murata, Pedro L Rosalen, Paolo Lombardi, Giuseppe Montalto, Melchiorre Cervello, Agnieszka Gizak, Dariusz Rakus, Pann-Gill Suh, Massimo Libra, James A McCubrey
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes...
May 2018: Advances in Biological Regulation
Ying Li, Meng Wang, Pei Zhi, Jian You, Jian-Qing Gao
Acquired resistance to chemo-drugs remains a major obstacle to successful cancer therapy. Metformin, a well-documented drug for treating type II diabetes, was recently proposed as a novel agent for tumor treatment. In this study, we found that metformin suppressed MCF7/ADR, a doxorubicin-resistant breast cancer cell line, and acted synergistically with doxorubicin by reversing drug-resistant phenotypes both in vitro and in vivo . Metformin alone dose-dependently inhibited tumor growth, especially the stressful tumor microenvironment of glucose deficiency, and the cytotoxicity of metformin was markedly enhanced by increasing ROS production and ATP depletion...
January 5, 2018: Oncotarget
Monica Gatti, Agnese Solari, Alessandra Pattarozzi, Chiara Campanella, Stefano Thellung, Lorella Maniscalco, Raffaella De Maria, Roberto Würth, Alessandro Corsaro, Adriana Bajetto, Alessandra Ratto, Angelo Ferrari, Antonio Daga, Federica Barbieri, Tullio Florio
Cancer stem cell (CSC) self-renewing and drug resistance cause treatment failure and tumor recurrence. Osteosarcoma is an aggressive bone tumor characterized by biological and molecular heterogeneity, possibly dependent on CSCs. CSC identification in osteosarcoma and their efficient targeting are still open questions. Spontaneous canine osteosarcoma shares clinical and biological features with the human tumors, representing a model for translational studies. We characterized three CSC-enriched canine osteosarcoma cultures...
February 1, 2018: Experimental Cell Research
Yunyun Di, Franklyn De Silva, Edward S Krol, Jane Alcorn
Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231...
February 2018: Nutrition and Cancer
Nina Hanke, Michael Teifel, Daniel Moj, Jan-Georg Wojtyniak, Hannah Britz, Babette Aicher, Herbert Sindermann, Nicola Ammer, Thorsten Lehr
PURPOSE: Zoptarelin doxorubicin is a fusion molecule of the chemotherapeutic doxorubicin and a luteinizing hormone-releasing hormone receptor (LHRHR) agonist, designed for drug targeting to LHRHR positive tumors. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) parent-metabolite model of zoptarelin doxorubicin and to apply it for drug-drug interaction (DDI) potential analysis. METHODS: The PBPK model was built in a two-step procedure...
February 2018: Cancer Chemotherapy and Pharmacology
Yaping Xie, Nan Shao, Yi Jin, Liang Zhang, Huan Jiang, Ningjie Xiong, Fangming Su, Haiyan Xu
Liposomal formulation of doxorubicin has been widely applied in clinic for treatment of various cancers. The separation and measurement of free drug (drug which is not entrapped in liposomes) and liposomal drug in the plasma after injection of liposomal doxorubicin is of prime importance due to toxicity and activity concerns. In this study, a rapid and convenient method was developed to isolate and determine the non-liposomal and liposomal drugs in plasma. Plasma samples were prepared by solid phase extraction (SPE) using Oasis HLB cartridges...
January 1, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Vahid Shafiei-Irannejad, Nasser Samadi, Bahman Yousefi, Roya Salehi, Kobra Velaei, Nosratollah Zarghami
Resistance against chemotherapy is still a major problem in successful cancer treatment in the clinic. Therefore, identifying new compounds with lower side-effects and higher efficacy is an important approach to overcome multidrug resistance (MDR). Here, we investigated the activity and possible mechanism of the antidiabetic drug, metformin, in human doxorubicin (DOX)-resistant breast cancer (MCF-7/DOX) cells. The effect of metformin on the cytotoxicity of DOX was evaluated by MTT assay. The P-gp mRNA/protein expression levels following treatment with metformin were determined using real-time polymerase chain reaction and Western blot analysis, respectively...
January 2018: Chemical Biology & Drug Design
Victor Constante Oliveira, Sarah Alves Rodrigues Constante, Priscila Capelari Orsolin, Júlio César Nepomuceno, Alexandre Azenha Alves de Rezende, Mário Antônio Spanó
Metformin (MET) is an anti-diabetic drug used to prevent hepatic glucose release and increase tissue insulin sensitivity. Diabetic cancer patients are on additional therapy with anticancer drugs. Doxorubicin (DXR) is a cancer chemotherapeutic agent that interferes with the topoisomerase II enzyme and generates free radicals. MET (2.5, 5, 10, 25 or 50 mM) alone was examined for mutagenicity, recombinogenicity and carcinogenicity, and combined with DXR (0.4 mM) for antimutagenicity, antirecombinogenicity and anticarcinogenicity, using the Somatic Mutation and Recombination Test and the Test for Detecting Epithelial Tumor Clones in Drosophila melanogaster...
August 2017: Food and Chemical Toxicology
Nahla E El-Ashmawy, Naglaa F Khedr, Hoda A El-Bahrawy, Hend E Abo Mansour
Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer...
May 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Depeng Shang, Ju Wu, Lianyi Guo, Yanju Xu, Lezi Liu, Jianmin Lu
Multiple drug resistance is reported to be a major obstacle in treatment of osteosarcoma (OS). Research has demonstrated that small subsets of cells called cancer stem cells (CSCs) are responsible for multiple drug resistance. CSCs are potential targets for reversing chemoresistance. In the present study, we compared cisplatin sensitivity between OS stem cells and OS non-stem cells. We confirmed that OS stem cells showed significant cisplatin-resistance compared with the OS non-CSCs. Mechanically, we proved that overexpression of the pyruvate kinase isoenzyme M2 (PKM2) was responsible for the resistance to cisplatin in OS stem cells...
May 2017: International Journal of Oncology
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