Abstract
Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their cytotoxicity. However, their precise mode of action has not been fully understood.
In the present work, we report for the first time the effect of the previously synthesised compounds, BNIPDaCHM and NPA, together with a new BNIP derivative (BNIP-3,4-DaDPM) in the in vitro growth of a non-small cell lung cancer cell line (NCI-H460). In addition, for the most potent compound (BNIPDaCHM), its activity as sirtuin inhibitor was investigated in vitro and further confirmed in silico. Results in the NCI-H460 cells showed that, from the compounds tested, BNIPDaCHM was the most potent (GI50 of 1.3 μM). In addition, a concentration-dependent alteration in the normal NCI-H460 cell cycle profile was observed following treatment with BNIPDaCHM as well as an increase in the sub-G1 peak (suggestive of apoptotis). This effect was further supported by Annexin V/PI staining and by analysing the expression of proteins related to apoptosis (cleaved PARP and Caspase-3) by Western blot. It was also observed that BNIPDaCHM inhibited the activity of SIRT2 in vitro, but not of SIRT1. Accordingly, this compound also caused a small increase in tubulin acetylation in NCI-H460 cells. To determine the binding potential of BNIPDaCHM on hSIRT2 and to further validate its inhibitory action, in silico docking studies were carried out, which revealed that BNIPDaCHM is composed of an entirely new SIRT2- inhibiting structural scaffold. In conclusion, this study indicates that BNIP derivatives with a novel structural backbone, such as BNIPDaCHM, may have potential as building blocks for novel antitumour agents which might selectively bind to hSIRT-2.Keywords: Apoptosis, SIRT2 inhibitor, Bisnaphthalimidopropyl derivatives, Anticancer agent, HDAC
Anti-Cancer Agents in Medicinal Chemistry
Title:Cytotoxicity and Cell Death Mechanisms Induced by a Novel Bisnaphthalimidopropyl Derivative against the NCI-H460 non-small Lung Cancer Cell Line
Volume: 13 Issue: 3
Author(s): Raquel T. Lima, Gemma A. Barron, Joanna A. Grabowska, Giovanna Bermano, Simranjeet Kaur, Nilanjan Roy, M. Helena Vasconcelos and Paul K.T. Lin
Affiliation:
Keywords: Apoptosis, SIRT2 inhibitor, Bisnaphthalimidopropyl derivatives, Anticancer agent, HDAC
Abstract: Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their cytotoxicity. However, their precise mode of action has not been fully understood.
In the present work, we report for the first time the effect of the previously synthesised compounds, BNIPDaCHM and NPA, together with a new BNIP derivative (BNIP-3,4-DaDPM) in the in vitro growth of a non-small cell lung cancer cell line (NCI-H460). In addition, for the most potent compound (BNIPDaCHM), its activity as sirtuin inhibitor was investigated in vitro and further confirmed in silico. Results in the NCI-H460 cells showed that, from the compounds tested, BNIPDaCHM was the most potent (GI50 of 1.3 μM). In addition, a concentration-dependent alteration in the normal NCI-H460 cell cycle profile was observed following treatment with BNIPDaCHM as well as an increase in the sub-G1 peak (suggestive of apoptotis). This effect was further supported by Annexin V/PI staining and by analysing the expression of proteins related to apoptosis (cleaved PARP and Caspase-3) by Western blot. It was also observed that BNIPDaCHM inhibited the activity of SIRT2 in vitro, but not of SIRT1. Accordingly, this compound also caused a small increase in tubulin acetylation in NCI-H460 cells. To determine the binding potential of BNIPDaCHM on hSIRT2 and to further validate its inhibitory action, in silico docking studies were carried out, which revealed that BNIPDaCHM is composed of an entirely new SIRT2- inhibiting structural scaffold. In conclusion, this study indicates that BNIP derivatives with a novel structural backbone, such as BNIPDaCHM, may have potential as building blocks for novel antitumour agents which might selectively bind to hSIRT-2.Export Options
About this article
Cite this article as:
T. Lima Raquel, A. Barron Gemma, A. Grabowska Joanna, Bermano Giovanna, Kaur Simranjeet, Roy Nilanjan, Helena Vasconcelos M. and K.T. Lin Paul, Cytotoxicity and Cell Death Mechanisms Induced by a Novel Bisnaphthalimidopropyl Derivative against the NCI-H460 non-small Lung Cancer Cell Line, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (3) . https://dx.doi.org/10.2174/1871520611313030005
DOI https://dx.doi.org/10.2174/1871520611313030005 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Recent Clinical Experience with Oncolytic Viruses
Current Pharmaceutical Biotechnology Lipoprotein Like Nanoparticles Used in Drug and Gene Delivery
Current Pharmaceutical Design NK Cell Function in HIV-1 Infection
Current HIV Research Recent Developments to Improve the Efficacy of Cytotoxic Nucleoside Analogues
Recent Patents on Anti-Cancer Drug Discovery Editorial (Thematic Issue: New Insights into a Classical Pathway: Key Roles of the Mevalonate Cascade in Different Diseases (Part I))
Current Molecular Pharmacology Development of Thiazole-5-carboxylate Derivatives as Selective Inhibitors of Monoacylglycerol Lipase as Target in Cancer
Mini-Reviews in Medicinal Chemistry Angiogenesis Inhibitors and Radiation in Multimodality Cancer Therapy: Preclinical and Clinical Studies
Current Angiogenesis (Discontinued) Interaction of Biologically Active Amines with Mitochondria and Their Role in the Mitochondrial-Mediated Pathway of Apoptosis
Current Medicinal Chemistry Analysis of Fish IL-1β and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design
Current Pharmaceutical Design Expression, Distribution and Regulation of Phosphodiesterase 5
Current Pharmaceutical Design HDAC as a Therapeutic Target for Treatment of Endometrial Cancers
Current Pharmaceutical Design May Oxygen-Ozone Therapy Improves Cardiovascular Disorders?
Cardiovascular & Hematological Disorders-Drug Targets Oncogenic Fusion Tyrosine Kinases as Molecular Targets for Anti-Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Redistribution of CD95 into the Lipid Rafts to Treat Cancer Cells?
Recent Patents on Anti-Cancer Drug Discovery Regulation of Radiation-Induced Apoptosis by Early Growth Response-1 Gene in Solid Tumors
Current Cancer Drug Targets Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas
Current Cancer Drug Targets How can Proteomics Reach Cancer Biomarkers?
Current Proteomics The Ubiquitin+Proteasome Protein Degradation Pathway as a Therapeutic Strategy in the Treatment of Solid Tumor Malignancies
Anti-Cancer Agents in Medicinal Chemistry α7 nAChR in Airway Respiratory Epithelial Cells
Current Drug Targets Recent Progress in the Synthesis of Naturally Occurring Triterpenoid Saponins
Mini-Reviews in Organic Chemistry