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Shetty SR, Debnath S, Majumdar K, Rajagopalan M, Ramaswamy A, Das A. Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics. Bioorg Chem 2024; 153:107849. [PMID: 39368144 DOI: 10.1016/j.bioorg.2024.107849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/07/2024]
Abstract
A high abundance of Epidermal Growth Factor Receptor (EGFR) in malignant cells makes them a prospective therapeutic target for basal breast tumors. Although EGFR inhibitors are in development as anticancer therapeutics, there exists limitations due to the dose-limiting cytotoxicity that limits their clinical utilization, thereby necessitating the advancement of effective inhibitors. In the present study, we have developed common pharmacophore hypotheses using 30 known EGFR inhibitors. The best pharmacophore hypothesis DHRRR_1 was utilized for virtual screening (VS) of the Phase database containing 4.3 × 106 fully prepared compounds. The top 1000 hits were further subjected to ADME filtration followed by structure-based VS and Molecular Dynamics (MD) simulation investigations. Based on pharmacophore hypothesis matching, XP glide score, interactions between ligands and active site residues, ADME properties, and MD simulations, the five best hits (SN-01 through SN-05) were preferred for in-vitro cytotoxicity studies. All the molecules except SN-02 exhibited cytotoxicity in Triple Negative Breast Cancer (TNBC) cells. These potential EGFR inhibitors effectively downregulated the EGF-induced proliferation, migration, in-vitro tumorigenic capability, and EGFR activation (pEGFR) in the TNBCs. Additionally, in combination with doxorubicin, the identified EGFR inhibitors significantly decreased the EGF-induced proliferation. SN-04, and SN-05 in the presence of a lower concentration of doxorubicin markedly increased the apoptotic markers expression in the TNBCs, an effect which was comparable to a higher concentration of doxorubicin treatment, alone. These observations suggest that both SN-04 and/or SN-05 can improve the efficacy of chemotherapeutic drug, doxorubicin at a lower concentration to avert the higher dose of chemotherapeutic-induced side effects during breast cancer treatment.
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Affiliation(s)
- Swathi R Shetty
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500007 TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sudhan Debnath
- Maharaja Bir Bikram College, Agartala, Tripura, India; Department of Chemistry, Netaji Subhash Mahavidyalaya, Udaipur, Tripura, India
| | | | - Muthukumaran Rajagopalan
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605014, INDIA
| | - Amutha Ramaswamy
- Department of Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605014, INDIA
| | - Amitava Das
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500007 TS, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Mangla B, Mittal P, Kumar P, Aggarwal G. Multifaceted role of erlotinib in various cancer: nanotechnology intervention, patent landscape, and advancements in clinical trials. Med Oncol 2024; 41:173. [PMID: 38864966 DOI: 10.1007/s12032-024-02414-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 05/23/2024] [Indexed: 06/13/2024]
Abstract
Erlotinib (ELB) is a tyrosine kinase inhibitor that targets the activity of Epidermal Growth Factor Receptor (EGFR) protein found in both healthy and cancerous cells. It binds reversibly to the ATP-binding site of the EGFR tyrosine kinase. ELB was approved by the US Food and Drug Administration (FDA) in 2004 for advanced non-small cell lung cancer (NSCLC) treatment in patients who relapsed after at least one other therapy. It was authorized for use with gemcitabine in 2005 for the treatment of advanced pancreatic cancer. In addition to lung cancer, ELB has shown promising results in the treatment of other cancers, including breast, prostate, colon, pancreatic, cervical, ovarian, and head and neck cancers. However, its limited water solubility, as a BCS class II drug, presents biopharmaceutical problems. Nanoformulations have been developed to overcome these issues, including increased solubility, controlled release, enhanced stability, tumor accumulation, reduced toxicity, and overcoming drug resistance. In older patients, ELB management should involve individualized dosing based on age-related changes in drug metabolism and close monitoring for adverse effects. Regular assessments of renal and hepatic functions are essential. This review provides an overview of ELB's role of ELB in treating various cancers, its associated biopharmaceutical issues, and the latest developments in ELB-related nanotechnology interventions. It also covers ELB patents granted in previous years and the ongoing clinical trials.
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Affiliation(s)
- Bharti Mangla
- Centre for Advanced Formulation and Technology, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Priya Mittal
- Centre for Advanced Formulation and Technology, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Pankaj Kumar
- Centre for Advanced Formulation and Technology, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India
| | - Geeta Aggarwal
- Centre for Advanced Formulation and Technology, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India.
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India.
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Rios SA, Oyervides S, Uribe D, Reyes AM, Fanniel V, Vazquez J, Keniry M. Emerging Therapies for Glioblastoma. Cancers (Basel) 2024; 16:1485. [PMID: 38672566 PMCID: PMC11048459 DOI: 10.3390/cancers16081485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Glioblastoma is most commonly a primary brain tumor and the utmost malignant one, with a survival rate of approximately 12-18 months. Glioblastoma is highly heterogeneous, demonstrating that different types of cells from the same tumor can manifest distinct gene expression patterns and biological behaviors. Conventional therapies such as temozolomide, radiation, and surgery have limitations. As of now, there is no cure for glioblastoma. Alternative treatment methods to eradicate glioblastoma are discussed in this review, including targeted therapies to PI3K, NFKβ, JAK-STAT, CK2, WNT, NOTCH, Hedgehog, and TGFβ pathways. The highly novel application of oncolytic viruses and nanomaterials in combating glioblastoma are also discussed. Despite scores of clinical trials for glioblastoma, the prognosis remains poor. Progress in breaching the blood-brain barrier with nanomaterials and novel avenues for targeted and combination treatments hold promise for the future development of efficacious glioblastoma therapies.
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Affiliation(s)
| | | | | | | | | | | | - Megan Keniry
- School of Integrative Biological and Chemical Sciences, College of Sciences, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA; (S.A.R.); (D.U.); (A.M.R.)
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Garczorz W, Kosowska A, Francuz T. Antidiabetic Drugs in Breast Cancer Patients. Cancers (Basel) 2024; 16:299. [PMID: 38254789 PMCID: PMC10813754 DOI: 10.3390/cancers16020299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs.
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Affiliation(s)
- Wojciech Garczorz
- Department of Biochemistry, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 18, 40-055 Katowice, Poland; (A.K.); (T.F.)
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A SERS/fluorescence dual-mode immuno-nanoprobe for investigating two anti-diabetic drugs on EGFR expressions. Mikrochim Acta 2023; 190:124. [PMID: 36894729 DOI: 10.1007/s00604-023-05705-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/11/2023] [Indexed: 03/11/2023]
Abstract
A surface-enhanced Raman scattering (SERS)/fluorescence dual-mode nanoprobe was proposed to assess anti-diabetic drug actions from the expression level of the epidermal growth factor receptor (EGFR), which is a significant biomarker of breast cancers. The nanoprobe has a raspberry shape, prepared by coating a dye-doped silica nanosphere with a mass of SERS tags, which gives high gains in fluorescence imaging and SERS measurement. The in situ detection of EGFR on the cell membrane surfaces after drug actions was achieved by using this nanoprobe, and the detection results agree with the enzyme-linked immunosorbent assay (ELISA) kit. Our study suggests that rosiglitazone hydrochloride (RH) may be a potential drug for diabetic patients with breast cancer, while the anti-cancer effect of metformin hydrochloride (MH) is debatable since MH slightly promotes the EGFR expression of MCF-7 cells in this study. This sensing platform endows more feasibility for highly sensitive and accurate feedback of pesticide effects at the membrane protein level.
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Song WM, Chia PL, Zhou X, Walsh M, Silva J, Zhang B. Pseudo-temporal dynamics of chemoresistant triple negative breast cancer cells reveal EGFR/HER2 inhibition as synthetic lethal during mid-neoadjuvant chemotherapy. iScience 2023; 26:106064. [PMID: 36824282 PMCID: PMC9942122 DOI: 10.1016/j.isci.2023.106064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/17/2022] [Accepted: 01/23/2023] [Indexed: 01/29/2023] Open
Abstract
In the absence of targetable hormonal axes, chemoresistance for triple-negative breast cancer (TNBC) often compromises patient outcomes. To investigate the underlying tumor dynamics, we performed trajectory analysis on the single-nuclei RNA-seq (snRNA-seq) of chemoresistant tumor clones during neoadjuvant chemotherapy (NAC). It revealed a common tumor trajectory across multiple patients with HER2-like expansions during NAC. Genome-wide CRISPR-Cas9 knock-out on mammary epithelial cells revealed chemosensitivity-promoting knock-outs were up-regulated along the tumor trajectory. Furthermore, we derived a consensus gene signature of TNBC chemoresistance by comparing the trajectory transcriptome with chemoresistant transcriptomes from TNBC cell lines and poor prognosis patient samples to predict FDA-approved drugs, including afatinib (pan-HER inhibitor), targeting the consensus signature. We validated the synergistic efficacy of afatinib and paclitaxel in chemoresistant TNBC cells and confirmed pharmacological suppression of the consensus signature. The study provides a dynamic model of chemoresistant tumor transcriptome, and computational framework for pharmacological intervention.
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Affiliation(s)
- Won-Min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Pei-Ling Chia
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Xianxiao Zhou
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Martin Walsh
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Jose Silva
- Department of Pathology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
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Pharmacodynamic Modeling to Evaluate the Impact of Cimetidine, an OCT2 Inhibitor, on the Anticancer Effects of Cisplatin. Cells 2022; 12:cells12010057. [PMID: 36611850 PMCID: PMC9818342 DOI: 10.3390/cells12010057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Despite potent anticancer activity, the clinical utilization of cisplatin is limited due to nephrotoxicity. As Organic Cation Transporter 2 (OCT2) has been shown to be one of the key transporters involved in the uptake of cisplatin into renal proximal tubules, OCT2 inhibitors such as cimetidine have been explored to suppress cisplatin-induced nephrotoxicity. Nonetheless, the impact of OCT2 inhibition or cimetidine on the anti-cancer effects of cisplatin has not been extensively examined. The main objective of the present study was to quantitatively characterize the anticancer effects of cisplatin and cimetidine and determine their nature of interactions in two cancer cell lines, OCT2-negative hepatocellular carcinoma (HCC) cell line, Huh7, and OCT2-positive breast cancer cell line, MDA-MB-468. First, we determined the static concentration-response curves of cisplatin and cimetidine as single agents. Next, with the help of three-dimensional (3D) response surface analyses and a competitive interaction model, we determined their nature of interactions at static concentrations to be modestly synergistic or additive in Huh7 and antagonistic in MDA-MB-468. These results were consistent with the cell-level pharmacodynamic (PD) modeling analysis which leveraged the time-course effects of drugs as single agents and drug combinations. Our developed PD model can be further used to design future preclinical studies to further investigate the cisplatin and cimetidine combinations in different in vitro and in vivo cancer models.
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Tsao SY. Potential of mRNA vaccines to become versatile cancer vaccines. World J Clin Oncol 2022; 13:663-674. [PMID: 36160466 PMCID: PMC9476609 DOI: 10.5306/wjco.v13.i8.663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/15/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
For centuries, therapeutic cancer vaccines have been developed and tried clinically. Way back in the late 19th century, the Father of Immunotherapy, William Coley had discovered that bacterial toxins were effective for inoperable sarcomas. In the 1970s, the Bacillus Calmette-Guérin (BCG) vaccine was repurposed, e.g., for advanced melanomas. Then, therapeutic cancer vaccines based on tumor-associated antigens (found on the surfaces of cancer cells) were tried clinically but apparently have not made a really significant clinical impact. For repurposed pathogen vaccines, only the BCG vaccine was approved in 1989 for local application to treat nonmuscle-invading bladder cancers. Although the mildly toxic vaccine adjuvants deliberately added to conventional pathogen vaccines are appropriate for seasonal applications, when repurposed for continual oncology usage, toxicity may be problematic. In 2010, even with the approval of sipuleucel-T as the very first cancer vaccine (dendritic cell) developed for designated prostate cancers, it has also not made a really significant clinical impact. Perhaps more "user friendly" cancer vaccines should be explored. As from approximately 30 years ago, the safety and effectiveness of mRNA vaccination for oncology had already been studied, the current coronavirus disease 2019 pandemic, though disastrous, has given such progressively advancing technology a kickstart. For oncology, other virtues of mRNA vaccines seem advantageous, e.g., rapid and versatile development, convenient modular design, and entirely cell-free synthesis, are being progressively recognized. Moreover, mRNAs encoding various oncology antigens for vaccination may also be tested with the combi-nation of relatively non-toxic modalities of oncology treatments, e.g., metformin or metronomic (low-dose, prolonged administration) chemotherapy. Admittedly, robust clinical data obtained through good quality clinical trials are mandatory.
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Affiliation(s)
- Shiu-Ying Tsao
- Department of Oncology, Hong Kong SAR Oncology Centre, Hong Kong SAR 999077, China
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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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Metformin and Breast Cancer: Where Are We Now? Int J Mol Sci 2022; 23:ijms23052705. [PMID: 35269852 PMCID: PMC8910543 DOI: 10.3390/ijms23052705] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/25/2022] [Accepted: 02/27/2022] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.
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Iancu G, Serban D, Badiu CD, Tanasescu C, Tudosie MS, Tudor C, Costea DO, Zgura A, Iancu R, Vasile D. Tyrosine kinase inhibitors in breast cancer (Review). Exp Ther Med 2022; 23:114. [PMID: 34970337 PMCID: PMC8713180 DOI: 10.3892/etm.2021.11037] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 09/20/2021] [Indexed: 12/23/2022] Open
Abstract
Anti-epidermal growth factor receptor (EGFR)-targeted therapy has been intensely researched in the last years, motivated by the favorable results obtained with monoclonal antibodies in HER2-enriched breast cancer (BC) patients. Most researched alternatives of anti-EGFR agents were tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. However, excluding monoclonal antibodies trastuzumab and pertuzumab, the remaining anti-EGFR molecules have exhibited disappointing results, due to the lack of specificity and frequent adverse side effects. TKIs have several advantages, including reduced cardiotoxicity, oral administration and favorable penetration of blood-brain barrier for brain metastatic BC. Lapatinib and neratinib and recently pyrotinib (approved only in China) are the only TKIs from dozens of molecules researched over the years that were approved to be used in clinical practice with limited indications, in a subset of BC patients, single or in combination with other chemotherapy or hormonal therapeutic agents. Improved identification of BC subtypes and improved characterization of aggressive forms (triple negative BC or inflammatory BC) should lead to advancements in shaping of targeted agents to improve the outcome of patients.
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Affiliation(s)
- George Iancu
- Department of Obstetrics and Gynecology, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gynecology, ‘Filantropia’ Clinical Hospital, 011132 Bucharest, Romania
| | - Dragos Serban
- Department of General Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Fourth Department of General Surgery, Emergency University Hospital, 050098 Bucharest, Romania
| | - Cristinel Dumitru Badiu
- Department of General Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of General Surgery, ‘Prof. Dr. Bagdasar Arseni’ Emergency Clinical Hospital, 041915 Bucharest, Romania
| | - Ciprian Tanasescu
- Third Clinico-Surgical Department, Faculty of Medicine, ‘Lucian Blaga’ University, 550169 Sibiu, Romania
| | - Mihai Silviu Tudosie
- Department of Orthopedia and Intensive care, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- ICU II Toxicology, Clinical Emergency Hospital, 014461 Bucharest, Romania
| | - Corneliu Tudor
- Department of General Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Daniel Ovidiu Costea
- Department of General Surgery, Faculty of Medicine, ‘Ovidius’ University, 900470 Constanta, Romania
- First Surgery Department, Emergency County Hospital, 900591 Constanta, Romania
| | - Anca Zgura
- Department of Oncology Radiotherapy, Institute of Oncology ‘Prof. Dr. Trestioreanu’, 022328 Bucharest, Romania
| | - Raluca Iancu
- Department of ENT-Opthalmology, Faculty of Medicine, Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Ophthalmology, Emergency University Hospital, 050098 Bucharest, Romania
| | - Danut Vasile
- Department of General Surgery, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- First Department of General Surgery, Emergency University Hospital, 050098 Bucharest, Romania
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Cheung PY, Harrison PT, Davidson AJ, Hollywood JA. In Vitro and In Vivo Models to Study Nephropathic Cystinosis. Cells 2021; 11:6. [PMID: 35011573 PMCID: PMC8750259 DOI: 10.3390/cells11010006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022] Open
Abstract
The development over the past 50 years of a variety of cell lines and animal models has provided valuable tools to understand the pathophysiology of nephropathic cystinosis. Primary cultures from patient biopsies have been instrumental in determining the primary cause of cystine accumulation in the lysosomes. Immortalised cell lines have been established using different gene constructs and have revealed a wealth of knowledge concerning the molecular mechanisms that underlie cystinosis. More recently, the generation of induced pluripotent stem cells, kidney organoids and tubuloids have helped bridge the gap between in vitro and in vivo model systems. The development of genetically modified mice and rats have made it possible to explore the cystinotic phenotype in an in vivo setting. All of these models have helped shape our understanding of cystinosis and have led to the conclusion that cystine accumulation is not the only pathology that needs targeting in this multisystemic disease. This review provides an overview of the in vitro and in vivo models available to study cystinosis, how well they recapitulate the disease phenotype, and their limitations.
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Affiliation(s)
- Pang Yuk Cheung
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand; (P.Y.C.); (A.J.D.)
| | - Patrick T. Harrison
- Department of Physiology, BioSciences Institute, University College Cork, T12 XF62 Cork, Ireland;
| | - Alan J. Davidson
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand; (P.Y.C.); (A.J.D.)
| | - Jennifer A. Hollywood
- Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand; (P.Y.C.); (A.J.D.)
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Hashemzadeh N, Aghanejad A, Dalir Abdolahinia E, Dolatkhah M, Barzegar-Jalali M, Omidi Y, Barar J, Adibkia K. Targeted combined therapy in 2D and 3D cultured MCF-7 cells using metformin and erlotinib-loaded mesoporous silica magnetic nanoparticles. J Microencapsul 2021; 38:472-485. [PMID: 34511038 DOI: 10.1080/02652048.2021.1979672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM This research aims to develop potential therapeutic nanostructures (NSs) encapsulating metformin (MET) and erlotinib (ER) for combinational therapy in breast cancer. METHODS The ER and MET, both were loaded on mesoporous silica magnetic nanoparticles conjugated with polyethylene glycol and methotrexate to achieve targeted NSs. The developed NSs were characterised using SEM, DLS, and FTIR. Afterward, MTT, Trypan blue, and DNA extraction assays were operated for biological evaluations in the 2D and 3D MCF-7 cells. RESULTS Physicochemical approaches indicated the mean diameter of 69.4 nm ± 9.5 (PDI = 0.64), and neutral charge (2 mv) for the developed NSs. MET and ER-loaded NSs exhibited 62.56% ± 4.41 and 67.73% ± 3.03 drug release amount in pH = 5.4, respectively. MTT assay revealed that ER- and MET-loaded NSs had less metabolic activity (≈ 20%) in comparison with non-targeted NSs. CONCLUSION Overall, our combined ER and MET-loaded targeted NSs result in a synergistic inhibitory impact on MCF-7 cells.
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Affiliation(s)
- Nastaran Hashemzadeh
- Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayuob Aghanejad
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elaheh Dalir Abdolahinia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mitra Dolatkhah
- Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Barzegar-Jalali
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khosro Adibkia
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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De Lellis L, Veschi S, Tinari N, Mokini Z, Carradori S, Brocco D, Florio R, Grassadonia A, Cama A. Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates. Cancers (Basel) 2021; 13:3946. [PMID: 34439102 PMCID: PMC8394389 DOI: 10.3390/cancers13163946] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.
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Affiliation(s)
- Laura De Lellis
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Serena Veschi
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Zhirajr Mokini
- European Society of Anaesthesiology and Intensive Care (ESAIC) Mentorship Programme, ESAIC, 24 Rue des Comédiens, BE-1000 Brussels, Belgium;
| | - Simone Carradori
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Davide Brocco
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Rosalba Florio
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
| | - Antonino Grassadonia
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (N.T.); (A.G.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Cama
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (S.V.); (S.C.); (D.B.); (R.F.)
- Center for Advanced Studies and Technology—CAST, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
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15
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Vazquez N, Lopez A, Cuello V, Persans M, Schuenzel E, Innis-Whitehouse W, Keniry M. NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells. Cancer Treat Res Commun 2021; 27:100340. [PMID: 33636591 DOI: 10.1016/j.ctarc.2021.100340] [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] [Received: 11/21/2020] [Revised: 02/04/2021] [Accepted: 02/16/2021] [Indexed: 12/19/2022]
Abstract
Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway activity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway inhibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and basal-like breast cancer (BBC) cell lines. We examined growth, gene expression, and apoptosis in cells treated with NVP-BEZ235 and/or JAKi. Growth and recovery assays showed no significant impact of dual treatment with NVP-BEZ235/JAKi compared to NVP-BEZ235 treatment alone. Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis. Stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples. Future in vivo studies may give further insight into the impact of combined NVP-BEZ235/JAKi treatment in GBM and BBC.
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Affiliation(s)
- Neftali Vazquez
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Alma Lopez
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Victoria Cuello
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Michael Persans
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Erin Schuenzel
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Wendy Innis-Whitehouse
- School of Medicine, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States
| | - Megan Keniry
- Department of Biology, University of Texas- Rio Grande Valley, 1201 W. University Dr., Edinburg, TX 78539, United States.
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16
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Salim E, El-Sisi AED, Sokar S, El-Sayad M, Moussa E. Metformin potentiates the chemotherapeutic effects of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b] pyridine-induced Mammary Carcinoma in rats. Fundam Clin Pharmacol 2020; 35:700-713. [PMID: 32905620 DOI: 10.1111/fcp.12604] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 11/28/2022]
Abstract
This study was carried out to evaluate the antitumor activity of Metformin (Met) and its impending utility to potentiate the chemotherapeutic action of doxorubicin on 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP)-induced rat mammary carcinogenesis. Female Sprague -Dawley (SD) rats were divided into seven groups (n = 15 each). Mammary carcinogenesis was induced by the administration of PhIP at a dose of 75 mg/kg by gavage. Met treatment was 2 mg/ml in drinking water for 26 weeks started after the last PhIP dose. Doxorubicin (Dox) treatment started after one month of the last PhIP dose with a dose of 4 mg/kg, i.v. once per week for 4 weeks. Compared to the PhIP group, the latency period of tumors in the PhIP+Dox, PhIP+Met, and PhIP+Dox+Met groups were significantly increased and tumors' incidences and multiplicities were significantly reduced. By immunohistochemistry, carcinomas from the combination treatment groups showed a significant decrease in the labeling indexes (LI%) of cellular proliferation and CD44 compared to the PhIP group while LI% for ERα was significantly decreased in all combination treatment groups compared to the PhIP-administered group. Moreover, the quantitative mRNA expression of ERα was significantly decreased in mammary tumors from PhIP + Dox+Met combined group more than the PhIP + Dox group. However, mRNA expression of EGF was found significantly lower in all combination treatment groups compared to the PhIP group. These findings suggest that Metformin potentiate the antitumor efficacy of doxorubicin and had beneficial effects on PhIP-induced mammary carcinogenesis through the prevention of cellular proliferation and mRNA expression of ERα and EGF.
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Affiliation(s)
- Elsayed Salim
- Department of Zoology, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Alaa El-Din El-Sisi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Samia Sokar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Magda El-Sayad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Ethar Moussa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
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17
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Khan HJ, Rohondia SO, Othman Ahmed ZS, Zalavadiya N, Dou QP. Increasing opportunities of drug repurposing for treating breast cancer by the integration of molecular, histological, and systemic approaches. DRUG REPURPOSING IN CANCER THERAPY 2020:121-172. [DOI: 10.1016/b978-0-12-819668-7.00005-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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18
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Bennani FE, Doudach L, Cherrah Y, Ramli Y, Karrouchi K, Ansar M, Faouzi MEA. Overview of recent developments of pyrazole derivatives as an anticancer agent in different cell line. Bioorg Chem 2019; 97:103470. [PMID: 32120072 DOI: 10.1016/j.bioorg.2019.103470] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 11/21/2019] [Accepted: 11/22/2019] [Indexed: 02/06/2023]
Abstract
Pyrazole is a five-membered aromatic heterocyclic ring with two adjacent nitrogen atoms C3H3N2H.The presence of this nucleus in pharmacological agents of various therapeutic categories gifts a broad spectrum of biological activities and pharmaceuticals that contain pyrazole like celecoxib (anti-inflammatory), CDPPB (antipsychotic), Rimonabant (anti-obesity), Difenamizole, (Analgesic), Betazole (H2 receptor agonist), Fezolamide (Antidepressant), etc… The pharmacological potential of the pyrazole fraction is proved in many publication where they synthesized and evaluated pyrazoles against several biological agents. The aim of this article review is to survey recent works linking pyrazole structures to anticancer activities corresponding to 9 different type of cancer.
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Affiliation(s)
- Fatima Ezzahra Bennani
- Laboratory of Pharmacology and Toxicology, Bio Pharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco; Laboratory of Therapeutic Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco.
| | - Latifa Doudach
- Department of Biomedical Engineering Medical Physiology, Higher School of Technical Education of Rabat, Mohammed V University in Rabat, BP 6203 Rabat, Morocco
| | - Yahia Cherrah
- Laboratory of Pharmacology and Toxicology, Bio Pharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco
| | - Youssef Ramli
- Laboratory of Therapeutic Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco
| | - Khalid Karrouchi
- Laboratory of Therapeutic Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco
| | - M'hammed Ansar
- Laboratory of Therapeutic Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco
| | - My El Abbes Faouzi
- Laboratory of Pharmacology and Toxicology, Bio Pharmaceutical and Toxicological Analysis Research Team, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, BP 6203, Rabat, Morocco
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19
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Samuel SM, Varghese E, Kubatka P, Triggle CR, Büsselberg D. Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer. Biomolecules 2019; 9:E846. [PMID: 31835318 PMCID: PMC6995629 DOI: 10.3390/biom9120846] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 12/25/2022] Open
Abstract
Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as 'Glucophage' among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.
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Affiliation(s)
- Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Chris R. Triggle
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
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20
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Chen H, Lin C, Lu C, Wang Y, Han R, Li L, Hao S, He Y. Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition. CLINICAL RESPIRATORY JOURNAL 2019; 13:781-790. [PMID: 31562701 DOI: 10.1111/crj.13091] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 07/22/2019] [Accepted: 09/19/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Hengyi Chen
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Caiyu Lin
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Conghua Lu
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Yubo Wang
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Rui Han
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Li Li
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Shuai Hao
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
| | - Yong He
- Department of Respiratory Disease Daping Hospital Army Medical University Chongqing China
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21
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Baker AEG, Bahlmann LC, Tam RY, Liu JC, Ganesh AN, Mitrousis N, Marcellus R, Spears M, Bartlett JMS, Cescon DW, Bader GD, Shoichet MS. Benchmarking to the Gold Standard: Hyaluronan-Oxime Hydrogels Recapitulate Xenograft Models with In Vitro Breast Cancer Spheroid Culture. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1901166. [PMID: 31322299 DOI: 10.1002/adma.201901166] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/28/2019] [Indexed: 06/10/2023]
Abstract
Many 3D in vitro models induce breast cancer spheroid formation; however, this alone does not recapitulate the complex in vivo phenotype. To effectively screen therapeutics, it is urgently needed to validate in vitro cancer spheroid models against the gold standard of xenografts. A new oxime-crosslinked hyaluronan (HA) hydrogel is designed, manipulating gelation rate and mechanical properties to grow breast cancer spheroids in 3D. This HA-oxime breast cancer model maintains the gene expression profile most similar to that of tumor xenografts based on a pan-cancer gene expression profile (comprising 730 genes) of three different human breast cancer subtypes compared to Matrigel or conventional 2D culture. Differences in gene expression between breast cancer cultures in HA-oxime versus Matrigel or 2D are confirmed for 12 canonical pathways by gene set variation analysis. Importantly, drug response is dependent on the culture method. Breast cancer cells respond better to the Rac inhibitor (EHT-1864) and the PI3K inhibitor (AZD6482) when cultured in HA-oxime versus Matrigel. This study demonstrates the superiority of an HA-based hydrogel as a platform for in vitro breast cancer culture of both primary, patient-derived cells and cell lines, and provides a hydrogel culture model that closely matches that in vivo.
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Affiliation(s)
- Alexander E G Baker
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Laura C Bahlmann
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Roger Y Tam
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Jeffrey C Liu
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Ahil N Ganesh
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Nikolaos Mitrousis
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
| | - Richard Marcellus
- Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Toronto, Ontario, M5G 0A3, Canada
| | - Melanie Spears
- Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Toronto, Ontario, M5G 0A3, Canada
- Department of Laboratory Medicine and Pathology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
| | - John M S Bartlett
- Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Toronto, Ontario, M5G 0A3, Canada
| | - David W Cescon
- Princess Margaret Cancer Centre, University Health Network, 610 University Ave., Toronto, Ontario, M5G 2C1, Canada
| | - Gary D Bader
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
| | - Molly S Shoichet
- The Donnelly Centre, University of Toronto, Toronto, 160 College St, Ontario, M5S 3E1, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, M5S 3E5, Canada
- Institute of Biomaterials and Biomedical Engineering, 164 College Street, Toronto, Ontario, M5S 3G9, Canada
- Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
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22
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Fenn K, Maurer M, Lee SM, Crew KD, Trivedi MS, Accordino MK, Hershman DL, Kalinsky K. Phase 1 Study of Erlotinib and Metformin in Metastatic Triple-Negative Breast Cancer. Clin Breast Cancer 2019; 20:80-86. [PMID: 31570268 DOI: 10.1016/j.clbc.2019.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple-negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC. PATIENTS AND METHODS Patients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3 + 3 design. Dose-limiting toxicities (DLT) were assessed during the first 5 weeks of therapy. The primary objective was to determine the maximum tolerated dose of metformin with fixed-dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression-free survival. RESULTS Eight patients were enrolled. The median number of prior therapies for metastatic disease was 2.5 (range, 1-6). No DLT events were reported during the DLT assessment period. Most adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 adverse events were reported. The best observed response was stable disease in 2 patients (25%). Median progression-free survival was 60 days (range, 36-61 days). CONCLUSION Erlotinib and metformin were well tolerated in a population of pretreated mTNBC patients but did not demonstrate efficacy in this population.
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Affiliation(s)
- Kathleen Fenn
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | | | - Shing M Lee
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | - Katherine D Crew
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Meghna S Trivedi
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Melissa K Accordino
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Dawn L Hershman
- Department of Medicine, Columbia University Irving Medical Center, New York NY
| | - Kevin Kalinsky
- Department of Medicine, Columbia University Irving Medical Center, New York NY.
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23
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Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer 2019; 44:100488. [PMID: 31235186 DOI: 10.1016/j.currproblcancer.2019.06.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/25/2019] [Accepted: 06/08/2019] [Indexed: 12/11/2022]
Abstract
Metformin, a well-acknowledged biguanide, safety profile and multiaction drug with low cost for management of type 2 diabetes, makes a first-class candidate for repurposing. The off-patent drug draws huge attention for repositioned for anticancer drug delivery recently. Still few unanswered questions are challenging, among them one leading question; can metformin use as a generic therapy for all breast cancer subtypes? And is metformin able to get over the problem of drug resistance? The review focused on the mechanisms of metformin action specifically for breast cancer therapy and overcoming the resistance; also discusses preclinical and ongoing and completed clinical trials. The existing limitation such as therapeutic dose specifically for cancer treatment, resistance of metformin in breast cancer and organic cation transporters heterogeneity of the drug opens up a new pathway for improved understanding and successful application as repurposed effective chemotherapeutics for breast cancer. However, much more additional research is needed to confirm the accurate efficacy of metformin treatment for prevention of cancer and its recurrence.
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24
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Cheng H, Ge X, Zhuo S, Gao Y, Zhu B, Zhang J, Shang W, Xu D, Ge W, Shi L. β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2. Front Pharmacol 2018; 9:1413. [PMID: 30555330 PMCID: PMC6284059 DOI: 10.3389/fphar.2018.01413] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 11/16/2018] [Indexed: 12/29/2022] Open
Abstract
The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical application. β-elemene is a natural sesquiterpene with potent anti-cancer ability, and also it is renowned for its plant-origin, safety and the additive effect with traditional therapies, which prompt us to explore its potential to co-operate with TKIs to achieve greater therapeutic efficacy. Impressively, our study demonstrates that, elemene, in combination of gefitinib, displayed a significantly higher activity in inhibiting lung cancer cellular proliferation, migration and invasion. More importantly, combinative treatment profoundly impaired the epithelial to mesenchymal transition (EMT), the stem-like properties and the self-renewal capacity of lung cancer cells, and hence impeded the in vivo tumor development. We also reveal that the synergistic anti-tumor effect of elemene and gefitinib was largely mediated their regulation of enhancer of zeste homolog 2 (EZH2), an oncogenic histone methyltransferase and gene transcriptional regulator. Thus, our data indicate that combinative treatment of elemene and gefitinib has greater anti-neoplastic activity and greater efficacies in targeting cancer stem-like properties, mainly through regulating the malignant gene modifier and hence the subsequent effector molecules required for cancer progression. The findings may have potential implications for treating aggressive and resistant lung cancers.
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Affiliation(s)
- Haibo Cheng
- Collaborative Innovation Center of Cancer Prevention and Treatment, The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiaoyin Ge
- School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shiqin Zhuo
- School of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yanan Gao
- School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Bo Zhu
- School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Junfeng Zhang
- School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Collaborative Innovation Center of Cancer Prevention and Treatment, The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dakang Xu
- Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Key Lab of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, China
- Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Weihong Ge
- School of Pharmaceutics, Zhejiang Chinese Medical University, Hangzhou, China
| | - Liyun Shi
- School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China
- Key Lab of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, China
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25
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Corigliano DM, Syed R, Messineo S, Lupia A, Patel R, Reddy CVR, Dubey PK, Colica C, Amato R, De Sarro G, Alcaro S, Indrasena A, Brunetti A. Indole and 2,4-Thiazolidinedione conjugates as potential anticancer modulators. PeerJ 2018; 6:e5386. [PMID: 30123711 PMCID: PMC6087425 DOI: 10.7717/peerj.5386] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 07/17/2018] [Indexed: 12/14/2022] Open
Abstract
Background Thiazolidinediones (TZDs), also called glitazones, are five-membered carbon ring molecules commonly used for the management of insulin resistance and type 2 diabetes. Recently, many prospective studies have also documented the impact of these compounds as anti-proliferative agents, though several negative side effects such as hepatotoxicity, water retention and cardiac issues have been reported. In this work, we synthesized twenty-six new TZD analogues where the thiazolidinone moiety is directly connected to an N-heterocyclic ring in order to lower their toxic effects. Methods By adopting a widely applicable synthetic method, twenty-six TZD derivatives were synthesized and tested for their antiproliferative activity in MTT and Wound healing assays with PC3 (prostate cancer) and MCF-7 (breast cancer) cells. Results Three compounds, out of twenty-six, significantly decreased cellular viability and migration, and these effects were even more pronounced when compared with rosiglitazone, a well-known member of the TZD class of antidiabetic agents. As revealed by Western blot analysis, part of this antiproliferative effect was supported by apoptosis studies evaluating BCL-xL and C-PARP protein expression. Conclusion Our data highlight the promising potential of these TZD derivatives as anti-proliferative agents for the treatment of prostate and breast cancer.
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Affiliation(s)
- Domenica M Corigliano
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Riyaz Syed
- Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
| | - Sebastiano Messineo
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Antonio Lupia
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Rahul Patel
- Department of Food Science and Biotechnology, Dongguk University, Ilsandong-gu, Goyang-si, Gyeonggi-do, South Korea
| | | | - Pramod K Dubey
- Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
| | - Carmela Colica
- CNR, IBFM UOS of Germaneto, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Rosario Amato
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | | | - Stefano Alcaro
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Adisherla Indrasena
- Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India
| | - Antonio Brunetti
- Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
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26
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Antognelli C, Cecchetti R, Riuzzi F, Peirce MJ, Talesa VN. Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control. J Cell Mol Med 2018; 22:2865-2883. [PMID: 29504694 PMCID: PMC5908125 DOI: 10.1111/jcmm.13581] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 01/23/2018] [Indexed: 01/07/2023] Open
Abstract
Metastasis is the primary cause of death in prostate cancer (PCa) patients. Effective therapeutic intervention in metastatic PCa is undermined by our poor understanding of its molecular aetiology. Defining the mechanisms underlying PCa metastasis may lead to insights into how to decrease morbidity and mortality in this disease. Glyoxalase 1 (Glo1) is the detoxification enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). Hydroimidazolone (MG-H1) and argpyrimidine (AP) are AGEs originating from MG-mediated post-translational modification of proteins at arginine residues. AP is involved in the control of epithelial to mesenchymal transition (EMT), a crucial determinant of cancer metastasis and invasion, whose regulation mechanisms in malignant cells are still emerging. Here, we uncover a novel mechanism linking Glo1 to the maintenance of the metastatic phenotype of PCa cells by controlling EMT by engaging the tumour suppressor miR-101, MG-H1-AP and TGF-β1/Smad signalling. Moreover, circulating levels of Glo1, miR-101, MG-H1-AP and TGF-β1 in patients with metastatic compared with non-metastatic PCa support our in vitro results, demonstrating their clinical relevance. We suggest that Glo1, together with miR-101, might be potential therapeutic targets for metastatic PCa, possibly by metformin administration.
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Affiliation(s)
- Cinzia Antognelli
- Department of Experimental MedicineUniversity of PerugiaPerugiaItaly
| | - Rodolfo Cecchetti
- Department of Experimental MedicineUniversity of PerugiaPerugiaItaly
| | - Francesca Riuzzi
- Department of Experimental MedicineUniversity of PerugiaPerugiaItaly
| | - Matthew J. Peirce
- Department of Experimental MedicineUniversity of PerugiaPerugiaItaly
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27
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Li Z, Wang L, Luo N, Zhao Y, Li J, Chen Q, Tian Y. Metformin inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the phosphorylation of Akt. Oncol Lett 2018; 15:7948-7954. [PMID: 29725482 DOI: 10.3892/ol.2018.8297] [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] [Received: 06/06/2016] [Accepted: 08/17/2017] [Indexed: 02/07/2023] Open
Abstract
Metformin (Met) is a therapeutic agent for the treatment of type 2 diabetes mellitus. There is evidence that Met may reduce the risk of cancer in patients with type 2 diabetes mellitus by inhibiting tumor cell growth, prolonging the overall survival time in patients with various types of malignancy. However, the function and mechanism of Met have not been fully elucidated in osteosarcoma (OS). The present study evaluated the anti-proliferative effect of Met on MG63 and U2OS OS cells, identifying that it acted in a dose- and time-dependent manner. Met also inhibited OS cell migration and invasion, potentially by regulating the epithelial-mesenchymal transition in OS cells. Mechanistically, Met was demonstrated to partly exert these functions through the suppression of Akt phosphorylation, which was associated with increased phosphatase and tensin (PTEN) expression. Silencing PTEN prevented the Met-induced inhibition of the growth and metastasis of OS cells. As Met has anti-proliferative and anti-metastatic effects on OS cells it is a potential candidate, in combination with other chemotherapeutic agents, for use in the treatment of OS.
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Affiliation(s)
- Zuohong Li
- Department of Orthopedics, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, P.R. China
| | - Lesheng Wang
- Department of Blood Transfusion, Chinese People's Liberation Army 210 Hospital, Dalian, Liaoning 116015, P.R. China
| | - Nan Luo
- Department of Infectious Diseases, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Yantao Zhao
- Department of Orthopedics, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, P.R. China
| | - Jiazhi Li
- Department of Pathology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Qiwei Chen
- Department of Pathology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yu Tian
- Department of Pathology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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28
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Rico M, Baglioni M, Bondarenko M, Laluce NC, Rozados V, André N, Carré M, Scharovsky OG, Menacho Márquez M. Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models. Oncotarget 2018; 8:2874-2889. [PMID: 27926515 PMCID: PMC5356849 DOI: 10.18632/oncotarget.13760] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 11/22/2016] [Indexed: 01/01/2023] Open
Abstract
Discovery of new drugs for cancer treatment is an expensive and time-consuming process and the percentage of drugs reaching the clinic remains quite low. Drug repositioning refers to the identification and development of new uses for existing drugs and represents an alternative drug development strategy. In this work, we evaluated the antitumor effect of metronomic treatment with a combination of two repositioned drugs, metformin and propranolol, in triple negative breast cancer models. By in vitro studies with five different breast cancer derived cells, we observed that combined treatment decreased proliferation (P < 0.001), mitochondrial activity (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). In vivo studies in immunocompetent mice confirmed the potential of this combination in reducing tumor growth (P < 0.001) and preventing metastasis (P < 0.05). Taken together our results suggest that metformin plus propranolol combined treatment might be beneficial for triple negative breast cancer control, with no symptoms of toxicity.
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Affiliation(s)
- María Rico
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina.,El Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina
| | - María Baglioni
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Maryna Bondarenko
- Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de Pharmacie, Marseille, France
| | - Nahuel Cesatti Laluce
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Viviana Rozados
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Nicolas André
- Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de Pharmacie, Marseille, France.,Service d'Hématologie and Oncologie Pédiatrique, AP-HM, Marseille, France.,Metronomics Global Health Initiative, Marseille, France
| | - Manon Carré
- Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de Pharmacie, Marseille, France
| | - O Graciela Scharovsky
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina.,El Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.,Metronomics Global Health Initiative, Marseille, France
| | - Mauricio Menacho Márquez
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina.,El Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina
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29
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Penkert J, Ripperger T, Schieck M, Schlegelberger B, Steinemann D, Illig T. On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer. Oncotarget 2018; 7:67626-67649. [PMID: 27590516 PMCID: PMC5341901 DOI: 10.18632/oncotarget.11759] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
Altered metabolism in tumor cells has been a focus of cancer research for as long as a century but has remained controversial and vague due to an inhomogeneous overall picture. Accumulating genomic, metabolomic, and lastly panomic data as well as bioenergetics studies of the past few years enable a more comprehensive, systems-biologic approach promoting deeper insight into tumor biology and challenging hitherto existing models of cancer bioenergetics. Presenting a compendium on breast cancer-specific metabolome analyses performed thus far, we review and compile currently known aspects of breast cancer biology into a comprehensive network, elucidating previously dissonant issues of cancer metabolism. As such, some of the aspects critically discussed in this review include the dynamic interplay or metabolic coupling between cancer (stem) cells and cancer-associated fibroblasts, the intratumoral and intertumoral heterogeneity and plasticity of cancer cell metabolism, the existence of distinct metabolic tumor compartments in need of separate yet simultaneous therapeutic targeting, the reliance of cancer cells on oxidative metabolism and mitochondrial power, and the role of pro-inflammatory, pro-tumorigenic stromal conditioning. Comprising complex breast cancer signaling networks as well as combined metabolomic and genomic data, we address metabolic consequences of mutations in tumor suppressor genes and evaluate their contribution to breast cancer predisposition in a germline setting, reasoning for distinct personalized preventive and therapeutic measures. The review closes with a discussion on central root mechanisms of tumor cell metabolism and rate-limiting steps thereof, introducing essential strategies for therapeutic targeting.
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Affiliation(s)
- Judith Penkert
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Tim Ripperger
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | | | | | - Doris Steinemann
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Thomas Illig
- Institute of Human Genetics, Hannover Medical School, Hannover, Germany.,Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
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30
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Li B, Li X, Ni Z, Zhang Y, Zeng Y, Yan X, Huang Y, He J, Lyu X, Wu Y, Wang Y, Zheng Y, He F. Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget 2018; 7:59458-59470. [PMID: 27449090 PMCID: PMC5312324 DOI: 10.18632/oncotarget.10694] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 07/09/2016] [Indexed: 12/17/2022] Open
Abstract
Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption. The in vivo experiments in nude mice also showed that DCA and Met synergistically suppressed the growth of xenograft ovarian tumors. These results may pave a way for developing novel strategies for the treatment of ovarian cancer based on the combined use of DCA and Met.
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Affiliation(s)
- Bo Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Xinzhe Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Zhenhong Ni
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yijun Zeng
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Xiaohuan Yan
- Department of Obstetrics and Gynecology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China
| | - Yan Huang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China
| | - Jintao He
- Battalion 17 of Students, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China
| | - Xilin Lyu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yaran Wu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yuting Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
| | - Yingru Zheng
- Department of Obstetrics and Gynecology, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China
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31
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Bartelink IH, Prideaux B, Krings G, Wilmes L, Lee PRE, Bo P, Hann B, Coppé JP, Heditsian D, Swigart-Brown L, Jones EF, Magnitsky S, Keizer RJ, de Vries N, Rosing H, Pawlowska N, Thomas S, Dhawan M, Aggarwal R, Munster PN, Esserman LJ, Ruan W, Wu AHB, Yee D, Dartois V, Savic RM, Wolf DM, van ’t Veer L. Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors. Breast Cancer Res 2017; 19:107. [PMID: 28893315 PMCID: PMC5594551 DOI: 10.1186/s13058-017-0896-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 08/14/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). RESULTS Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001). CONCLUSIONS PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.
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Affiliation(s)
- Imke H. Bartelink
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Brendan Prideaux
- Rutgers New Jersey Medical School, Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Ave, Newark, NJ USA
| | - Gregor Krings
- Department of Pathology, University of California, San Francisco, CA USA
| | - Lisa Wilmes
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA USA
| | - Pei Rong Evelyn Lee
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Pan Bo
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Byron Hann
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Jean-Philippe Coppé
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Diane Heditsian
- Patient advocate University of California, San Francisco Breast Science Advocacy Core, San Francisco, CA USA
| | - Lamorna Swigart-Brown
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Ella F. Jones
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA USA
| | - Sergey Magnitsky
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA USA
| | - Ron J Keizer
- Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, USA
| | - Niels de Vries
- Department of Clinical Pharmacy, Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, NKI-AVL, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Clinical Pharmacy, Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, NKI-AVL, Amsterdam, The Netherlands
| | - Nela Pawlowska
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Scott Thomas
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Mallika Dhawan
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Rahul Aggarwal
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Pamela N. Munster
- Department of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA 9411 USA
| | - Laura J. Esserman
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Weiming Ruan
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA USA
| | - Alan H. B. Wu
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA USA
| | - Douglas Yee
- Division of Hematology Oncology, University of Minnesota, Minneapolis, MN USA
| | - Véronique Dartois
- Rutgers New Jersey Medical School, Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Ave, Newark, NJ USA
| | - Radojka M. Savic
- Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, USA
| | - Denise M. Wolf
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
| | - Laura van ’t Veer
- Department of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA USA
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32
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Alanazi IO, Khan Z. Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications. Asian Pac J Cancer Prev 2017; 17:445-53. [PMID: 26925626 DOI: 10.7314/apjcp.2016.17.2.445] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Epidermal growth factor receptors (EGFRs/HERs) and downstream signaling pathways have been implicated in the pathogenesis of several malignancies including breast cancer and its resistance to treatment with chemotherapeutic drugs. Consequently, several monoclonal antibodies as well as small molecule inhibitors targeting these pathways have emerged as therapeutic tools in the recent past. However, studies have shown that utilizing these molecules in combination with chemotherapy has yielded only limited success. This review describes the current understanding of EGFRs/HERs and associated signaling pathways in relation to development of breast cancer and responses to various cancer treatments in the hope of pointing to improved prevention, diagnosis and treatment. Also, we review the role of breast cancer stem cells (BCSCs) in disease and the potential to target these cells.
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Affiliation(s)
- Ibrahim O Alanazi
- King Abdulaziz City for Science and Technology, Genome Center, King Saud University, Riyadh, Kingdom of Saudi Arabia E-mail :
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33
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Biernacka KM, Persad RA, Bahl A, Gillatt D, Holly JMP, Perks CM. Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2. Endocr Relat Cancer 2017; 24:17-30. [PMID: 27754854 PMCID: PMC5118949 DOI: 10.1530/erc-16-0095] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.
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Affiliation(s)
- K M Biernacka
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - R A Persad
- Department of UrologySouthmead Hospital, Bristol, UK
| | - A Bahl
- Department of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK
| | - D Gillatt
- Department of UrologySouthmead Hospital, Bristol, UK
| | - J M P Holly
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - C M Perks
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
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Hopkins BD, Goncalves MD, Cantley LC. Obesity and Cancer Mechanisms: Cancer Metabolism. J Clin Oncol 2016; 34:4277-4283. [PMID: 27903152 DOI: 10.1200/jco.2016.67.9712] [Citation(s) in RCA: 260] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Obesity is a risk factor for cancer development and is associated with poor prognosis in multiple tumor types. The positive energy balance linked with obesity induces a variety of systemic changes including altered levels of insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, and cytokines. Each of these factors alters the nutritional milieu and has the potential to create an environment that favors tumor initiation and progression. Although the complete ramifications of obesity as it relates to cancer are still unclear, there is convincing evidence that reducing the magnitude of the systemic hormonal and inflammatory changes has significant clinical benefits. This review will examine the changes that occur in the obese state and review the biologic mechanisms that connect these changes to increased cancer risk. Understanding the metabolic changes that occur in obese individuals may also help to elucidate more effective treatment options for these patients when they develop cancer. Moving forward, targeted clinical trials examining the effects of behavioral modifications such as reduced carbohydrate intake, caloric restriction, structured exercise, and/or pharmacologic interventions such as the use of metformin, in obese populations may help to reduce their cancer risk.
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Affiliation(s)
- Benjamin D Hopkins
- All authors: Meyer Cancer Center, Weill Cornell Medical College, New York, NY
| | - Marcus D Goncalves
- All authors: Meyer Cancer Center, Weill Cornell Medical College, New York, NY
| | - Lewis C Cantley
- All authors: Meyer Cancer Center, Weill Cornell Medical College, New York, NY
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35
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Zimmermann M, Arachchige-Don APS, Donaldson MS, Patriarchi T, Horne MC. Cyclin G2 promotes cell cycle arrest in breast cancer cells responding to fulvestrant and metformin and correlates with patient survival. Cell Cycle 2016; 15:3278-3295. [PMID: 27753529 DOI: 10.1080/15384101.2016.1243189] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest. Moreover, insulin and insulin-like growth factor-1 (IGF-1) receptor signaling strongly represses CycG2. Here we show that blockade of ER-signaling in MCF7 and T47D BC cell lines enhances the expression and nuclear localization of CycG2. Knockdown of CycG2 attenuated the cell cycle arrest response of E2-depleted and fulvestrant treated MCF7 cells. These muted responses were accompanied by sustained inhibitory phosphorylation of retinoblastoma (RB) protein, expression of cyclin D1, phospho-activation of ERK1/2 and MEK1/2 and expression of cRaf. Our work indicates that CycG2 can form complexes with CDK10, a CDK linked to modulation of RAF/MEK/MAPK signaling and tamoxifen resistance. We determined that metformin upregulates CycG2 and potentiates fulvestrant-induced CycG2 expression and cell cycle arrest. CycG2 knockdown blunts the enhanced anti-proliferative effect of metformin on fulvestrant treated cells. Meta-analysis of BC tumor microarrays indicates that CCNG2 expression is low in aggressive, poor-prognosis BC and that high CCNG2 expression correlates with longer periods of patient survival. Together these findings indicate that CycG2 contributes to signaling networks that limit BC.
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Affiliation(s)
- Maike Zimmermann
- a Department of Pharmacology , University of California , Davis , CA , USA.,b Department of Pharmacology , University of Iowa , Iowa City , IA , USA.,c Department of Internal Medicine , Division of Hematology and Oncology, University of California Davis , Sacramento , CA , USA
| | | | | | - Tommaso Patriarchi
- a Department of Pharmacology , University of California , Davis , CA , USA
| | - Mary C Horne
- a Department of Pharmacology , University of California , Davis , CA , USA.,b Department of Pharmacology , University of Iowa , Iowa City , IA , USA
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36
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Menendez JA, Martin-Castillo B, Joven J. Metformin and cancer: Quo vadis et cui bono? Oncotarget 2016; 7:54096-54101. [PMID: 27356748 PMCID: PMC5342329 DOI: 10.18632/oncotarget.10262] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 06/03/2016] [Indexed: 12/21/2022] Open
Abstract
How many lives have already been saved by the anti-cancer drug metformin? Inadvertently perhaps, among the millions of type 2 diabetics with occult or known cancers and who have been prescribed metformin since the 1950s, thousands may have benefited from the anticancer properties of this first-line pharmacotherapy. Quo vadis? Now, researchers aim to move metformin from a non-targeted stage of cancer therapy that has been mostly developed retrospectively and empirically into a targeted therapy by following a biological rationale and a predefined mechanism of action. But, who might benefit from metformin? Cui bono? Because metformin is on the leading edge of a new generation of cancer metabolism-targeted therapies, perhaps it is the right time to provide solutions to the challenges that metformin and other onco-biguanides will face in the coming years before becoming incorporated into the therapeutic armamentarium against cancer.
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Affiliation(s)
- Javier A. Menendez
- Metabolism and Cancer Group, ProCURE (Program Against Cancer Therapeutic Resistance), Catalan Institute of Oncology, Girona, Catalonia, Spain
- Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
| | - Begoña Martin-Castillo
- Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
- Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain
| | - Jorge Joven
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain
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37
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Ismail NS, Ali EM, Ibrahim DA, Serya RA, Abou El Ella DA. Pyrazolo[3,4-d]pyrimidine based scaffold derivatives targeting kinases as anticancer agents. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2016. [DOI: 10.1016/j.fjps.2016.02.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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38
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Wang Y, Wei J, Li L, Fan C, Sun Y. Combined Use of Metformin and Everolimus Is Synergistic in the Treatment of Breast Cancer Cells. Oncol Res 2016; 22:193-201. [PMID: 26351208 PMCID: PMC7838426 DOI: 10.3727/096504015x14348950540999] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Everolimus inhibits mammalian target of rapamycin (mTOR) and leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5′-monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. Histopathological and biochemical studies of breast cancer show frequent dysregulation of the AMPK and the mTOR pathway. Therefore, we investigated the efficacy of the mTOR inhibitor everolimus and metformin in the treatment of breast cancer cells. This study evaluated the in vitro and in vivo effects of everolimus alone or in combination with metformin on breast cancer cells. MTT assay was used to quantify the inhibitory effect of the drugs on breast cancer cells in vitro. SCID mice injected with HCC1428 cells followed by different treatments were used to assess the in vivo efficacy of different agents. Data showed that the combination of everolimus and metformin exerted synergistic inhibitory effects on the growth of breast cancer cells both in culture and in a mouse xenograft model. Further, this combination abrogated S6 and 4EBP1phosphorylation. Collectively, we suggest that the combination of everolimus and metformin may be an effective regimen for treatment of breast cancer, hence warranting further evaluation of the combination in the clinic.
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Affiliation(s)
- Yunshan Wang
- Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China
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39
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Zhang HH, Guo XL. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol 2016; 78:13-26. [PMID: 27118574 DOI: 10.1007/s00280-016-3037-3] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 04/12/2016] [Indexed: 12/11/2022]
Abstract
Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review.
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Affiliation(s)
- Hui-Hui Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, No. 44 Wen Hua Xi Road, Jinan, 250012, People's Republic of China
| | - Xiu-Li Guo
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, No. 44 Wen Hua Xi Road, Jinan, 250012, People's Republic of China.
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40
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Chen LP, Wang P, Sun YJ, Wu YJ. Direct interaction of avermectin with epidermal growth factor receptor mediates the penetration resistance in Drosophila larvae. Open Biol 2016; 6:150231. [PMID: 27249340 PMCID: PMC4852453 DOI: 10.1098/rsob.150231] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 03/15/2016] [Indexed: 12/13/2022] Open
Abstract
With the widespread use of avermectins (AVMs) for managing parasitic and agricultural pests, the resistance of worms and insects to AVMs has emerged as a serious threat to human health and agriculture worldwide. The reduced penetration of AVMs is one of the main reasons for the development of the resistance to the chemicals. However, the detailed molecular mechanisms remain elusive. Here, we use the larvae of Drosophila melanogaster as the model organism to explore the molecular mechanisms underlying the development of penetration resistance to AVMs. We clearly show that the chitin layer is thickened and the efflux transporter P-glycoprotein (P-gp) is overexpressed in the AVM-resistant larvae epidermis. We reveal that the activation of the transcription factor Relish by the over-activated epidermal growth factor receptor (EGFR)/AKT/ERK pathway induces the overexpression of the chitin synthases DmeCHS1/2 and P-gp in the resistant larvae. Interestingly, we discover for the first time, to the best of our knowledge, that AVM directly interacts with EGFR and leads to the activation of the EGFR/AKT/ERK pathway, which activates the transcription factor Relish and induces the overexpression of DmeCHS1/2 and P-gp. These findings provide new insights into the molecular mechanisms underlying the development of penetration resistance to drugs.
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Affiliation(s)
- Li-Ping Chen
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
| | - Pan Wang
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China
| | - Ying-Jian Sun
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China Department of Veterinary Medicine and Animal Science, Beijing Agriculture College, Beijing 102206, People's Republic of China
| | - Yi-Jun Wu
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China
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41
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Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ, Kwong A, Tsumura A, Murphy R, Rappersberger K, Ortiz-Urda S. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 2015; 6:969-78. [PMID: 25504439 PMCID: PMC4359268 DOI: 10.18632/oncotarget.2824] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 11/24/2014] [Indexed: 12/22/2022] Open
Abstract
Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers.
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Affiliation(s)
- Igor Vujic
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.,Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria
| | - Martina Sanlorenzo
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.,Department of Medical Sciences, Section of Dermatology, University of Turin, Italy
| | - Christian Posch
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA.,Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria
| | - Rosaura Esteve-Puig
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
| | - Adam J Yen
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
| | - Andrew Kwong
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
| | - Aaron Tsumura
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
| | - Ryan Murphy
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
| | - Klemens Rappersberger
- Rudolfstiftung Hospital, Academic Teaching Hospital, Department of Dermatology, Juchgasse, Vienna, Austria
| | - Susana Ortiz-Urda
- University of California, San Francisco, Department of Dermatology, Mt. Zion Cancer Research Center, San Francisco, CA, USA
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42
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Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Lett 2015; 369:97-102. [PMID: 26341687 DOI: 10.1016/j.canlet.2015.08.024] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/06/2015] [Accepted: 08/02/2015] [Indexed: 02/05/2023]
Abstract
BACKGROUND Acquired resistance has become the bottleneck affecting the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Studies have shown that the antidiabetic drug metformin could effectively increase the sensitivity of TKI-resistant lung cancer cells to EGFR-TKI. This study aimed to evaluate the effect of metformin in combination with EGFR-TKI on the prognosis of non-small cell lung cancer (NSCLC) patients with diabetes mellitus type 2 (DM2). METHODS Data of NSCLC patients with DM2 who received treatment in six hospitals in China between January 2006 and January 2014 were reviewed retrospectively. They were divided into two groups: Group A, where the patients (n = 44) received EGFR-TKI plus metformin; and Group B, where the patients (n = 46) received EGFR-TKI plus hypoglycemic agents other than metformin. Prognostic differences between the two groups were assessed. RESULTS The median progression-free survival (PFS) and median overall survival (OS) in Group A were significantly longer than those in Group B (19.0 months vs. 8.0 months, P = .005; 32.0 months vs. 23.0 months, P = .002). The objective response rate (ORR) and disease control rate (DCR) in Group A were significantly higher than those in Group B (70.5% vs. 45.7%, P = .017; 97.7% vs. 80.4%, P = .009). Secondary data analysis showed that metformin use significantly prolonged the median PFS in subgroups using either first-line EGFR-TKI or second-line EGFR-TKI. CONCLUSIONS Metformin and EGFR-TKI have a synergistic effect in the treatment of DM2 NSCLC patients harboring EGFR-activating mutations. Metformin use is associated with improved survival and delayed onset of acquired resistance to EGFR-TKI.
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43
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Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2015; 16:839-47. [DOI: 10.1016/s1470-2045(15)00027-3] [Citation(s) in RCA: 267] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 04/01/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023]
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44
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Biguanides and targeted anti-cancer treatments. Genes Cancer 2015; 6:82-3. [PMID: 26000092 PMCID: PMC4426946 DOI: 10.18632/genesandcancer.59] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 04/16/2015] [Indexed: 01/12/2023] Open
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45
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Hamilton N, Márquez-Garbán D, Mah V, Elshimali Y, Elashoff D, Garon E, Vadgama J, Pietras R. Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer. Crit Rev Oncog 2015; 20:373-90. [PMID: 27279236 PMCID: PMC5495464 DOI: 10.1615/critrevoncog.v20.i5-6.100] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Triple-negative breast cancers (TNBCs) lack estrogen receptor-α (ERα), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) amplification and account for almost half of all breast cancer deaths. This breast cancer subtype largely affects women who are premenopausal, African-American, or have BRCA1/2 mutations. Women with TNBC are plagued with higher rates of distant metastasis that significantly diminish their overall survival and quality of life. Due to their poor response to chemotherapy, patients with TNBC would significantly benefit from development of new targeted therapeutics. Research suggests that the insulin-like growth factor (IGF) family and estrogen receptor beta-1 (ERβ1), due to their roles in metabolism and cellular regulation, might be attractive targets to pursue for TNBC management. Here, we review the current state of the science addressing the roles of ERβ1 and the IGF family in TNBC. Further, the potential benefit of metformin treatment in patients with TNBC as well as areas of therapeutic potential in the IGF-ERβ1 pathway are highlighted.
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Affiliation(s)
- Nalo Hamilton
- UCLA School of Nursing, Los Angeles, CA
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
| | - Diana Márquez-Garbán
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
- Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Vei Mah
- Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Yayha Elshimali
- Department of Medicine, Division of Cancer Research and Training, Charles Drew University School of Medicine and Science, Los Angeles, CA
| | - David Elashoff
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
- Department of Medicine, Division of General Internal Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Edward Garon
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
- Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA
| | - Jaydutt Vadgama
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
- Department of Medicine, Division of Cancer Research and Training, Charles Drew University School of Medicine and Science, Los Angeles, CA
| | - Richard Pietras
- UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA
- Department of Medicine, Division of Hematology-Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA
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