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Mohamed NM, Mohamed RH, Kennedy JF, Elhefnawi MM, Hamdy NM. A comprehensive review and in silico analysis of the role of survivin (BIRC5) in hepatocellular carcinoma hallmarks: A step toward precision. Int J Biol Macromol 2025; 311:143616. [PMID: 40306500 DOI: 10.1016/j.ijbiomac.2025.143616] [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: 02/13/2025] [Revised: 04/25/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) is a complex malignancy driven by the dysregulation of multiple cellular pathways. Survivin, a key member of the inhibitor of apoptosis (IAP) family, plays a central role in HCC tumorigenesis and progression. Despite significant research, a comprehensive understanding of the contributions of survivin to the hallmarks of cancer, its molecular network, and its potential as a therapeutic target remains incomplete. In this review, we integrated bioinformatics analysis with an extensive literature review to provide deeper insights into the role of survivin in HCC. Using bioinformatics tools such as the Human Protein Atlas, GEPIA, STRING, TIMER, and Metascape, we analyzed survivin expression and its functional associations and identified the top 20 coexpressed genes in HCC. These include TK1, SPC25, SGO2, PTTG1, PRR11, PLK1, NCAPH, KPNA2, KIF2C, KIF11, HJURP, GTSE1, FOXM1, CEP55, CENPA, CDCA3, CDC45, CCNB2, CCNB1 and CTD-2510F5.4. Our findings also revealed significant protein-protein interactions among these genes, which were enriched in pathways associated with the FOXM1 oncogenic signaling cascade, and biological processes such as cell cycle regulation, mitotic checkpoints, and diseases such as liver neoplasms. We also discussed the involvement of survivin in key oncogenic pathways, including the PI3K/AKT, WNT/β-catenin, Hippo, and JAK/STAT3 pathways, and its role in modulating cell cycle checkpoints, apoptosis, and autophagy. Furthermore, we explored its interactions with the tumor microenvironment, particularly its impact on immune modulation through myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and natural killer cell function in HCC. Additionally, we highlighted its involvement in alkylglycerone phosphate synthase (AGPS)-mediated lipid reprogramming and identified important gaps in the survivin network that warrant further investigation. This review also examined the role of survivin in cancer stemness, inflammation, and virally mediated hepatocarcinogenesis. We evaluated its potential as a diagnostic, prognostic, predictive, and pharmacodynamic biomarker in HCC, emphasizing its relevance in precision medicine. Finally, we summarized emerging survivin-targeted therapeutics and ongoing clinical trials, underscoring the need for novel strategies to effectively target survivin in HCC.
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Affiliation(s)
- Nermin M Mohamed
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abassia, 11566 Cairo, Egypt
| | - John F Kennedy
- Chembiotech Laboratories, Kyrewood House, Tenbury Wells, Worcestershire, United Kingdom
| | - Mahmoud M Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
| | - Nadia M Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Abassia, 11566 Cairo, Egypt.
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Lin GB, Chen WT, Kuo YY, Liu HH, Chen YM, Leu SJ, Chao CY. Thermal cycling‑hyperthermia sensitizes non‑small cell lung cancer A549 cells to EGFR tyrosine kinase inhibitor erlotinib. Oncol Rep 2025; 53:58. [PMID: 40183398 PMCID: PMC11976370 DOI: 10.3892/or.2025.8891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Molecular targeted therapy has emerged as a mainstream treatment for non‑small cell lung cancer (NSCLC), the most common type of lung cancer and the leading cause of cancer‑related death in both men and women. Erlotinib (Erl), a targeted therapy inhibiting EGFR pathways, has shown notable response rate in NSCLC cells. However, limited efficacy of the treatment has been reported due to resistance among a proportion of patients with NSCLC. Therefore, sensitizers are required to potentiate the efficacy of Erl in NSCLC treatment. The present study proposed a novel thermal therapy, thermal cycling‑hyperthermia (TC‑HT), as a supplement to amplify the effects of Erl. It was demonstrated that TC‑HT reduced the half‑maximal inhibitory concentration of Erl to 0.5 µM and TC‑HT sensitized A549 NSCLC cells to Erl via the downstream EGFR signaling cascades. Furthermore, the combination treatment of Erl and TC‑HT induced G2/M cell cycle arrest and inhibition of cell proliferation and migration. In addition, by slightly raising the temperature of TC‑HT, TC‑HT treatment alone produced antineoplastic effects without damaging the normal IMR‑90 lung cells. The method presented in this study may be applicable to other combination therapies and could potentially act as a starter for anticancer treatments, with fewer side effects.
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Affiliation(s)
- Guan-Bo Lin
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Wei-Ting Chen
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Yu-Yi Kuo
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
| | - Hsu-Hsiang Liu
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
| | - You-Ming Chen
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
| | - Shr-Jeng Leu
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan, R.O.C
| | - Chih-Yu Chao
- Department of Physics, Laboratory for Medical Physics and Biomedical Engineering, National Taiwan University, Taipei 106319, Taiwan, R.O.C
- Molecular Imaging Center, National Taiwan University College of Medicine, Taipei 100233, Taiwan, R.O.C
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei 106319, Taiwan, R.O.C
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Chun JH, Kimura K, Rajput M, Hsu MH, Liang YC, Shanbhag AR, Chiang PJ, Jackson TLB, Huang RCC. Evidence to Support the Collaboration of SP1, MYC, and HIF1A and Their Association with microRNAs. Curr Issues Mol Biol 2024; 46:12481-12496. [PMID: 39590335 PMCID: PMC11592871 DOI: 10.3390/cimb46110741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
This study provides evidence to support the concept proposed by Kimura et al. in 2023 that the inhibitors of SP1, MYC, and HIF1A should induce strong anticancer activity by reducing the expression of stem cell-related proteins. In LN229 and U87MG glioblastoma cells, either tetra-methyl-O-nordihydroguaiaretic acid (M4N) or tetra-acetyl-O-nordihydroguaiaretic acid (A4N) suppressed SP1 and only a few stem cell-related proteins and induced only a small amount of cell death; in contrast, the combination treatment of M4N with A4N greatly suppressed the expression of SP1, MYC, and HIF1A, as well as all of the stem cell-related proteins examined, and greatly induced cell death. The bioinformatic analysis showed that the proteins associated with SP1, MYC, and HIF1A were specifically involved in the regulation of transcription and that various microRNAs (miRNAs) that had been shown to induce either anti- or procancer activity were associated with SP1, MYC, and HIF1A, which suggested that the inhibition of SP1, MYC, and HIF1A could modulate the transcription of both coding and noncoding RNAs and affect cancers. These data overall supported our concept.
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Affiliation(s)
- Jong Ho Chun
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
| | - Kotohiko Kimura
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
| | - Monika Rajput
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Ming-Hua Hsu
- Department of Chemistry, National Changhua University of Education, Changhua 500, Taiwan
| | - Yu-Chuan Liang
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Akanksha Ramadas Shanbhag
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
- Advanced Academic Programs, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Pei-Ju Chiang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA;
| | - Tiffany L. B. Jackson
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
| | - Ru Chih C. Huang
- Department of Biology, Johns Hopkins University, 3400 N. Charles St-Levi Hall 250, Baltimore, MD 21218, USA (M.R.); (A.R.S.)
- Academia Sinica, Taipei 115, Taiwan
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4
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Ahluwalia MS, Ozair A, Rudek M, Ye X, Holdhoff M, Lieberman FS, Piotrowski AF, Nabors B, Desai A, Lesser G, Huang RC, Glenn S, Khosla AA, Peereboom DM, Wen PY, Grossman SA. A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR). Cell Rep Med 2024; 5:101630. [PMID: 38955178 PMCID: PMC11293336 DOI: 10.1016/j.xcrm.2024.101630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 03/26/2024] [Accepted: 06/07/2024] [Indexed: 07/04/2024]
Abstract
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
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Affiliation(s)
- Manmeet S Ahluwalia
- Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA; Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
| | - Ahmad Ozair
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Michelle Rudek
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xiaobu Ye
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthias Holdhoff
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Frank S Lieberman
- Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Anna F Piotrowski
- Department of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Burt Nabors
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Arati Desai
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Glenn Lesser
- Department of Hematology and Oncology, Wake Forest Medical Center, Winston, NC, USA
| | - Ru Chih Huang
- Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Steve Glenn
- Independent Consultant to Erimos Pharmaceuticals, Houston, TX, USA
| | - Atulya A Khosla
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - David M Peereboom
- Rose and Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
| | - Patrick Y Wen
- Department of Neurology, Harvard Medical School, Boston, MA, USA; Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Stuart A Grossman
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Wang Q, Greene MI. Survivin as a Therapeutic Target for the Treatment of Human Cancer. Cancers (Basel) 2024; 16:1705. [PMID: 38730657 PMCID: PMC11083197 DOI: 10.3390/cancers16091705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
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Affiliation(s)
- Qiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mark I. Greene
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Cui Q, Huang C, Liu JY, Zhang JT. Small Molecule Inhibitors Targeting the "Undruggable" Survivin: The Past, Present, and Future from a Medicinal Chemist's Perspective. J Med Chem 2023; 66:16515-16545. [PMID: 38092421 PMCID: PMC11588358 DOI: 10.1021/acs.jmedchem.3c01130] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Survivin, a homodimeric protein and a member of the IAP family, plays a vital function in cell survival and cycle progression by interacting with various proteins and complexes. Its expression is upregulated in cancers but not detectable in normal tissues. Thus, it has been regarded and validated as an ideal cancer target. However, survivin is "undruggable" due to its lack of enzymatic activities or active sites for small molecules to bind/inhibit. Academic and industrial laboratories have explored different strategies to overcome this hurdle over the past two decades, with some compounds advanced into clinical testing. These strategies include inhibiting survivin expression, its interaction with binding partners and homodimerization. Here, we provide comprehensive analyses of these strategies and perspective on different small molecule survivin inhibitors to help drug discovery targeting "undruggable" proteins in general and survivin specifically with a true survivin inhibitor that will prevail in the foreseeable future.
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Affiliation(s)
- Qingbin Cui
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Caoqinglong Huang
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Jian-Ting Zhang
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
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Kimura K, Jackson TLB, Huang RCC. Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development. Curr Issues Mol Biol 2023; 45:9262-9283. [PMID: 37998757 PMCID: PMC10670631 DOI: 10.3390/cimb45110580] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/09/2023] [Accepted: 11/11/2023] [Indexed: 11/25/2023] Open
Abstract
Specificity protein 1 (SP1), hypoxia-inducible factor 1 (HIF-1), and MYC are important transcription factors (TFs). SP1, a constitutively expressed housekeeping gene, regulates diverse yet distinct biological activities; MYC is a master regulator of all key cellular activities including cell metabolism and proliferation; and HIF-1, whose protein level is rapidly increased when the local tissue oxygen concentration decreases, functions as a mediator of hypoxic signals. Systems analyses of the regulatory networks in cancer have shown that SP1, HIF-1, and MYC belong to a group of TFs that function as master regulators of cancer. Therefore, the contributions of these TFs are crucial to the development of cancer. SP1, HIF-1, and MYC are often overexpressed in tumors, which indicates the importance of their roles in the development of cancer. Thus, proper manipulation of SP1, HIF-1, and MYC by appropriate agents could have a strong negative impact on cancer development. Under these circumstances, these TFs have naturally become major targets for anticancer drug development. Accordingly, there are currently many SP1 or HIF-1 inhibitors available; however, designing efficient MYC inhibitors has been extremely difficult. Studies have shown that SP1, HIF-1, and MYC modulate the expression of each other and collaborate to regulate the expression of numerous genes. In this review, we provide an overview of the interactions and collaborations of SP1, HIF1A, and MYC in the regulation of various cancer-related genes, and their potential implications in the development of anticancer therapy.
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Affiliation(s)
| | | | - Ru Chih C. Huang
- Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218-2685, USA
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Abbasi Dezfouli S, Rajendran AP, Claerhout J, Uludag H. Designing Nanomedicines for Breast Cancer Therapy. Biomolecules 2023; 13:1559. [PMID: 37892241 PMCID: PMC10605068 DOI: 10.3390/biom13101559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
In 2020, breast cancer became the most diagnosed cancer worldwide. Conventional chemotherapies have major side effects due to their non-specific activities. Alternatively, short interfering RNA(siRNA)-carrying nanoparticles (NPs) have a high potential to overcome this non-specificity. Lipid-substituted polyethyleneimine (PEI) polymers (lipopolymers) have been reported as efficient non-viral carriers of siRNA. This study aims to engineer novel siRNA/lipopolymer nanocomplexes by incorporating anionic additives to obtain gene silencing through siRNA activity with minimal nonspecific toxicity. We first optimized our polyplexes in GFP+ MDA-MB-231 cells to effectively silence the GFP gene. Inclusion of phosphate buffer with pH 8.0 as complex preparation media and N-Lauroylsarcosine Sodium Salt as additive, achieved ~80% silencing with the least amount of undesired cytotoxicity, which was persistent for at least 6 days. The survivin gene was then selected as a target in MDA-MB-231 cells since there is no strong drug (i.e., small organic molecule) for inhibition of its oncogenic activity. The qRT-PCR, flow cytometry analysis and MTT assay revealed >80% silencing, ~95% cell uptake and >70% cell killing by the same formulation. We conclude that our lipopolymer can be further investigated as a lead non-viral carrier for breast cancer gene therapy.
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Affiliation(s)
- Saba Abbasi Dezfouli
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2V2, Canada;
| | - Amarnath P. Rajendran
- Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2V2, Canada;
| | - Jillian Claerhout
- Department of Biological Sciences, Faculty of Science, University of Alberta, Edmonton, AB T6G 2V2, Canada;
| | - Hasan Uludag
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2V2, Canada;
- Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2V2, Canada;
- Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2V2, Canada
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Survivin Small Molecules Inhibitors: Recent Advances and Challenges. Molecules 2023; 28:molecules28031376. [PMID: 36771042 PMCID: PMC9919791 DOI: 10.3390/molecules28031376] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/24/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Survivin, as a member of the inhibitor of apoptosis proteins (IAPs) family, acts as a suppressor of apoptosis and plays a central role in cell division. Survivin has been considered as an important cancer drug target because it is highly expressed in many types of human cancers, while it is effectively absent from terminally differentiated normal tissues. Moreover, survivin is involved in tumor cell resistance to chemotherapy and radiation. Preclinically, downregulation of survivin expression or function reduced tumor growth induced apoptosis and sensitized tumor cells to radiation and chemotherapy in different human tumor models. This review highlights the role of survivin in promoting cellular proliferation and inhibiting apoptosis and summarizes the recent advances in and challenges of developing small-molecule survivin inhibitors.
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10
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Anders NM, Romo CG, Hemingway A, Ahluwalia MS, Rudek MA. Quantitation of terameprocol in human plasma by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 2022; 209:114525. [PMID: 34906921 PMCID: PMC8742791 DOI: 10.1016/j.jpba.2021.114525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/02/2021] [Accepted: 12/05/2021] [Indexed: 02/07/2023]
Abstract
The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.
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Affiliation(s)
- Nicole M Anders
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA
| | - Carlos G Romo
- Department of Neurology, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA; Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA
| | - Avelina Hemingway
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
| | - Manmeet S Ahluwalia
- Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Michelle A Rudek
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA; Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, USA.
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11
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Bhurta D, Bharate SB. Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and revisiting the clinical and preclinical pipeline. Med Res Rev 2021; 42:654-709. [PMID: 34605036 DOI: 10.1002/med.21856] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 07/04/2021] [Accepted: 09/21/2021] [Indexed: 12/17/2022]
Abstract
Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin-dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino-pyrimidine is a well-represented scaffold. The three-nitrogen framework of amino-pyrimidine is a fundamental hinge-binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose-limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP-binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.
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Affiliation(s)
- Deendyal Bhurta
- Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
| | - Sandip B Bharate
- Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.,Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
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12
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Gao F, Li M, Yu X, Liu W, Zhou L, Li W. Licochalcone A inhibits EGFR signalling and translationally suppresses survivin expression in human cancer cells. J Cell Mol Med 2020; 25:813-826. [PMID: 33247550 PMCID: PMC7812290 DOI: 10.1111/jcmm.16135] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 10/27/2020] [Accepted: 11/09/2020] [Indexed: 12/16/2022] Open
Abstract
Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non–small‐cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti‐tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild‐type (WT) or activating mutation EGFR‐expressed NSCLC cells. Licochalcone A bound with L858R single‐site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E‐BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR‐targeted therapy.
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Affiliation(s)
- Feng Gao
- Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, China.,Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China
| | - Ming Li
- Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China.,Changsha Stomatological Hospital, Changsha, China
| | - Xinfang Yu
- Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China.,Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Wenbin Liu
- Department of Pathology, Hunan Cancer Hospital, Changsha, China
| | - Li Zhou
- Department of Pathology, Xiangya Hospital of Central South University, Changsha, China
| | - Wei Li
- Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China.,Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, China
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13
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Liu SH, Yu J, Creeden JF, Sutton JM, Markowiak S, Sanchez R, Nemunaitis J, Kalinoski A, Zhang JT, Damoiseaux R, Erhardt P, Brunicardi FC. Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma. Cancer Lett 2020; 491:97-107. [PMID: 32829010 DOI: 10.1016/j.canlet.2020.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/23/2020] [Accepted: 08/01/2020] [Indexed: 12/12/2022]
Abstract
Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.
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Affiliation(s)
- Shi-He Liu
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Juehua Yu
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Justin F Creeden
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Jeffrey M Sutton
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Stephen Markowiak
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Robbi Sanchez
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - John Nemunaitis
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Andrea Kalinoski
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Jian-Ting Zhang
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Robert Damoiseaux
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Paul Erhardt
- Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, USA
| | - F Charles Brunicardi
- Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
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14
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Abstract
Survivin is one of the most cancer-specific proteins overexpressed in almost all malignancies, but is nearly undetectable in most normal tissues in adults. Functionally, as a member of the inhibitor of apoptosis family, survivin has been shown to inhibit apoptosis and increase proliferation. The antiapoptotic function of survivin seems to be related to its ability to inhibit caspases directly or indirectly. Furthermore, the role of survivin in cell cycle division control is related to its role in the chromosomal passenger complex. Consistent with its determining role in these processes, survivin plays a crucial role in cancer progression and cancer cell resistance to anticancer drugs and ionizing radiation. On the basis of these findings, recently survivin has been investigated intensively as an ideal tumor biomarker. Thus, multiple molecular approaches such as use of the RNA interfering technique, antisense oligonucleotides, ribozyme, and small molecule inhibitors have been used to downregulate survivin regulation and inhibit its biological function consequently. In this review, all these approaches are explained and other compounds that induced apoptosis in different cell lines through survivin inhibition are also reported.
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15
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Manda G, Rojo AI, Martínez-Klimova E, Pedraza-Chaverri J, Cuadrado A. Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases. Front Pharmacol 2020; 11:151. [PMID: 32184727 PMCID: PMC7058590 DOI: 10.3389/fphar.2020.00151] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 02/05/2020] [Indexed: 12/11/2022] Open
Abstract
Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.
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Affiliation(s)
- Gina Manda
- Department Cellular and Molecular Medicine, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Ana I Rojo
- Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria la Paz (idiPAZ), Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Madrid, Spain
| | - Elena Martínez-Klimova
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - José Pedraza-Chaverri
- Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Antonio Cuadrado
- Department Cellular and Molecular Medicine, Victor Babes National Institute of Pathology, Bucharest, Romania.,Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria la Paz (idiPAZ), Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Madrid, Spain
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16
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Bernardo PS, Lemos LGT, de Moraes GN, Maia RC. Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications. Blood Rev 2020; 43:100671. [PMID: 32107072 DOI: 10.1016/j.blre.2020.100671] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/15/2020] [Accepted: 01/30/2020] [Indexed: 02/07/2023]
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL oncoprotein, known to drive leukemogenesis by orchestrating multiple signaling pathways ultimately involved in cell survival. Despite successful response rates of CML patients to tyrosine kinase inhibitors (TKIs), resistance eventually arises due to BCR-ABL-dependent and independent mechanisms. Survivin is an inhibitor of apoptosis protein acting in the interface between apoptosis deregulation and cell cycle progression. In CML, high levels of survivin have been associated with late stages of disease and therapy resistance. In this review, we provide an overview of important aspects concerning survivin subcellular localization and expression pattern in CML patients and cell lines. Moreover, we highlight the relevance of molecular networks involving survivin for disease progression and treatment resistance. Finally, we discuss the mechanisms accounting for survivin overexpression, as well as novel therapeutic interventions that have been designed to counteract survivin-associated malignancy in CML.
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Affiliation(s)
- Paula Sabbo Bernardo
- Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Lauana Greicy Tonon Lemos
- Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Gabriela Nestal de Moraes
- Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Raquel Ciuvalschi Maia
- Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
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17
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Surface plasmon resonance immunosensor for label-free detection of BIRC5 biomarker in spontaneously occurring canine mammary tumours. Sci Rep 2019; 9:13485. [PMID: 31530877 PMCID: PMC6748992 DOI: 10.1038/s41598-019-49998-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 09/02/2019] [Indexed: 01/17/2023] Open
Abstract
We report detection of Baculoviral inhibitor of apoptosis repeat containing-5 (BIRC5) protein biomarker in dog serum by label-free surface plasmon resonance (SPR) immunosensor. Initially, overexpression of BIRC5 in canine mammary tumour (CMT) tissues was confirmed by real-time PCR. Recombinant BIRC5 was produced and protein specific antibodies developed in guinea pig specifically reacted with native protein in immunohistochemistry and immunocytochemistry. SPR immunosensor was developed by fabricating anti-BIRC5 antibodies on gold sensor disc. The equilibrium dissociation constant, (KD = kd/ka) was 12.1 × 10−12 M; which indicates that antibodies are of high affinity with sensitivity in picomolar range. The SPR assay could detect as low as 6.25 pg/ml of BIRC5 protein in a calibration experiment (r2 = 0.9964). On testing real clinical samples, 95% specificity and 73.33% sensitivity were recorded. The average amount of serum BIRC5 in dogs with CMT was 110.02 ± 9.77 pg/ml; whereas, in non-cancerous disease conditions, 44.79 ± 4.28 pg/ml and in healthy dog sera 30.28 ± 2.99 pg/ml protein was detected. The SPR immunosensor for detection of BIRC5 in dog sera is reported for the first time and this may find prognostic and diagnostic applications in management of CMT. In future, ‘on-site’ sensors can be developed using this technique for near-patient testing.
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18
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Kim S, Ko D, Lee Y, Jang S, Lee Y, Lee IY, Kim S. Anti-cancer activity of the novel 2-hydroxydiarylamide derivatives IMD-0354 and KRT1853 through suppression of cancer cell invasion, proliferation, and survival mediated by TMPRSS4. Sci Rep 2019; 9:10003. [PMID: 31292507 PMCID: PMC6620293 DOI: 10.1038/s41598-019-46447-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 06/25/2019] [Indexed: 12/17/2022] Open
Abstract
Elevated expression of transmembrane serine protease 4 (TMPRSS4) correlates with poor prognosis in non-small cell lung cancer, gastric cancer, colorectal cancer, prostate cancer, and other cancer patients. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, proliferation, and metastasis. In addition, we reported novel 2-hydroxydiarylamide derivatives, IMD-0354 and KRT1853, as TMPRSS4 serine protease inhibitors. Here, we further evaluated the effects of the representative derivatives on TMPRSS4-mediated cellular function and signaling. IMD-0354 and KRT1853 inhibited cancer cell invasion, migration, and proliferation in TMPRSS4-expressing prostate, colon, and lung cancer cells. Both compounds suppressed TMPRSS4-mediated induction of Sp1/3, AP-1, and NF-κB transcription factors. Furthermore, TMPRSS4 promoted cancer cell survival and drug resistance, and both compounds enhanced anoikis sensitivity as well as reduced bcl-2 and survivin levels. Importantly, KRT1853 efficiently reduced tumor growth in prostate and colon cancer xenograft models. These results strongly recommend KRT1853 for further development as a novel anti-cancer agent.
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Affiliation(s)
- Solbi Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Korea.,Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea
| | - Dongjoon Ko
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Korea.,Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea
| | - Yunhee Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Korea.,Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, 34141, Korea
| | - Seonghui Jang
- Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, 34141, Korea
| | - Younghoon Lee
- Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, 34141, Korea
| | - Ill Young Lee
- Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejon, 34114, Korea
| | - Semi Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Korea. .,Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea. .,Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, 34141, Korea.
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19
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Rafatmanesh A, Behjati M, Mobasseri N, Sarvizadeh M, Mazoochi T, Karimian M. The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer. J Cell Physiol 2019; 235:725-744. [PMID: 31250439 DOI: 10.1002/jcp.29027] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/11/2019] [Indexed: 12/16/2022]
Abstract
Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The -31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed.
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Affiliation(s)
- Atieh Rafatmanesh
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Mohaddeseh Behjati
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Narges Mobasseri
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran.,Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mostafa Sarvizadeh
- The Advocate Center for Clinical Research, Ayatollah Yasrebi Hospital, Kashan, Iran
| | - Tahereh Mazoochi
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Karimian
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran.,Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
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20
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Cyclin-dependent kinase 1 and survivin as potential therapeutic targets against nasal natural killer/T-cell lymphoma. J Transl Med 2019; 99:612-624. [PMID: 30664711 DOI: 10.1038/s41374-018-0182-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 11/13/2018] [Accepted: 11/17/2018] [Indexed: 01/30/2023] Open
Abstract
Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma.
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21
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The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2. J Mol Med (Berl) 2018; 96:1251-1266. [PMID: 30298385 DOI: 10.1007/s00109-018-1699-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/07/2018] [Accepted: 09/26/2018] [Indexed: 01/09/2023]
Abstract
Oncogenic PIK3CA mutations are common in endometrial cancers, and the PI3K/AKT/mTOR pathway is targetable by drugs. We sought to investigate whether the combination of an mTOR inhibitor, everolimus (RAD001), and an AKT inhibitor, terameprocol (M4N), exerts better antiproliferative effects in endometrial cancer. The molecular mechanisms underlying their pharmacological action were also examined. The combination of RAD001 and M4N exerted in vitro synergistic effects on cell viability, apoptosis, and expression of IGFBP2 in endometrial cancer cells. Mechanistically, the Sp1 site on the IGFBP2 promoter was required for RAD001- and M4N-induced downregulation. IGFBP2 protein expression was higher in endometrial cancer than in the normal endometrium (P < 0.001). Furthermore, elevated IGFBP2 histoscores were significantly associated with a lower overall survival (P = 0.021). In conclusion, our in vitro results demonstrate that RAD001 and M4N exert synergistic antiproliferative effects against endometrial cancer cells, which appeared to be mediated by the inhibition of IGFBP2, a key anti-apoptotic regulator. Further clinical studies of this drug combination in patients with endometrial cancer may be warranted, especially in the presence of PIK3CA and IGFBP2 aberrations. KEY MESSAGES: RAD001 and M4N synergistically suppress endometrial cancer growth. IGFBP2 is overexpressed in endometrial cancer. The combination of RAD001 and M4N significantly reduces IGFBP2 overexpression. Sp1 binding site on the IGFBP2 promoter is required for RAD001- and M4N-induced downregulation. High IGFBP2 histoscore in endometrial cancer portends a poor prognosis.
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22
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Chen ZM, Huang L, Li MM, Meng L, Ying SC, Xu AM. Inhibitory effects of isocryptotanshinone on gastric cancer. Sci Rep 2018; 8:9307. [PMID: 29915371 PMCID: PMC6006307 DOI: 10.1038/s41598-018-27638-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 06/07/2018] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common digestive malignancies globally, and the prognosis of patients with advanced tumors remains poor. Isocryptotanshinone (ICTS), isolated from Salvia miltiorrhiza, was found to inhibit the proliferation of lung and breast cancer cells. However, whether ICTS has anticancer activities against GC is unknown. In the present study, we reported that the proliferation of GC cells was inhibited by ICTS in a dose- and time-dependent manner. After treatment with ICTS, GC cells were arrested in the G1/G0 phase of cell cycle and the apoptotic cells were induced in a dose-dependent manner. Additionally, ICTS suppressed the expression of cell cycle- and apoptosis-associated proteins (e.g., Cyclin D1, phosphorylated Rb, E2F1, Mcl-1, Bcl-2, and Survivin). ICTS inhibited the phosphorylation of STAT3 in a dose-dependent manner. Down-regulated STAT3 attenuated the expression of Cyclin D1, p-Rb, and Survivin, which remarkably increased the sensitivity of ICTS in GC cells; overexpression of STAT3 restored the cell growth and proliferation and the protein expression suppressed by ICTS. ICTS also suppressed the xenograft tumor growth in BALB/c nude mice. Together, these data indicate that ICTS inhibits GC proliferation by inducing G1/G0 cell cycle arrest and apoptosis via inhibiting the STAT3 signaling pathway.
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Affiliation(s)
- Zhang-Ming Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Lei Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Miao-Miao Li
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Lei Meng
- Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Song-Cheng Ying
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
| | - A-Man Xu
- Department of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
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23
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Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors. Eur J Med Chem 2018; 149:211-224. [PMID: 29501942 DOI: 10.1016/j.ejmech.2018.02.045] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/12/2018] [Accepted: 02/13/2018] [Indexed: 02/07/2023]
Abstract
The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC-112 with an indole moiety was preferred to other moieties. Among these UC-112 analogs, 10f, 10h, 10k, 10n showed the most potent antiproliferative activities. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold.
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24
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Ko D, Kim S. Cooperation between ZEB2 and Sp1 promotes cancer cell survival and angiogenesis during metastasis through induction of survivin and VEGF. Oncotarget 2017; 9:726-742. [PMID: 29416649 PMCID: PMC5787504 DOI: 10.18632/oncotarget.23139] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 11/14/2017] [Indexed: 01/11/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a process implicated in tumor invasion and metastasis. During EMT, epithelial cells undergo molecular changes to acquire mesenchymal phenotypes, which are mediated by EMT-inducing transcription factors. Previously, we showed that ZEB2 cooperates with the transcription factor Sp1 to function as a transcriptional activator of vimentin, integrin α5, and cadherin-11, which promotes cancer cell invasion. We hypothesized that ZEB2, through cooperation with Sp1, would mediate diverse cellular functions beyond EMT and invasion during metastasis. ZEB2 upregulated the expression of Sp1-regulated genes such as survivin, bcl-2, cyclin D1, and vascular endothelial growth factor in an Sp1-dependent manner, resulting in increased cancer cell survival and proliferation and endothelial cell activation in vitro, and increased circulating tumor cell survival and tumor angiogenesis in vivo. In addition, Sp1 enhanced ZEB2 stability, suggesting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data showed that ZEB2 expression was positively associated with Sp1 expression, and that the expression of both of these factors had prognostic significance for predicting survival in cancer patients. This study suggests that invasion is linked to cancer cell survival and angiogenesis by ZEB2 during cancer progression, and increases our understanding of the pathways via which EMT-inducing transcription factors regulate the complex process of metastasis.
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Affiliation(s)
- Dongjoon Ko
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.,Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea
| | - Semi Kim
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.,Department of Functional Genomics, Korea University of Science and Technology, Daejon, Korea.,Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea
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25
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Werner TA, Dizdar L, Nolten I, Riemer JC, Mersch S, Schütte SC, Driemel C, Verde PE, Raba K, Topp SA, Schott M, Knoefel WT, Krieg A. Survivin and XIAP - two potential biological targets in follicular thyroid carcinoma. Sci Rep 2017; 7:11383. [PMID: 28900184 PMCID: PMC5595817 DOI: 10.1038/s41598-017-11426-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 07/17/2017] [Indexed: 12/22/2022] Open
Abstract
Follicular thyroid carcinoma's (FTC) overall good prognosis deteriorates if the tumour fails to retain radioactive iodine. Therefore, new druggable targets are in high demand for this subset of patients. Here, we investigated the prognostic and biological role of survivin and XIAP in FTC. Survivin and XIAP expression was investigated in 44 FTC and corresponding non-neoplastic thyroid specimens using tissue microarrays. Inhibition of both inhibitor of apoptosis proteins (IAP) was induced by shRNAs or specific small molecule antagonists and functional changes were investigated in vitro and in vivo. Survivin and XIAP were solely expressed in FTC tissue. Survivin expression correlated with an advanced tumour stage and recurrent disease. In addition, survivin proved to be an independent negative prognostic marker. Survivin or XIAP knockdown caused a significant reduction in cell viability and proliferation, activated caspase3/7 and was associated with a reduced tumour growth in vivo. IAP-targeting compounds induced a decrease of cell viability, proliferation and cell cycle activity accompanied by an increase in apoptosis. Additionally, YM155 a small molecule inhibitor of survivin expression significantly inhibited tumour growth in vivo. Both IAPs demonstrate significant functional implications in the oncogenesis of FTCs and thus prove to be viable targets in patients with advanced FTC.
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Affiliation(s)
- Thomas A Werner
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Levent Dizdar
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Inga Nolten
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Jasmin C Riemer
- Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Sabrina Mersch
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Sina C Schütte
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Christiane Driemel
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Pablo E Verde
- Coordination Centre for Clinical Trials, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Katharina Raba
- Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Stefan A Topp
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Matthias Schott
- Division for Specific Endocrinology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Wolfram T Knoefel
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Andreas Krieg
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
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26
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Khan Z, Khan AA, Yadav H, Prasad GBKS, Bisen PS. Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma. Cell Mol Biol Lett 2017; 22:8. [PMID: 28536639 PMCID: PMC5415770 DOI: 10.1186/s11658-017-0038-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/27/2017] [Indexed: 12/14/2022] Open
Abstract
Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.
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Affiliation(s)
- Zakir Khan
- School of Studies in Biotechnology, Jiwaji University, Gwalior, 474001 MP India.,Department of Biomedical Sciences, Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA
| | - Abdul Arif Khan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hariom Yadav
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA
| | | | - Prakash Singh Bisen
- School of Studies in Biotechnology, Jiwaji University, Gwalior, 474001 MP India
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27
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Nogueira-Ferreira R, Ferreira-Pinto MJ, Silva AF, Vitorino R, Justino J, Costa R, Moreira-Gonçalves D, Quignard JF, Ducret T, Savineau JP, Leite-Moreira AF, Ferreira R, Henriques-Coelho T. HMGB1 down-regulation mediates terameprocol vascular anti-proliferative effect in experimental pulmonary hypertension. J Cell Physiol 2017; 232:3128-3138. [PMID: 28036116 DOI: 10.1002/jcp.25763] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 12/23/2016] [Accepted: 12/29/2016] [Indexed: 11/07/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.
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Affiliation(s)
- Rita Nogueira-Ferreira
- QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal.,Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
| | - Manuel J Ferreira-Pinto
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
| | - Ana Filipa Silva
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
| | - Rui Vitorino
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.,iBiMED, Departamento de Ciências Médicas, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Joana Justino
- QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Raquel Costa
- Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
| | - Daniel Moreira-Gonçalves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.,CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal
| | - Jean-François Quignard
- Université Bordeaux Segalen, Bordeaux, France.,Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France
| | - Thomas Ducret
- Université Bordeaux Segalen, Bordeaux, France.,Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France
| | - Jean-Pierre Savineau
- Université Bordeaux Segalen, Bordeaux, France.,Inserm, Centre de Recherche Cardio-Thoracique, Bordeaux, France
| | - Adelino F Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
| | - Rita Ferreira
- QOPNA, Departamento de Química, Universidade de Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Tiago Henriques-Coelho
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal
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28
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Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KSVGK, Chintala R, Duddukuri GR. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 2016; 40-41:48-81. [PMID: 26853158 DOI: 10.1016/j.semcancer.2016.02.001] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/23/2016] [Accepted: 02/01/2016] [Indexed: 12/16/2022]
Abstract
Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.
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Affiliation(s)
- Nagendra Sastry Yarla
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia
| | - Pallu Reddanna
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India
| | - Arunasree M Kalle
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India; Department of Environmental Health Sciences, Laboratory of Human Environmental Epigenomes, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Bhadrapura Lakkappa Dhananjaya
- Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain Global Campus, Jain University, Kanakapura Taluk, Ramanagara 562 112, Karnataka, India
| | - Kaladhar S V G K Dowluru
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India; Department of Microbiology and Bioinformatics, Bilaspur University, Bilaspur 495 001, Chhattisgarh, India
| | - Ramakrishna Chintala
- Department of Environmental Sciences, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Govinda Rao Duddukuri
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India.
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29
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Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a unique target for tumor therapy. Cancer Cell Int 2016; 16:49. [PMID: 27340370 PMCID: PMC4917988 DOI: 10.1186/s12935-016-0326-1] [Citation(s) in RCA: 323] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 06/10/2016] [Indexed: 12/13/2022] Open
Abstract
Survivin is the smallest member of the Inhibitor of apoptosis (IAP) family of proteins, involved in inhibition of apoptosis and regulation of cell cycle. These functional attributes make Survivin a unique protein exhibiting divergent functions i.e. regulating cell proliferation and cell death. Expression pattern of Survivin is also distinctive; it is prominently expressed during embryonal development, absent in most normal, terminally differentiated tissues but upregulated in a variety of human cancers. Expression of Survivin in tumours correlates with not only inhibition of apoptosis and a decreased rate of cell death, but also resistance to chemotherapy and aggressiveness of tumours. Therefore, Survivin is an important target for cancer vaccines and therapeutics. Survivin has also been found to be prominently expressed on both human and embryonic stem cells and many somatic stem cell types indicating its yet unexplored role in stem cell generation and maintenance. Overall, Survivin emerges as a molecule with much wider role in cellular homeostasis. This review will discuss various aspects of Survivin biology and its role in regulation of apoptosis, cell division, chemo-resistance and tumour progression. Various molecular and immunotherapeutic approaches targeting Survivin will also be discussed.
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Affiliation(s)
- Himani Garg
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, J-3 Block, Room No: LG21, Sector 125, Noida, Uttar Pradesh 201303 India
| | - Prerna Suri
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector 125, Noida, India
| | - Jagdish C Gupta
- Talwar Research Foundation, E-8 Neb Valley, Neb Sarai, New Delhi, 110 068 India
| | - G P Talwar
- Talwar Research Foundation, E-8 Neb Valley, Neb Sarai, New Delhi, 110 068 India
| | - Shweta Dubey
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, J-3 Block, Room No: LG21, Sector 125, Noida, Uttar Pradesh 201303 India
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30
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Kimura K, Huang RCC. Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01. PLoS One 2016; 11:e0148685. [PMID: 26886430 PMCID: PMC4757551 DOI: 10.1371/journal.pone.0148685] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 01/20/2016] [Indexed: 12/19/2022] Open
Abstract
The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments.
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Affiliation(s)
- Kotohiko Kimura
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Ru Chih C. Huang
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
- * E-mail:
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31
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Hua X, Ding J, Li R, Zhang Y, Huang Z, Guo Y, Chen Q. Anti-tumor effect of ultrasound-induced Nordy-loaded microbubbles destruction. J Drug Target 2016; 24:703-8. [PMID: 26811100 DOI: 10.3109/1061186x.2016.1144058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Synthesized dl-Nordihydroguaiaretic acid (dl-NGDA or "Nordy") can inhibit the growth of malignant human tumors, especially the tumor angiogenesis. However, its liposoluble nature limits its in vivo efficacy in the hydrosoluble circulation of human. PURPOSE We tried to use the ultrasonic microbubble as the carrier and the ultrasound-induced destruction for the targeted release of Nordy and evaluate its in vitro and in vivo anti-tumor effect. METHODS Nordy-loaded lipid microbubbles were prepared by mechanical vibration. Effects of ultrasound-induced Nordy-loaded microbubbles destruction on proliferation of human umbilical vein endothelial cells (HUVECs), tumor derived endothelial cells (Td-ECs), and rabbit transplanted VX2 tumor models were evaluated. RESULTS The ultrasound-induced Nordy-loaded microbubbles destruction inhibited the proliferations of HUVECs and Td-ECs in vitro, and inhibited the tumor growth and the microvasculature in vivo. Its efficacy was higher than those of Nordy used only and Nordy with ultrasound exposure. CONCLUSION Ultrasonic microbubbles can be used as the carrier of Nordy and achieve its targeted release with improved anti-tumor efficacy in the condition of ultrasound-induced microbubbles destruction.
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Affiliation(s)
- Xing Hua
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Jun Ding
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Rui Li
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Ying Zhang
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Zejun Huang
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Yanli Guo
- a Third Military Medical University, Southwest Hospital , Chongqing , China
| | - Qinghai Chen
- a Third Military Medical University, Southwest Hospital , Chongqing , China
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32
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Broekgaarden M, Weijer R, van Gulik TM, Hamblin MR, Heger M. Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev 2015; 34:643-90. [PMID: 26516076 PMCID: PMC4661210 DOI: 10.1007/s10555-015-9588-7] [Citation(s) in RCA: 185] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.
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Affiliation(s)
- Mans Broekgaarden
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Ruud Weijer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Thomas M van Gulik
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Dermatology, Harvard Medical School, Boston, MA, USA
- Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA, USA
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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33
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Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene 2015; 35:2052-61. [DOI: 10.1038/onc.2015.264] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 06/03/2015] [Accepted: 06/06/2015] [Indexed: 12/19/2022]
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34
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Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus. Mol Cancer Ther 2015; 14:1404-13. [DOI: 10.1158/1535-7163.mct-14-1036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/17/2015] [Indexed: 11/16/2022]
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35
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Gnabre J, Bates R, Huang RC. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy. J Tradit Complement Med 2015; 5:119-26. [PMID: 26151022 PMCID: PMC4488564 DOI: 10.1016/j.jtcme.2014.11.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 10/02/2014] [Accepted: 11/13/2014] [Indexed: 12/31/2022] Open
Abstract
The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies.
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Affiliation(s)
- John Gnabre
- Mal-4 Research Institute, Baltimore, MD, USA
| | - Robert Bates
- Department of Chemistry, University of Arizona, Tucson, AZ, USA
| | - Ru Chih Huang
- Department of Biology, Johns Hopkins University, Mudd Hall, Baltimore, MD, USA
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36
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Xiao M, Li W. Recent Advances on Small-Molecule Survivin Inhibitors. Curr Med Chem 2015; 22:1136 - 1146. [PMID: 25613234 DOI: 10.2174/0929867322666150114102146] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/07/2014] [Accepted: 12/09/2014] [Indexed: 12/18/2022]
Abstract
Survivin, a member of the inhibitor of apoptosisproteins family, is highly expressed in most human neoplasms, but its expression is very low or undetectable in terminally differentiated normal tissues. Survivin has been shown to inhibit cancer cell apoptosis and promote cell proliferation. The overexpression of survivin closely correlates with tumor progression and drug resistance. Because of its key role in tumor formation and maintenance, survivin is considered as an ideal target for anticancer treatment. However, the development of small-molecule survivin inhibitors has been challenging due to the requirement to disrupt the protein-protein interactions. Currently only a limited number of survivin inhibitors have been developed in recent years, and most of these inhibitors reduce survivin levels by interacting with other biomolecules instead of directly interacting with survivin protein. Despite these challenges, developing potent and selective small-molecule survivin inhibitors will be important in both basic science to better understand survivin biology and in translational research to develop potentially more effective, broad-spectrum anticancer agents. In this review, the functions of survivin and its role in cancer are summarized. Recent developments, challenges, and future direction of small-molecule survivin inhibitors are also discussed in detail.
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Affiliation(s)
| | - Wei Li
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
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Davies C, Hogarth LA, Mackenzie KL, Hall AG, Lock RB. p21(WAF1) modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia. Cell Cycle 2015; 14:3602-12. [PMID: 26506264 PMCID: PMC4825786 DOI: 10.1080/15384101.2015.1100774] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/21/2015] [Accepted: 09/22/2015] [Indexed: 10/22/2022] Open
Abstract
p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.
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Affiliation(s)
- Carwyn Davies
- Children's Cancer Institute; Lowy Cancer Research Centre; UNSW Australia; Sydney, NSW, Australia
- Clinical Pharmacology Modeling and Simulation; GlaxoSmithKline R&D; Sydney, Australia
| | - Linda A Hogarth
- Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne; Tyne and Wear, UK
| | - Karen L Mackenzie
- Children's Cancer Institute; Lowy Cancer Research Centre; UNSW Australia; Sydney, NSW, Australia
| | - Andrew G Hall
- Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne; Tyne and Wear, UK
| | - Richard B Lock
- Children's Cancer Institute; Lowy Cancer Research Centre; UNSW Australia; Sydney, NSW, Australia
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Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias. Invest New Drugs 2014; 33:389-96. [PMID: 25523151 DOI: 10.1007/s10637-014-0198-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 12/08/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. PATIENTS AND METHODS Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. RESULTS Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. CONCLUSION Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.
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Redmond WJ, Camo M, Mitchell V, Vaughan CW, Connor M. Nordihydroguaiaretic acid activates hTRPA1 and modulates behavioral responses to noxious cold in mice. Pharmacol Res Perspect 2014; 2:e00079. [PMID: 25505619 PMCID: PMC4186454 DOI: 10.1002/prp2.79] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 07/31/2014] [Accepted: 08/01/2014] [Indexed: 01/25/2023] Open
Abstract
Nordihydroguaiaretic acid (NDGA) is a major biologically active component of the creosote bush, Larrea tridentate, widely used in unregulated therapies. NDGA is a lipoxygenase inhibitor while a derivative, terameprocol, has been trialed as a chemotherapeutic agent. When investigating fatty acid activation of the human transient receptor potential cation channel subfamily A, member 1 (hTRPA1), we found that NDGA activated the channel. Here we investigate the actions of NDGA and terameprocol at hTRPA1 and the consequences of this for noxious cold sensitivity in mice. hTRPA1 was stably expressed in HEK 293 cells (HEK 293-TRPA1) and channel activity examined by measuring changes in intracellular calcium ([Ca]i) using a fluorescent dye and activation of membrane currents using patch clamp electrophysiology. The effects of local NDGA and terameprocol application on acetone-induced paw flinching were examined in mice. NDGA (pEC50 of 5.4 ± 0.1, maximum change in fluorescence of 385 ± 30%) and terameprocol (pEC50 4.5 ± 0.2, maximum 550 ± 75%) increased [Ca]i in HEK 293-hTRPA1 cells. NDGA also induced an increase in membrane conductance in HEK 293-hTRPA1 cells. These effects were prevented by the TRPA1 antagonist HC-030031, and were dependent on the presence of Cys621, Cys 641, and Cys 665 in hTRPA1. Neither NDGA nor terameprocol alone produced spontaneous pain behaviors in mice after hind paw injection, but both enhanced responses to acetone. NDGA and terameprocol are efficacious activators of TRPA1. NDGA should be used with care to probe lipoxygenase involvement in nociception while TRPA1 activity should be considered when considering use of these drugs in humans.
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Affiliation(s)
- William John Redmond
- Australian School of Advanced Medicine, Macquarie University New South Wales, 2109, Australia
| | - Maxime Camo
- Australian School of Advanced Medicine, Macquarie University New South Wales, 2109, Australia
| | - Vanessa Mitchell
- Pain Management Research Institute, Kolling Institute, University of Sydney New South Wales, 2065, Australia
| | - Christopher Walter Vaughan
- Pain Management Research Institute, Kolling Institute, University of Sydney New South Wales, 2065, Australia
| | - Mark Connor
- Australian School of Advanced Medicine, Macquarie University New South Wales, 2109, Australia
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Kogiso T, Nagahara H, Hashimoto E, Ariizumi S, Yamamoto M, Shiratori K. Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells. PLoS One 2014; 9:e100495. [PMID: 24960176 PMCID: PMC4069002 DOI: 10.1371/journal.pone.0100495] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 05/23/2014] [Indexed: 12/20/2022] Open
Abstract
Transforming growth factor-β1 (TGF-β1) potently inhibits human hepatocellular carcinoma (HCC) cell growth. Here we demonstrated that TGF-β1-induced apoptosis is mediated by decreased phosphorylation of cdc2 at Tyr15 accompanied by down-regulation of Wee1 kinase expression. As expected from these results, a Wee1 kinase inhibitor efficiently induced apoptosis in HCC cells in the absence of TGF-β1 treatment. In surgically resected samples, Wee1 kinase was expressed in moderately to poorly differentiated HCC, whereas no Wee1 kinase expression was observed in non-cancerous tissue, including cirrhotic tissue. Our results suggest that Wee1 kinase inhibitors may be a practical novel therapeutic option against advanced HCC.
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Affiliation(s)
- Tomomi Kogiso
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Hikaru Nagahara
- Aoyama hospital, Tokyo Women's Medical University, Tokyo, Japan
| | - Etsuko Hashimoto
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Shunichi Ariizumi
- Institute of Gastroenterology, Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Masakazu Yamamoto
- Institute of Gastroenterology, Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Keiko Shiratori
- Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan
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Fulciniti M, Amodio N, Bandi RL, Munshi M, Yang G, Xu L, Hunter Z, Tassone P, Anderson KC, Treon SP, Munshi NC. MYD88-independent growth and survival effects of Sp1 transactivation in Waldenstrom macroglobulinemia. Blood 2014; 123:2673-81. [PMID: 24622324 PMCID: PMC3999753 DOI: 10.1182/blood-2014-01-550509] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 03/02/2014] [Indexed: 12/16/2022] Open
Abstract
Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in a number of malignancies, including multiple myeloma. In this study, we investigate and report its aberrant activation in Waldenström macroglobulinemia (WM). Both loss of and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated the effect of a small molecule inhibitor, terameprocol (TMP), targeting Sp1 activity in WM. Treatment with TMP inhibited the growth and survival and impaired nuclear factor-κB and signal transducer and activator of transcription activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knockdown WM cells. Moreover, we observed that Bruton's tyrosine kinase, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. The combined use of TMP with Bruton's tyrosine kinase or interleukin-1 receptor-associated kinase 1 and 4 inhibitors resulted in a significant and synergistic dose-dependent antiproliferative effect in MYD88-L265P-expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation, and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway.
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Affiliation(s)
- Mariateresa Fulciniti
- Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
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Survivin as a preferential target for cancer therapy. Int J Mol Sci 2014; 15:2494-516. [PMID: 24531137 PMCID: PMC3958864 DOI: 10.3390/ijms15022494] [Citation(s) in RCA: 138] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 01/31/2014] [Accepted: 02/07/2014] [Indexed: 11/16/2022] Open
Abstract
Cancer is typically a consequence of imbalance between cell death and proliferation in a way favorable to cell proliferation and survival. Most conventional cancer therapies are based on targeting rapidly growing cancerous cells to block growth or enhance cell death, thereby, restoring the balance between these processes. In many instances, malignancies that develop resistance to current treatment modalities, such as chemotherapy, immunotherapy, and radiotherapy often present the greatest challenge in subsequent management of the patient. Studies have shown that under normal circumstances, cells utilize different death mechanisms, such as apoptosis (programmed cell death), autophagy, mitotic catastrophe, and necrosis to maintain homeostasis and physiological integrity of the organism, but these processes often appear to be altered in cancer. Thus, in recent years developing various strategies for administration of cytotoxic chemotherapeutics in combination with apoptosis-sensitizing reagents is receiving more emphasis. Here, we review the properties of the anti-apoptotic protein, survivin, a member of the inhibitor of apoptosis protein (IAP) family and the clinical feasibility and anti-cancer potential of drugs targeting this protein. We also discuss some key points and concerns that should be taken into consideration while developing drugs that target apoptotic proteins, such as survivin.
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Rauch A, Hennig D, Schäfer C, Wirth M, Marx C, Heinzel T, Schneider G, Krämer OH. Survivin and YM155: how faithful is the liaison? Biochim Biophys Acta Rev Cancer 2014; 1845:202-20. [PMID: 24440709 DOI: 10.1016/j.bbcan.2014.01.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Revised: 01/01/2014] [Accepted: 01/04/2014] [Indexed: 02/07/2023]
Abstract
Survivin belongs to the family of apoptosis inhibitors (IAPs), which antagonizes the induction of cell death. Dysregulated expression of IAPs is frequently observed in cancers, and the high levels of survivin in tumors compared to normal adult tissues make it an attractive target for pharmacological interventions. The small imidazolium-based compound YM155 has recently been reported to block the expression of survivin via inhibition of the survivin promoter. Recent data, however, question that this is the sole and main effect of this drug, which is already being tested in ongoing clinical studies. Here, we critically review the current data on YM155 and other new experimental agents supposed to antagonize survivin. We summarize how cells from various tumor entities and with differential expression of the tumor suppressor p53 respond to this agent in vitro and as murine xenografts. Additionally, we recapitulate clinical trials conducted with YM155. Our article further considers the potency of YM155 in combination with other anti-cancer agents and epigenetic modulators. We also assess state-of-the-art data on the sometimes very promiscuous molecular mechanisms affected by YM155 in cancer cells.
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Affiliation(s)
- Anke Rauch
- Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Dorle Hennig
- Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Claudia Schäfer
- Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Matthias Wirth
- II Department of Internal Medicine, Technical University of Munich, Munich, Germany
| | - Christian Marx
- Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Thorsten Heinzel
- Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany
| | - Günter Schneider
- II Department of Internal Medicine, Technical University of Munich, Munich, Germany
| | - Oliver H Krämer
- Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131 Mainz, Germany.
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Ho SSH, Go ML. Restraining the flexibility of the central linker in terameprocol results in constrained analogs with improved growth inhibitory activity. Bioorg Med Chem Lett 2013; 23:6127-33. [PMID: 24080463 DOI: 10.1016/j.bmcl.2013.09.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/12/2013] [Accepted: 09/05/2013] [Indexed: 10/26/2022]
Abstract
The semi-synthetic lignan terameprocol inhibits the transcription of several inflammatory and oncogenic genes and has been evaluated for its anti-cancer properties. Here we investigated the effect of restricting the flexibility of the carbon linker connecting the terminal rings of terameprocol on its growth inhibitory activity. Conformational restriction was explored by introducing unsaturation, inserting polar entities with limited flexibility and cyclization of the connecting linker. Twenty three compounds were synthesized and evaluated on a panel of malignant human cells. The most promising compounds were those with non-polar linkers, as seen in butadiene 1a and the cyclized benzylideneindane analog 7. Both compounds were more potent than terameprocol on pancreatic BxPC-3 cells with GI50 values of 3.4 and 8.1 μM, respectively. Selected isomers of 1a (E,E) and 7 (Z) adopted low energy bent conformations that mimicked the low energy conformer of terameprocol. It is tempting to propose that conformational similarity to terameprocol may have contributed to their good activity. The scaffolds of 1a and 7 should be further investigated for their anticancer potential.
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Affiliation(s)
- Sherman Si Han Ho
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore
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Hensley P, Mishra M, Kyprianou N. Targeting caspases in cancer therapeutics. Biol Chem 2013; 394:831-43. [PMID: 23509217 DOI: 10.1515/hsz-2013-0128] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 03/15/2013] [Indexed: 02/01/2023]
Abstract
The identification of the fundamental role of apoptosis in the growth balance and normal homeostasis against cell proliferation led to the recognition of its loss contributing to tumorigenesis. The mechanistic significance of reinstating apoptosis signaling towards selective targeting of malignant cells heavily exploits the caspase family of death-inducing molecules as a powerful therapeutic platform for the development of potent anticancer strategies. Some apoptosis inhibitors induce caspase expression and activity in preclinical models and clinical trials by targeting both the intrinsic and extrinsic apoptotic pathways and restoring the apoptotic capacity in human tumors. Furthermore, up-regulation of caspases emerges as a sensitizing mechanism for tumors exhibiting therapeutic resistance to radiation and adjuvant chemotherapy. This review provides a comprehensive discussion of the functional involvement of caspases in apoptosis control and the current understanding of reactivating caspase-mediated apoptosis signaling towards effective therapeutic modalities in cancer treatment.
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Affiliation(s)
- Patrick Hensley
- Department of Urology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA
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Chu HL, Cheng TM, Chen HW, Chou FH, Chang YC, Lin HY, Liu SY, Liang YC, Hsu MH, Wu DS, Li HY, Ho LP, Wu PC, Chen FR, Chen GS, Shieh DB, Chang CS, Su CH, Yao Z, Chang CC. Synthesis of apolipoprotein B lipoparticles to deliver hydrophobic/amphiphilic materials. ACS APPLIED MATERIALS & INTERFACES 2013; 5:7509-16. [PMID: 23834261 PMCID: PMC3744920 DOI: 10.1021/am401808e] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 07/08/2013] [Indexed: 05/23/2023]
Abstract
To develop a drug delivery system (DDS), it is critical to address challenging tasks such as the delivery of hydrophobic and amphiphilic compounds, cell uptake, and the metabolic fate of the drug delivery carrier. Low-density lipoprotein (LDL) has been acknowledged as the human serum transporter of natively abundant lipoparticles such as cholesterol, triacylglycerides, and lipids. Apolipoprotein B (apo B) is the only protein contained in LDL, and possesses a binding moiety for the LDL receptor that can be internalized and degraded naturally by the cell. Therefore, synthetic/reconstituting apoB lipoparticle (rABL) could be an excellent delivery carrier for hydrophobic or amphiphilic materials. Here, we synthesized rABL in vitro, using full-length apoB through a five-step solvent exchange method, and addressed its potential as a DDS. Our rABL exhibited good biocompatibility when evaluated with cytotoxicity and cell metabolic response assays, and was stable during storage in phosphate-buffered saline at 4 °C for several months. Furthermore, hydrophobic superparamagnetic iron oxide nanoparticles (SPIONPs) and the anticancer drug M4N (tetra-O-methyl nordihydroguaiaretic acid), used as an imaging enhancer and lipophilic drug model, respectively, were incorporated into the rABL, leading to the formation of SPIONPs- and M4N- containing rABL (SPIO@rABL and M4N@rABL, respectively). Fourier transform infrared spectroscopy suggested that rABL has a similar composition to that of LDL, and successfully incorporated SPIONPs or M4N. SPIO@rABL presented significant hepatic contrast enhancement in T2-weighted magnetic resonance imaging in BALB/c mice, suggesting its potential application as a medical imaging contrast agent. M4N@rABL could reduce the viability of the cancer cell line A549. Interestingly, we developed solution-phase high-resolution transmission electron microscopy to observe both LDL and SPIO@rABL in the liquid state. In summary, our LDL-based DDS, rABL, has significant potential as a novel DDS for hydrophobic and amphiphilic materials, with good cell internalization properties and metabolicity.
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Affiliation(s)
- Hsueh-Liang Chu
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Tsai-Mu Cheng
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
- Graduate Institute of Translational
Medicine, College of Medicine and Technology, Taipei
Medical University, Taipei 11031, Taiwan
| | - Hung-Wei Chen
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Fu-Hsuan Chou
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
- Department of Materials Science
and Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan
| | - Yu-Chuan Chang
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Hsin-Yu Lin
- Department
of Engineering and System Science and Nuclear Science and Technology Development
Center, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Shih-Yi Liu
- Department
of Engineering and System Science and Nuclear Science and Technology Development
Center, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yu-Chuan Liang
- Agricultural
Biotechnology Research Center and Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan
| | - Ming-Hua Hsu
- Department
of Engineering and System Science and Nuclear Science and Technology Development
Center, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Dian-Shyeu Wu
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Hsing-Yuan Li
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Li-Ping Ho
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
| | - Ping-Ching Wu
- Institute of Oral Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Fu-Rong Chen
- Department
of Engineering and System Science and Nuclear Science and Technology Development
Center, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Gong-Shen Chen
- Department of Hematology, Mackay Memorial Hospital, Taipei 10449, Taiwan
| | - Dar-Bin Shieh
- Institute of Oral Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chia-Seng Chang
- Agricultural
Biotechnology Research Center and Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan
| | - Chia-Hao Su
- Center for Translational Research
in Biomedical Sciences, Kaohsiung Chang Gung Memorial
Hospital, Kaohsiung 83342, Taiwan
| | - Zemin Yao
- Department of Biochemistry,
Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
| | - Chia-Ching Chang
- Department
of Biological Science
and Technology, National Chiao Tung University, Hsinchu 30050, Taiwan
- Agricultural
Biotechnology Research Center and Institute of Physics, Academia Sinica, Nankang, Taipei 11529, Taiwan
- E-mail: . Tel: 886-3-5731633. Fax: 886-3-5733259
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Nogueira-Ferreira R, Vitorino R, Ferreira-Pinto MJ, Ferreira R, Henriques-Coelho T. Exploring the role of post-translational modifications on protein-protein interactions with survivin. Arch Biochem Biophys 2013; 538:64-70. [PMID: 23938875 DOI: 10.1016/j.abb.2013.07.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 07/17/2013] [Accepted: 07/25/2013] [Indexed: 12/31/2022]
Abstract
Survivin is a member of the inhibitor of apoptosis protein (IAP) family with crucial roles in apoptosis and cell cycle regulation. Post-translational modifications (PTMs) have a ubiquitous role in the regulation of a diverse range of proteins' cellular functions and survivin is not an exception. Phosphorylation, acetylation and ubiquitination seem to regulate survivin anti-apoptotic and mitotic roles and also its nuclear localization. In the present review we explore the role of PTMs on protein-protein interactions focused on survivin to provide new insights into the functions and cell localization of this IAP in pathophysiological conditions, which might help the envisioning of novel targeted therapies for diseases characterized by impaired survivin activity. Protein-protein interaction analysis was performed with bioinformatics tools based on published data aiming to give an integrated perspective of this IAP's role in the cell.
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Affiliation(s)
- Rita Nogueira-Ferreira
- QOPNA, Department of Chemistry, University of Aveiro, Aveiro, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
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Li X, Jiang JH, Chen Q, Xiao SX, Li CH, Gu HW, Zhang H, Hu JL, Yao FH, Li QG. Synthesis of nordihydroguaiaretic acid derivatives and their bioactivities on S. pombe and K562 cell lines. Eur J Med Chem 2013; 62:605-13. [DOI: 10.1016/j.ejmech.2013.01.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 01/14/2013] [Accepted: 01/22/2013] [Indexed: 10/27/2022]
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Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia. Blood 2013; 121:2029-37. [PMID: 23321252 DOI: 10.1182/blood-2012-05-427773] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.
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Tetra-O-methyl nordihydroguaiaretic acid, an inhibitor of Sp1-mediated survivin transcription, induces apoptosis and acts synergistically with chemo-radiotherapy in glioblastoma cells. Invest New Drugs 2013; 31:858-70. [DOI: 10.1007/s10637-012-9917-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 12/14/2012] [Indexed: 12/12/2022]
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