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Zhao YY, Li J, Wang HQ, Zheng HB, Ma SW, Zhou GZ. Activation of autophagy promotes the inhibitory effect of curcumin analog EF-24 against MDA-MB-231 cancer cells. J Biochem Mol Toxicol 2024; 38:e23642. [PMID: 38348710 DOI: 10.1002/jbt.23642] [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: 10/02/2023] [Revised: 12/20/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024]
Abstract
Breast cancer is the leading cause of cancer deaths in women worldwide. EF-24, an analog of curcumin, has been shown to possess promising anticancer effects. However, the underlying mechanism remains elusive. In the present study, the inhibitory effect of EF-24 against one breast cancer cell line, MDA-MB-231, and its anti-migration ability were assessed by MTT, wound healing, and Transwell assay. Furthermore, we found that EF-24 could induce initiation of autophagy as evidenced by fluorescence and electron microscope observation. EF-24 also induced mitochondrial apoptosis in MDA-MB-231 cells as detected by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. In addition, the early autophagy inhibitor 3-MA could reduce the cleavage of PARP protein and protect cells from EF-24-induced apoptosis, while the autophagy inducer (rapamycin) could enhance the anticancer effect of EF-24 in MDA-MB-231 cells, which suggest that EF-24 induces crosstalk between autophagy and apoptosis, which herein participate in the antiproliferative effect of EF-24 in breast cancer cells. Moreover, removal of EF-24-activated ROS with NAC significantly reversed migration ability of MDA-MB-231 cells, indicating that EF-24 exerted an inhibitory effect through a ROS-mediating pathway. These results will help to elucidate the antitumor mechanism of curcumin analogs and to explore future potential clinical applications.
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Affiliation(s)
- Yin-Yin Zhao
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Jun Li
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Hao-Qi Wang
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Hao-Bo Zheng
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Shi-Wei Ma
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Guang-Zhou Zhou
- College of Bioengineering, Henan University of Technology, Zhengzhou, China
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Tai Y, Shang J. Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma. Front Endocrinol (Lausanne) 2024; 14:1260701. [PMID: 38269250 PMCID: PMC10806569 DOI: 10.3389/fendo.2023.1260701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 12/20/2023] [Indexed: 01/26/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
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Affiliation(s)
- Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jiwen Shang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Department of Ambulatory Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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Sazdova I, Keremidarska-Markova M, Dimitrova D, Mitrokhin V, Kamkin A, Hadzi-Petrushev N, Bogdanov J, Schubert R, Gagov H, Avtanski D, Mladenov M. Anticarcinogenic Potency of EF24: An Overview of Its Pharmacokinetics, Efficacy, Mechanism of Action, and Nanoformulation for Drug Delivery. Cancers (Basel) 2023; 15:5478. [PMID: 38001739 PMCID: PMC10670065 DOI: 10.3390/cancers15225478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
EF24, a synthetic monocarbonyl analog of curcumin, shows significant potential as an anticancer agent with both chemopreventive and chemotherapeutic properties. It exhibits rapid absorption, extensive tissue distribution, and efficient metabolism, ensuring optimal bioavailability and sustained exposure of the target tissues. The ability of EF24 to penetrate biological barriers and accumulate at tumor sites makes it advantageous for effective cancer treatment. Studies have demonstrated EF24's remarkable efficacy against various cancers, including breast, lung, prostate, colon, and pancreatic cancer. The unique mechanism of action of EF24 involves modulation of the nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, disrupting cancer-promoting inflammation and oxidative stress. EF24 inhibits tumor growth by inducing cell cycle arrest and apoptosis, mainly through inhibiting the NF-κB pathway and by regulating key genes by modulating microRNA (miRNA) expression or the proteasomal pathway. In summary, EF24 is a promising anticancer compound with a unique mechanism of action that makes it effective against various cancers. Its ability to enhance the effects of conventional therapies, coupled with improvements in drug delivery systems, could make it a valuable asset in cancer treatment. However, addressing its solubility and stability challenges will be crucial for its successful clinical application.
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Affiliation(s)
- Iliyana Sazdova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University ‘St. Kliment Ohridski’, 1504 Sofia, Bulgaria; (I.S.); (M.K.-M.); (H.G.)
| | - Milena Keremidarska-Markova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University ‘St. Kliment Ohridski’, 1504 Sofia, Bulgaria; (I.S.); (M.K.-M.); (H.G.)
| | - Daniela Dimitrova
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
| | - Vadim Mitrokhin
- Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia; (V.M.); (A.K.)
| | - Andre Kamkin
- Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia; (V.M.); (A.K.)
| | - Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia;
| | - Jane Bogdanov
- Institute of Chemistry, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia;
| | - Rudolf Schubert
- Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Universitätsstrasse 2, 86159 Augsburg, Germany;
| | - Hristo Gagov
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University ‘St. Kliment Ohridski’, 1504 Sofia, Bulgaria; (I.S.); (M.K.-M.); (H.G.)
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Mitko Mladenov
- Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia; (V.M.); (A.K.)
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia;
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Li J, Wang SH, Liu YT, Zhang Q, Zhou GZ. Inhibition of autophagic flux by the curcumin analog EF-24 and its antiproliferative effect on MCF-7 cancer cells. J Biochem Mol Toxicol 2023; 37:e23307. [PMID: 36633067 DOI: 10.1002/jbt.23307] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 11/17/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
5-Bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24) is a curcumin analog, which was identified for its physiochemical stability and diverse pharmacological functions. In the present study, EF-24 was added to the breast cancer cell line MCF-7 and its cellular effects were characterized. The results indicated that EF-24 possessed antiproliferative and antimigratory activities on MCF-7 cells as determined by MTT assay, wound healing, and transwell assay, respectively. In addition, the autophagosomal vesicles could be detected by acridine orange staining and electron microscope analysis in EF-24-treated cells. Conversion of LC3-I to LC3-II was also investigated following EF-24 treatment of the cells. However, the expression analysis of p62 and LC3 revealed that EF-24 could inhibit autophagic flux in MCF-7 cells. Confocal microscopy suggested that EF-24 could inhibit the degradation of autophagic vesicles by blocking the fusion of autophagosomes with lysosomes. EF-24 could also induce apoptosis of MCF-7 cells as determined by Hoechst 33342 staining, flow cytometry analysis, and western blot analysis. Moreover, treatment of the cells with the autophagy inhibitor 3-MA enhanced the PARP1 cleavage of EF-24-treated MCF-7 cells, which indicated the crosstalk between autophagy and apoptosis in breast cancer cells. Additional investigation of EF-24 should be performed in future studies to assess its antiproliferation and antimigratory effects on MCF-7 cells. However, the current results provide a solid foundation for the potential in vivo anticancer activity of this compound.
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Affiliation(s)
- Jun Li
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Song-He Wang
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Yang-Ting Liu
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
| | - Qin Zhang
- Division of Aquaculture and Genetic Breeding, Henan Academy of Fishery Sciences, Zhengzhou, China
| | - Guang-Zhou Zhou
- Department of Biotechnology, College of Bioengineering, Henan University of Technology, Zhengzhou, China
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Velur G, Kusanur R. Herbal Drugs in Cancer Treatment. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2022. [DOI: 10.1134/s1068162022060267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Alabdali A, Kzar M, Chinnappan S, R M, Khalivulla SI, H R, Abd Razik BM. Antioxidant activity of Curcumin. RESEARCH JOURNAL OF PHARMACY AND TECHNOLOGY 2021:6741-6746. [DOI: 10.52711/0974-360x.2021.01164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
In the past few years, multiple drugs have been produced from traditional raw materials and recent pandemic disease COVID-19 once again research on this matter is being conducted to determine potential therapeutic purposes of different Ayurvedic Indian medicines and herbs. One such medicinal herb is Curcuma longa. Curcumin is strong antioxidant, anti-inflammatory, antispasmodic, antiangiogenic, anti-carcinogenic, as shown by multiple in vitro and in vivo studies. The action of the growth factor receptors is inhibited by curcumin. The anti-inflammatory effect of curcumin is obtained on the cytokines, proteolytic enzymes, eicosanoids, and lipid mediators. The superoxide radicals, nitric oxide and hydrogen peroxide, are sifted by curcumin, while lipid peroxidation is inhibited. Such properties of the compound thus form the foundation for its various therapeutic and pharmacological effects could also hold antiviral properties including COVID-19. The aim of this research is to summarize the updated pharmacological activities of curcumin.
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Affiliation(s)
- Aya Alabdali
- The University of Mashreq, College of Pharmacy, Baghdad, Iraq
| | - Marwah Kzar
- The University of Mashreq, College of Pharmacy, Baghdad, Iraq
| | - Sasikala Chinnappan
- Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University Kuala Lumpur (South Wing), No.1, Jalan Menara Gading, UCSI Heights 56000 Cheras, Kuala Lumpur, Malaysia
| | - Mogana R
- Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University Kuala Lumpur (South Wing), No.1, Jalan Menara Gading, UCSI Heights 56000 Cheras, Kuala Lumpur, Malaysia
| | - Shaik Ibrahim Khalivulla
- Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, UCSI University Kuala Lumpur (South Wing), No.1, Jalan Menara Gading, UCSI Heights 56000 Cheras, Kuala Lumpur, Malaysia
| | - Rahman H
- PSG College of Pharmacy, Coimbatore, India
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Zhang K, Zhu S, Li J, Jiang T, Feng L, Pei J, Wang G, Ouyang L, Liu B. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease. Acta Pharm Sin B 2021; 11:3015-3034. [PMID: 34729301 PMCID: PMC8546670 DOI: 10.1016/j.apsb.2021.02.016] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/28/2021] [Accepted: 02/19/2021] [Indexed: 02/08/2023] Open
Abstract
Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.
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Key Words
- 3-MA, 3-methyladenine
- 5-HT2A, Serotonin 2A
- 5-HT2C, serotonin 2C
- A2A, adenosine 2A
- AADC, aromatic amino acid decarboxylase
- ALP, autophagy-lysosomal pathway
- AMPK, 5ʹAMP-activated protein kinase
- ATG, autophagy related protein
- ATP13A2, ATPase cation transporting 13A2
- ATTEC, autophagosome-tethering compound
- AUC, the area under the curve
- AUTAC, autophagy targeting chimera
- Autophagy
- BAF, bafilomycinA1
- BBB, blood−brain barrier
- CL, clearance rate
- CMA, chaperone-mediated autophagy
- CNS, central nervous system
- COMT, catechol-O-methyltransferase
- DA, dopamine
- DAT, dopamine transporter
- DJ-1, Parkinson protein 7
- DR, dopamine receptor
- ER, endoplasmic reticulum
- ERRα, estrogen-related receptor alpha
- F, oral bioavailability
- GAPDH, glyceraldehyde 3-phosphate dehydrogenase
- GBA, glucocerebrosidase β acid
- GWAS, genome-wide association study
- HDAC6, histone deacetylase 6
- HSC70, heat shock cognate 71 kDa protein
- HSPA8, heat shock 70 kDa protein 8
- IMPase, inositol monophosphatase
- IPPase, inositol polyphosphate 1-phosphatase
- KI, knockin
- LAMP2A, lysosome-associated membrane protein 2 A
- LC3, light chain 3
- LIMP-2, lysosomal integrated membrane protein-2
- LRRK2, leucine-rich repeat sequence kinase 2
- LRS, leucyl-tRNA synthetase
- LUHMES, lund human mesencephalic
- Lamp2a, type 2A lysosomal-associated membrane protein
- MAO-B, monoamine oxidase B
- MPP+, 1-methyl-4-phenylpyridinium
- MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine
- MYCBP2, MYC-binding protein 2
- NMDA, N-methyl-d-aspartic acid
- ONRs, orphan nuclear receptors
- PD therapy
- PD, Parkinson's disease
- PDE4, phosphodiesterase 4
- PI3K, phosphatidylinositol 3-kinase
- PI3P, phosphatidylinositol 3-phosphate
- PINK1, PTEN-induced kinase 1
- PLC, phospholipase C
- PREP, prolyl oligopeptidase
- Parkin, parkin RBR E3 ubiquitin−protein ligase
- Parkinson's disease (PD)
- ROS, reactive oxygen species
- SAR, structure–activity relationship
- SAS, solvent accessible surface
- SN, substantia nigra
- SNCA, α-synuclein gene
- SYT11, synaptotagmin 11
- Small-molecule compound
- TFEB, transcription factor EB
- TSC2, tuberous sclerosis complex 2
- Target
- ULK1, UNC-51-like kinase 1
- UPS, ubiquitin−proteasome system
- mAChR, muscarinic acetylcholine receptor
- mTOR, the mammalian target of rapamycin
- α-syn, α-synuclein
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Targeting Drug Chemo-Resistance in Cancer Using Natural Products. Biomedicines 2021; 9:biomedicines9101353. [PMID: 34680470 PMCID: PMC8533186 DOI: 10.3390/biomedicines9101353] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.
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Subramani A, Ali LB, Rosi V, Shabeer T. Photophysical, Theoretical, Pharmacogenomics And Biological Studies Of Synthesized New Symmetrical Diol Schiff Base And 4-Arylidene Curcumin Monomers. J Mol Struct 2020. [DOI: 10.1016/j.molstruc.2020.128491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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An Update on the Pharmacological Usage of Curcumin: Has it Failed in the Drug Discovery Pipeline? Cell Biochem Biophys 2020; 78:267-289. [PMID: 32504356 DOI: 10.1007/s12013-020-00922-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 05/26/2020] [Indexed: 12/15/2022]
Abstract
The pharmacological propensities of curcumin have been reported in a plethora of pre-clinical and clinical studies. However, innate attributes account for extremely low oral bioavailability which impedes its development as a therapeutic agent. Regardless, these drawbacks have not deterred researchers from optimizing its potentials. This review discussed the pharmacokinetic properties of curcumin relative to its outlook as a lead compound in drug discovery. Also, we highlighted therapeutic strategies that have expedited improvements in curcumin oral bioavailability and delivery to target sites over the years. Recent implementations of these strategies were also covered. More research efforts should be directed towards investigating the pharmacokinetic impacts of these novel curcumin formulations in human clinical studies since inter-species disparities could limit the accuracies of animal studies. We envisaged that integrative-clinical research would help determine 'actual' improvements in curcumin pharmacokinetics coupled with suitable administrative routes, optimal dosing, and drug-enzyme or drug-drug interactions. In addition, this could help determine formulations for achieving higher systemic exposure of parent curcumin thereby providing a strong impetus towards the development of curcumin as a drug candidate in disease treatment.
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The Curcumin Analogue, MS13 (1,5-Bis(4-hydroxy-3- methoxyphenyl)-1,4-pentadiene-3-one), Inhibits Cell Proliferation and Induces Apoptosis in Primary and Metastatic Human Colon Cancer Cells. Molecules 2020; 25:molecules25173798. [PMID: 32825505 PMCID: PMC7504349 DOI: 10.3390/molecules25173798] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/26/2020] [Accepted: 08/10/2020] [Indexed: 02/06/2023] Open
Abstract
The cytotoxic and apoptotic effects of turmeric (Curcuma longa) on colon cancer have been well documented but specific structural modifications of curcumin have been shown to possess greater growth-suppressive potential on colon cancer than curcumin. Therefore, the aim of this study is to identify the anti-cancer properties of curcumin analogue-MS13, a diarylpentanoid on the cytotoxicity, anti-proliferative and apoptotic activity of primary (SW480) and metastatic (SW620) human colon cancer cells. A cell viability assay showed that MS13 has greater cytotoxicity effect on SW480 (EC50: 7.5 ± 2.8 µM) and SW620 (EC50: 5.7 ± 2.4 µM) compared to curcumin (SW480, EC50: 30.6 ± 1.4 µM) and SW620, EC50: 26.8 ± 2.1 µM). Treatment with MS13 at two different doses 1X EC50 and 2X EC50 suppressed the colon cancer cells growth with lower cytotoxicity against normal cells. A greater anti-proliferative effect was also observed in MS13 treated colon cancer cells compared to curcumin at 48 and 72 h. Subsequent analysis on the induction of apoptosis showed that MS13 treated cells exhibited morphological features associated with apoptosis. The findings are also consistent with cellular apoptotic activities shown by increased caspase-3 activity and decreased Bcl-2 protein level in both colon cancer cell lines. In conclusion, MS13 able to suppress colon cancer cell growth by inhibiting cell proliferation and induce apoptosis in primary and metastatic human colon cancer cells.
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Labbozzetta M, Notarbartolo M, Poma P. Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View. Int J Mol Sci 2020; 21:ijms21093070. [PMID: 32349210 PMCID: PMC7246796 DOI: 10.3390/ijms21093070] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023] Open
Abstract
Multidrug resistance (MDR), of the innate and acquired types, is one of major problems in treating tumor diseases with a good chance of success. In this review, we examine the key role of nuclear factor-kappa B (NF-κB) to induce MDR in three tumor models characterized precisely by innate or acquired MDR, in particular triple negative breast cancer (TNBC), hepatocellular carcinoma (HCC), and acute myeloid leukemia (AML). We also present different pharmacological approaches that our group have employed to reduce the expression/activation of this transcriptional factor and thus to restore chemo-sensitivity. Finally, we examine the latest scientific evidence found by other groups, the most significant clinical trials regarding NF-κB, and new perspectives on the possibility to consider this transcriptional factor a valid drug target in neoplastic diseases.
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13
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Synthesis and bioevaluation of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones. CHEMICAL PAPERS 2020. [DOI: 10.1007/s11696-019-00908-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Domarecka E, Skarzynska M, Szczepek AJ, Hatzopoulos S. Use of zebrafish larvae lateral line to study protection against cisplatin-induced ototoxicity: A scoping review. Int J Immunopathol Pharmacol 2020; 34:2058738420959554. [PMID: 33084473 PMCID: PMC7786420 DOI: 10.1177/2058738420959554] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/26/2020] [Indexed: 12/18/2022] Open
Abstract
AIM The present review aimed to consolidate and analyze the recent information about the use of zebrafish in studies concerning cisplatin-induced ototoxicity and otoprotection. MATERIAL AND METHODS The PubMed, Web of Science, and Scopus databanks were searched using the following MESH terms: zebrafish, cisplatin, ototoxicity. The identified publications were screened according to inclusion and exclusion criteria and the 26 qualifying manuscripts were included in the full-text analysis. The experimental protocols, including cisplatin concentrations, the exposure duration and the outcome measurements used in zebrafish larvae studies, were evaluated and the reported knowledge was summarized. RESULTS Twenty-six substances protecting from cisplatin-induced toxicity were identified with the use of zebrafish larvae. These substances include quinine, salvianolic acid B, berbamine 6, benzamil, quercetin, dexmedetomidine, dexamethsanone, quinoxaline, edaravone, apocynin, dimethyl sulfoxide, KR-22335, SRT1720, ORC-13661, 3-MA, D-methionine, mdivi-1, FUT-175, rapamycin, Z-LLF-CHO, ATX, NAC, CYM-5478, CHCP1, CHCP2 and leupeptin. The otoprotective effects of compounds were attributed to their anti-ROS, anti-apoptotic and cisplatin uptake-blocking properties. The broadest range of protection was achieved when the experimental flow used preconditioning with an otoprotective compound and later a co-incubation with cisplatin. Protection against a high concentration of cisplatin was observed only in protocols using short exposure times (4 and 6 h). CONCLUSIONS The data extracted from the selected papers confirm that despite the differences between the human and the zebra fish hearing thresholds (as affected by cisplatin), the sensory cells of zebrafish and larval zebrafish are a valuable tool which could be used: (i) for the discovery of novel otoprotective substances and compounds; (ii) to screen their side effects and (iii) to extend the knowledge on the mechanisms of cisplatin-induced inner ear damage. For future studies, the development of a consensus experimental protocol is highly recommended.
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Affiliation(s)
- Ewa Domarecka
- Department of Otorhinolaryngology, Head and Neck Surgery, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Magda Skarzynska
- Institute of Sensory Organs, Kajetany, Poland
- Institute of Physiology and Pathology of Hearing, Warsaw, Poland
| | - Agnieszka J Szczepek
- Department of Otorhinolaryngology, Head and Neck Surgery, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
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Yang J, Meng SS, Zhao YJ, Li GY, Ge LY, Zhang HL, Liu GY. 3,5-Bis(2-Trifluomethoxybenzylidene)-4-Piperidone Induces Apoptosis in A549 Cells Through Reactive Oxygen Species-Mediated Pathways. Pharm Chem J 2019. [DOI: 10.1007/s11094-019-02044-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Zhao S, Pi C, Ye Y, Zhao L, Wei Y. Recent advances of analogues of curcumin for treatment of cancer. Eur J Med Chem 2019; 180:524-535. [PMID: 31336310 DOI: 10.1016/j.ejmech.2019.07.034] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 06/26/2019] [Accepted: 07/09/2019] [Indexed: 01/01/2023]
Abstract
Curcumin (CU), an edible natural pigment from Curcuma Longa, has demonstrated extensive anti-tumor effect in vivo and in vitro. With the property of reversing drug resistance and low toxicity, CU has been considered to develop a new adjuvant chemotherapy protocol of cancer. However, the poor stability, solubility, in vivo bioavailability and weak activity of CU greatly limit its clinical application. Therefore, CU analogues have been extensively studied. Starting from the study of natural CU analogues, multiple approaches are being sought to obtain more stable, soluble and effective analogues of CU. This review focuses on the progress of these approaches to more potent CU analogues.
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Affiliation(s)
- Shijie Zhao
- Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 319, Zhongshan Rd Sanduan, Luzhou, Sichuan, 646000, PR China
| | - Chao Pi
- Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 319, Zhongshan Rd Sanduan, Luzhou, Sichuan, 646000, PR China
| | - Yun Ye
- Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 319, Zhongshan Rd Sanduan, Luzhou, Sichuan, 646000, PR China; Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, No.25, Taiping Street, Luzhou, Sichuan, 646000, China
| | - Ling Zhao
- Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 319, Zhongshan Rd Sanduan, Luzhou, Sichuan, 646000, PR China.
| | - Yumeng Wei
- Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 319, Zhongshan Rd Sanduan, Luzhou, Sichuan, 646000, PR China.
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Biological Effects of EF24, a Curcumin Derivative, Alone or Combined with Mitotane in Adrenocortical Tumor Cell Lines. Molecules 2019; 24:molecules24122202. [PMID: 31212829 PMCID: PMC6630722 DOI: 10.3390/molecules24122202] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. METHOD AND RESULTS EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 ± 2.4 μM and 4.9 ± 2.8 μM for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/β-catenin, NF-κB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. CONCLUSION This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models.
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Ye C, Wang W, Xia G, Yu C, Yi Y, Hua C, Tu F, Shen L, Chen C, Sun W, Zheng Z. A novel curcumin derivative CL-6 exerts antitumor effect in human gastric cancer cells by inducing apoptosis through Hippo-YAP signaling pathway. Onco Targets Ther 2019; 12:2259-2269. [PMID: 30988630 PMCID: PMC6441554 DOI: 10.2147/ott.s196914] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Purpose Gastric carcinoma is the second most frequently diagnosed cancer and leading cause of cancer death in China. As a new generation of cancer therapeutic drug, CL-6, a curcumin derivative, shows better bioavailability than curcumin, which has shown anticancer effects in gastric cancer (GC). However, whether CL-6 shows similar activities in GC has not been examined. Materials and methods Cell proliferation assay, colony-forming assay, flow cytometric analysis, wound healing assay, and Transwell invasion assay were performed to examine the effects of CL-6 on proliferation, apoptosis, migration, and invasion on human AGS and MGC-803 cell lines. Western blot was used to evaluate protein levels of Bax, Bcl-2, YAP, p-YAP, and Lats, and gene expression was measured by real-time quantitative PCR (RT-qPCR). Results CL-6 dose dependently reduced proliferation, increased apoptosis, and inhibited the migration and invasion abilities of AGS and MGC-803 cells. CL-6 also increased levels of pro-apoptotic protein Bax, decreased levels of antiapoptotic protein Bcl-2, and increased the Bax/Bcl-2 ratio. CL-6 treatment also inhibited YAP and YAP protein and mRNA expression, while it induced the expression of Lats and p-YAP (Ser127). Conclusion CL-6 induces apoptosis of GC cells by activating the Hippo–YAP signaling pathway. These results indicate the therapeutic potential of the novel curcumin derivative CL-6 in GC.
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Affiliation(s)
- Chenmin Ye
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Wenqian Wang
- Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Guojun Xia
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Chengyang Yu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Yongdong Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, People's Republic of China
| | - Fuyang Tu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Leibin Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Canjin Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ; .,The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China
| | - Weijian Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ;
| | - Zhiqiang Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325027, People's Republic of China, ;
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EF24 Suppresses Cholangiocellular Carcinoma Progression, Inhibits STAT3 Phosphorylation, and Induces Apoptosis via ROS-Mediated Oxidative Stress. JOURNAL OF ONCOLOGY 2019; 2019:8701824. [PMID: 30949204 PMCID: PMC6425401 DOI: 10.1155/2019/8701824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/17/2019] [Accepted: 02/11/2019] [Indexed: 02/08/2023]
Abstract
Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.
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Lee HK, Park SB, Chang SY, Jung SJ. Antipruritic effect of curcumin on histamine-induced itching in mice. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2018; 22:547-554. [PMID: 30181701 PMCID: PMC6115343 DOI: 10.4196/kjpp.2018.22.5.547] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 06/01/2018] [Accepted: 06/07/2018] [Indexed: 11/29/2022]
Abstract
Itching is a common clinical symptom of skin disease that significantly affects a patient's quality of life. Transient receptor potential vanilloid 1 (TRPV1) receptors of keratinocytes and peripheral nerve fibers in skin are involved in the regulation of itching as well as pain. In this study, we investigated whether curcumin, which acts on TRPV1 receptors, affects histamine-induced itching in mice, using behavioral tests and electrophysiological approaches. We found that histamine-induced itching was blocked by topical application of curcumin in a concentration-dependent manner. In ex-vivo recordings, histamine-induced discharges of peripheral nerves were reduced by the application of curcumin, indicating that curcumin acts directly on peripheral nerves. Additionally, curcumin blocked the histamine-induced inward current via activation of TRPV1 (curcumin IC50=523 nM). However, it did not alter chloroquine-induced itching behavior in mice, which is associated with transient receptor potential ankyrin 1 (TRPA1). Taken together, our results suggest that histamine-induced itching can be blocked by topical application of curcumin through the inhibitory action of curcumin on TRPV1 receptors in peripheral nerves.
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Affiliation(s)
- Han Kyu Lee
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Seok Bum Park
- Department of Physiology, College of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Su-youne Chang
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA
| | - Sung Jun Jung
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
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Zhang Y, Liu Z, Wu J, Bai B, Chen H, Xiao Z, Chen L, Zhao Y, Lum H, Wang Y, Zhang H, Liang G. New MD2 inhibitors derived from curcumin with improved anti-inflammatory activity. Eur J Med Chem 2018; 148:291-305. [PMID: 29466778 DOI: 10.1016/j.ejmech.2018.02.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/24/2018] [Accepted: 02/03/2018] [Indexed: 11/25/2022]
Abstract
An overactive Toll-like receptor (TLR) signaling complex is a significant pathogenic factor of acute and chronic inflammatory diseases. The natural product curcumin is reported to inhibit the TLR4 co-receptor, MD2 (myeloid differentiation protein 2), but its low in vivo bioavailability limits its therapeutic potential. We developed new curcumin analogs (MACs) with removal of the β-diketone moiety and substituted residues in benzene rings, and identify these as potential MD2 inhibitors with improved inhibition potency and stability over that of curcumin. Specifically, MAC 17 and 28 showed the highest anti-inflammatory activity, with >90% inhibition of LPS-stimulated cytokine secretion from macrophages, and protected against LPS-induced acute lung injury and sepsis. The MACs inhibited the TLR4-MD2 signaling complex through competition with LPS for binding on MD2, likely at Arg90. Our findings indicated that MAC 17 and 28 are promising candidates for future development as therapeutic drugs for inflammatory diseases with an endotoxin etiology.
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Affiliation(s)
- Yali Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Zhiguo Liu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jianzhang Wu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Bin Bai
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hongjin Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhongxiang Xiao
- Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Lingfeng Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yunjie Zhao
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hazel Lum
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hong Zhang
- The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Pharmacy, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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22
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Skoupa N, Dolezel P, Ruzickova E, Mlejnek P. Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells. Int J Mol Sci 2017; 18:E2289. [PMID: 29088066 PMCID: PMC5713259 DOI: 10.3390/ijms18112289] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 11/26/2022] Open
Abstract
The synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism. Here, we studied the effects of N-acetylcysteine (NAC) on EF-24-induced cell death. We also addressed the question of whether the main drug transporters, ABCB1 and ABCG2, affect the cytotoxic of EF-24. We observed that EF-24 induced cell death with apoptotic hallmarks in human leukemia K562 cells. Importantly, the loss of cell viability was preceded by production of reactive oxygen species (ROS), and by a decrease of reduced glutathione (GSH). However, neither ROS production nor the decrease in GSH predominantly contributed to the EF-24-induced cell death. We found that EF-24 formed an adduct with GSH, which is likely the mechanism contributing to the decrease of GSH. Although NAC abrogated ROS production, decreased GSH and prevented cell death, its protective effect was mainly due to a rapid conversion of intra- and extra-cellular EF-24 into the EF-24-NAC adduct without cytotoxic effects. Furthermore, we found that neither overexpression of ABCB1 nor ABCG2 reduced the antiproliferative effects of EF-24. In conclusion, a redox-dependent-mediated mechanism only marginally contributes to the EF-24-induced apoptosis in K562 cells. The main mechanism of NAC protection against EF-24-induced apoptosis is conversion of cytotoxic EF-24 into the noncytotoxic EF-24-NAC adduct. Neither ABCB1 nor ABCG2 mediated resistance to EF-24.
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Affiliation(s)
- Nikola Skoupa
- Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
| | - Petr Dolezel
- Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
| | - Eliska Ruzickova
- Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
| | - Petr Mlejnek
- Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
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23
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Tawfike AF, Tate R, Abbott G, Young L, Viegelmann C, Schumacher M, Diederich M, Edrada-Ebel R. Metabolomic Tools to Assess the Chemistry and Bioactivity of EndophyticAspergillusStrain. Chem Biodivers 2017; 14. [DOI: 10.1002/cbdv.201700040] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Ahmed F. Tawfike
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
- Department of Pharmacognosy; Faculty of Pharmacy; Helwan University; Cairo Egypt
| | - Rothwelle Tate
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
| | - Gráinne Abbott
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
| | - Louise Young
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
| | - Christina Viegelmann
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
| | - Marc Schumacher
- Laboratoire de Biologie Moleculaire et Cellulaire du Cancer; Fondation de Recherche Cancer et Sang; Hopital Kirchberg; 9 rue Edward Steichen 2540 Luxembourg City Luxembourg
| | - Marc Diederich
- Laboratoire de Biologie Moleculaire et Cellulaire du Cancer; Fondation de Recherche Cancer et Sang; Hopital Kirchberg; 9 rue Edward Steichen 2540 Luxembourg City Luxembourg
- Department of Pharmacy; College of Pharmacy; Seoul National University; 1 Gwanak-ro Gwanak-gu, Seoul 08826 Korea
| | - RuAngelie Edrada-Ebel
- Strathclyde Institute of Pharmacy and Biomedical Sciences; University of Strathclyde; The John Arbuthnott Building, 161 Cathedral Street Glasgow G4 0NR UK
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3,5-Bis(2-fluorobenzylidene)-4-piperidone induce reactive oxygen species-mediated apoptosis in A549 cells. Med Chem Res 2017. [DOI: 10.1007/s00044-017-2056-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Haris P, Mary V, Aparna P, Dileep KV, Sudarsanakumar C. A comprehensive approach to ascertain the binding mode of curcumin with DNA. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2017; 175:155-163. [PMID: 28033562 DOI: 10.1016/j.saa.2016.11.049] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 11/25/2016] [Accepted: 11/30/2016] [Indexed: 06/06/2023]
Abstract
Curcumin is a natural phytochemical from the rhizoma of Curcuma longa, the popular Indian spice that exhibits a wide range of pharmacological properties like antioxidant, anticancer, anti-inflammatory, antitumor, and antiviral activities. In the published literatures we can see different studies and arguments on the interaction of curcumin with DNA. The intercalative binding, groove binding and no binding of curcumin with DNA were reported. In this context, we conducted a detailed study to understand the mechanism of recognition of dimethylsulfoxide-solubilized curcumin by DNA. The interaction of curcumin with calf thymus DNA (ctDNA) was confirmed by agarose gel electrophoresis. The nature of binding and energetics of interaction were studied by Isothermal Titration Calorimetry (ITC), Differential Scanning Calorimetry (DSC), UV-visible, fluorescence and melting temperature (Tm) analysis. The experimental data were compared with molecular modeling studies. Our investigation confirmed that dimethylsulfoxide-solubilized curcumin binds in the minor groove of the ctDNA without causing significant structural alteration to the DNA.
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Affiliation(s)
- P Haris
- School of Pure and Applied Physics, Mahatma Gandhi University, Kottayam, Kerala 686560, India
| | - Varughese Mary
- School of Pure and Applied Physics, Mahatma Gandhi University, Kottayam, Kerala 686560, India
| | - P Aparna
- School of Pure and Applied Physics, Mahatma Gandhi University, Kottayam, Kerala 686560, India
| | - K V Dileep
- Department of Biotechnology and Microbiology, Kannur University, Thalassery Campus, Palayad, Kerala 670661, India
| | - C Sudarsanakumar
- School of Pure and Applied Physics, Mahatma Gandhi University, Kottayam, Kerala 686560, India; Center for High Performance Computing, Mahatma Gandhi University, Kottayam, Kerala 686560, India.
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Sharma V, Pathak K. Effect of hydrogen bond formation/replacement on solubility characteristics, gastric permeation and pharmacokinetics of curcumin by application of powder solution technology. Acta Pharm Sin B 2016; 6:600-613. [PMID: 27818928 PMCID: PMC5071626 DOI: 10.1016/j.apsb.2016.05.015] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 03/23/2016] [Accepted: 04/21/2016] [Indexed: 11/24/2022] Open
Abstract
The present research aimed to improve the dissolution rate and bioavailability of curcumin using the potential of liquisolid technology. Twelve drug-loaded liquisolid systems (LS-1 to LS-12) were prepared using different vehicles (PEG 200, PEG 400 and Tween 80) and curcumin concentrations in vehicle (40%, 50%, 60% and 70%, w/w). The carrier [microcrystalline cellulose (MCC) PH102] to coat (Aerosil®) ratio was 20 in all formulations. The systems were screened for pre-compression properties before being compressed to liquisolid tablets (LT-1 to LT-12). Post compression tests and in vitro dissolution of LTs were conducted and the results compared with those obtained for a directly compressed tablet (DCT) made of curcumin, MCC PH102 and Aerosil®. LTs exhibited higher cumulative drug release (CDR) than the DCT and the optimum formulation, LT-9 (made using Tween 80), was studied by powder XRD, DSC, SEM and FTIR. Ex-vivo permeation of curcumin from LT-9 through goat gastrointestinal mucosa was significantly (P<0.05) enhanced and its oral bioavailability was increased 18.6-fold in New Zealand rabbits. In vitro cytotoxicity (IC50) of LT-9 towards NCL 87 cancer cells was 40.2 µmol/L substantiating its anticancer efficacy. Accelerated stability studies revealed insignificant effects of temperature and humidity on LT-9. In summary, solubility enhancement of curcumin in LTs produced significant improvements in its permeation and bioavailability.
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Makarov MV, Rybalkina EY, Anikina LV, Pukhov SA, Klochkov SG, Mischenko DV, Neganova ME, Khrustalev VN, Klemenkova ZS, Brel VK. 1,5-Diaryl-3-oxo-1,4-pentadienes based on (4-oxopiperidin-1-yl)(aryl)methyl phosphonate scaffold: synthesis and antitumor properties. Med Chem Res 2016. [DOI: 10.1007/s00044-016-1726-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines. Bioorg Med Chem Lett 2016; 26:4223-32. [DOI: 10.1016/j.bmcl.2016.07.053] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/27/2016] [Accepted: 07/22/2016] [Indexed: 11/21/2022]
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Yin DL, Liang YJ, Zheng TS, Song RP, Wang JB, Sun BS, Pan SH, Qu LD, Liu JR, Jiang HC, Liu LX. EF24 inhibits tumor growth and metastasis via suppressing NF-kappaB dependent pathways in human cholangiocarcinoma. Sci Rep 2016; 6:32167. [PMID: 27571770 PMCID: PMC5004153 DOI: 10.1038/srep32167] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023] Open
Abstract
A synthetic monoketone analog of curcumin, termed 3, 5-bis (2-flurobenzylidene) piperidin-4-one (EF24), has been reported to inhibit the growth of a variety of cancer cells both in vitro and in vivo. However, whether EF24 has anticancer effects on cholangiocarcinoma (CCA) cells and the mechanisms remain to be investigated. The aim of our study was to evaluate the molecular mechanisms underlying the anticancer effects of EF24 on CCA tumor growth and metastasis. Cell proliferation, apoptosis, migration, invasion, tumorigenesis and metastasis were examined. EF24 exhibited time- and dose-dependent inhibitory effects on HuCCT-1, TFK-1 and HuH28 human CCA cell lines. EF24 inhibited CCA cell proliferation, migration, and induced G2/M phase arrest. EF24 induced cell apoptosis along with negative regulation of NF-κB- X-linked inhibitor of apoptosis protein (XIAP) signaling pathway. XIAP inhibition by lentivirus mediated RNA interference enhanced EF24-induced apoptosis, while XIAP overexpression reduced it in CCA cells. In vivo, EF24 significantly suppressed the growth of CCA tumor xenografts and tumor metastasis while displaying low toxicity levels. Our findings indicate that EF24 is a potent antitumor agent that inhibits tumor growth and metastasis by inhibiting NF-κB dependent signaling pathways. EF24 may represent a novel approach for CCA treatment.
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Affiliation(s)
- Da-long Yin
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
| | - Ying-jian Liang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Tong-sen Zheng
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Rui-peng Song
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
| | - Jia-bei Wang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Bo-shi Sun
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Shang-ha Pan
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Lian-dong Qu
- National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, P.R. China
| | - Jia-ren Liu
- Department of Anaesthesia, Harvard Medical School, Boston, MA, USA
| | - Hong-chi Jiang
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
| | - Lian-xin Liu
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education. No23, Youzheng Street, Nangang District, Harbin, Heilongjiang Province, 150001, P.R.China
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China
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Song JX, Sun YR, Peluso I, Zeng Y, Yu X, Lu JH, Xu Z, Wang MZ, Liu LF, Huang YY, Chen LL, Durairajan SSK, Zhang HJ, Zhou B, Zhang HQ, Lu A, Ballabio A, Medina DL, Guo Z, Li M. A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition. Autophagy 2016; 12:1372-1389. [PMID: 27172265 PMCID: PMC4968239 DOI: 10.1080/15548627.2016.1179404] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 04/07/2016] [Accepted: 04/11/2016] [Indexed: 10/21/2022] Open
Abstract
Autophagy dysfunction is a common feature in neurodegenerative disorders characterized by accumulation of toxic protein aggregates. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models. Currently known TFEB activators are mainly inhibitors of MTOR (mechanistic target of rapamycin [serine/threonine kinase]), which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions. Thus, the identification of TFEB modulators acting without inhibiting the MTOR pathway would be preferred and probably less deleterious to cells. In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR-independent activator of TFEB. Compound C1 specifically binds to TFEB at the N terminus and promotes TFEB nuclear translocation without inhibiting MTOR activity. By activating TFEB, C1 enhances autophagy and lysosome biogenesis in vitro and in vivo. Collectively, compound C1 is an orally effective activator of TFEB and is a potential therapeutic agent for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Ju-Xian Song
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Yue-Ru Sun
- Department of Chemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Ivana Peluso
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
| | - Yu Zeng
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xing Yu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Zheng Xu
- Department of Chemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Ming-Zhong Wang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Liang-Feng Liu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Ying-Yu Huang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Lei-Lei Chen
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Siva Sundara Kumar Durairajan
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Hong-Jie Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Bo Zhou
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu, China
| | - Hong-Qi Zhang
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Aiping Lu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
| | - Diego L. Medina
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
| | - Zhihong Guo
- Department of Chemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
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31
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Bisht S, Schlesinger M, Rupp A, Schubert R, Nolting J, Wenzel J, Holdenrieder S, Brossart P, Bendas G, Feldmann G. A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies. J Nanobiotechnology 2016; 14:57. [PMID: 27401816 PMCID: PMC4940769 DOI: 10.1186/s12951-016-0209-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/28/2016] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal of human malignancies known to date and shows relative insensitivity towards most of the clinically available therapy regimens. 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), a novel synthetic curcumin analog, has shown promising in vitro therapeutic efficacy in various human cancer cells, but insufficient water solubility and systemic bioavailability limit its clinical application. Here, we describe nano-encapsulation of EF24 into pegylated liposomes (Lipo-EF24) and evaluation of these particles in preclinical in vitro and in vivo model systems of pancreatic cancer. RESULTS Transmission electron microscopy and size distribution studies by dynamic light scattering confirmed intact spherical morphology of the formed liposomes with an average diameter of less than 150 nm. In vitro, treatment with Lipo-EF24 induced growth inhibition and apoptosis in MIAPaCa and Pa03C pancreatic cancer cells as assessed by using cell viability and proliferation assays, replating and soft agar clonogenicity assays as well as western blot analyses. Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha. In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine. In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues. CONCLUSION Due to its promising therapeutic efficacy and favorable toxicity profile Lipo-EF24 might be a promising starting point for development of future combinatorial therapeutic regimens against pancreatic cancer.
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Affiliation(s)
- Savita Bisht
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
| | | | - Alexander Rupp
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany
| | - Rolf Schubert
- Department of Pharmaceutical Technology and Biopharmacy, Albert-Ludwigs-Universität, Freiburg im Breisgau, Germany
| | - Jens Nolting
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
| | - Jörg Wenzel
- Department of Dermatology, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Bonn, Germany
| | - Stefan Holdenrieder
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany
| | - Peter Brossart
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
| | - Gerd Bendas
- Pharmaceutical Department, University of Bonn, Bonn, Germany
| | - Georg Feldmann
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
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32
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Ye H, Wei X, Wang Z, Zhang S, Ren J, Yao S, Shi L, Yang L, Qiu P, Wu J, Liang G. A novel double carbonyl analog of curcumin induces the apoptosis of human lung cancer H460 cells via the activation of the endoplasmic reticulum stress signaling pathway. Oncol Rep 2016; 36:1640-8. [DOI: 10.3892/or.2016.4911] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 04/29/2016] [Indexed: 11/05/2022] Open
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33
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Shahzad M, Millhouse E, Culshaw S, Edwards CA, Ramage G, Combet E. Selected dietary (poly)phenols inhibit periodontal pathogen growth and biofilm formation. Food Funct 2016; 6:719-29. [PMID: 25585200 DOI: 10.1039/c4fo01087f] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Periodontitis (PD) is a chronic infectious disease mediated by bacteria in the oral cavity. (Poly)phenols (PPs), ubiquitous in plant foods, possess antimicrobial activities and may be useful in the prevention and management of periodontitis. The objective of this study was to test the antibacterial effects of selected PPs on periodontal pathogens, on both planktonic and biofilm modes of growth. Selected PPs (n = 48) were screened against Streptococcus mitis (S. mitis), Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), Fusobacterium nucleatum (F. nucleatum) and Porphyromonas gingivalis (P. gingivalis). The antibacterial potential of each compound was evaluated in terms of planktonic minimum inhibitory concentration (PMIC) and planktonic minimum bactericidal concentration (PMBC) using standardized broth microdilution assays. The most active PPs were further tested for their effect on mono-species and multi-species biofilms using a colorimetric resazurin-based viability assay and scanning electron microscopy. Of the 48 PPs tested, 43 showed effective inhibition of planktonic growth of one or more test strains, of which curcumin was the most potent (PMIC range = 7.8-62.5 μg mL(-1)), followed by pyrogallol (PMIC range = 2.4-2500 μg mL(-1)), pyrocatechol (MIC range = 4.9-312.5 μg mL(-1)) and quercetin (PMIC range = 31.2-500 μg mL(-1)). At this concentration, adhesion of curcumin and quercetin to the substrate also inhibited adhesion of S. mitis, and biofilm formation and maturation. While both curcumin and quercetin were able to alter architecture of mature multi-species biofilms, only curcumin-treated biofilms displayed a significantly reduced metabolic activity. Overall, PPs possess antibacterial activities against periodontopathic bacteria in both planktonic and biofilm modes of growth. Further cellular and in vivo studies are necessary to confirm their beneficial activities and potential use in the prevention and or treatment of periodontal diseases.
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Affiliation(s)
- Muhammad Shahzad
- Human Nutrition, School of Medicine, Glasgow Royal Infirmary, College of Medical, Veterinary and Life Sciences, The University of Glasgow, Glasgow G31 2ER, UK.
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Huang S, Peng S, Zhu F, Lei X, Xiao Q, Su W, Liu Y, Huang C, Zhang L. Multispectroscopic Investigation of the Interaction Between two Ruthenium(II) Arene Complexes of Curcumin Analogs and Human Serum Albumin. Biol Trace Elem Res 2016; 169:189-203. [PMID: 26170171 DOI: 10.1007/s12011-015-0416-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 06/15/2015] [Indexed: 12/22/2022]
Abstract
The interaction between two ruthenium(II) arene complexes of curcumin analogs and human serum albumin (HSA) was systematically investigated by multispectroscopic techniques. The fluorescence spectral results indicated that two complexes quenched the intrinsic fluorescence of HSA through static quenching mode. The quenching constants and the corresponding thermodynamic parameters at different temperatures were calculated. The binding interactions of two complexes with HSA resulted in the complex formation of complex-HSA, and the van der Waals interactions and hydrogen bond interactions played major roles in the complex stabilization. The distances between HSA and two complexes were obtained according to fluorescence resonance energy transfer theory. The site competitive replacement experiments illustrated that two complexes mainly bounded with HSA on site I. The results of synchronous fluorescence spectra, three-dimensional fluorescence spectra, FT-IR spectra, and circular dichroism spectra indicated that the secondary structure of HSA was changed at the present of two complexes. The results of mass spectrometry further validated the binding interaction and the binding number between two complexes and HSA.
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Affiliation(s)
- Shan Huang
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
- Collaborative Innovation Center of Southwest Ethnic Medicine, Guangxi Normal University, Guilin, 541004, People's Republic of China
| | - Shushu Peng
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
| | - Fawei Zhu
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
| | - Xiaolin Lei
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
| | - Qi Xiao
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China.
- Collaborative Innovation Center of Southwest Ethnic Medicine, Guangxi Normal University, Guilin, 541004, People's Republic of China.
- State Key Laboratory of Virology, Wuhan University, Wuhan, 430072, People's Republic of China.
| | - Wei Su
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
| | - Yi Liu
- State Key Laboratory of Virology, Wuhan University, Wuhan, 430072, People's Republic of China
| | - Chusheng Huang
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
- Collaborative Innovation Center of Southwest Ethnic Medicine, Guangxi Normal University, Guilin, 541004, People's Republic of China
| | - Lixia Zhang
- College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, People's Republic of China
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35
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Li Y, Zhang LP, Dai F, Yan WJ, Wang HB, Tu ZS, Zhou B. Hexamethoxylated Monocarbonyl Analogues of Curcumin Cause G2/M Cell Cycle Arrest in NCI-H460 Cells via Michael Acceptor-Dependent Redox Intervention. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:7731-7742. [PMID: 26255837 DOI: 10.1021/acs.jafc.5b02011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Curcumin, derived from the dietary spice turmeric, holds promise for cancer prevention. This prompts much interest in investigating the action mechanisms of curcumin and its analogues. Two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogues were reported to possess significantly enhanced cytotoxicity compared with the parent molecule. However, the detailed mechanisms remain unclear. In this study, compounds 1 and 2 were identified as the G2/M cell cycle arrest agents to mediate the cytotoxicity toward NCI-H460 cells via Michael acceptor-dependent redox intervention. Compared with curcumin, they could more easily induce a burst of reactive oxygen species (ROS) and collapse of the redox buffering system. One possible reason is that they could more effectively target intracellular TrxR to convert this antioxidant enzyme into a ROS promoter. Additionally, they caused up-regulation of p53 and p21 and down-regulation of redox-sensitive Cdc25C along with cyclin B1/Cdk1 in a Michael acceptor- and ROS-dependent fashion. Interestingly, in comparison with compound 2, compound 1 displayed a relatively weak ability to generate ROS but increased cell cycle arrest activity and cytotoxicity probably due to its Michael acceptor-dependent microtubule-destabilizing effect and greater GST-inhibitory activity, as well as its enhanced cellular uptake. This work provides useful information for understanding Michael acceptor-dependent and redox-mediated cytotoxic mechanisms of curcumin and its active analogues.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
- Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Institute of Applied Chemistry, Shaoxing University , Shaoxing, Zhejiang 312000, China
| | - Li-Ping Zhang
- Gansu Provincial Hosipital , Lanzhou, Gansu 730000, China
| | - Fang Dai
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
| | - Wen-Jing Yan
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
| | - Hai-Bo Wang
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
| | - Zhi-Shan Tu
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
| | - Bo Zhou
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, Gansu 730000, China
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36
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Kalinski T. [Inflammation as molecular target in chondrosarcoma]. DER PATHOLOGE 2015; 35 Suppl 2:249-53. [PMID: 25394974 DOI: 10.1007/s00292-014-1968-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Inflammation is a hallmark in the development and progression of malignant tumors. In chondrosarcoma the inflammatory changes are relatively discrete; however, tumor-associated macrophages (TAM) may exert tumor-promoting effects. Interleukin (IL)-1 is an inflammatory cytokine which is produced by TAMs and which leads to the expression of NF-κB-regulated genes in chondrosarcoma cells, such as vascular endothelial growth factor A (VEGF-A). Through IL-1 antagonists and substances, such as curcumin IL-1-induced VEGF-A expression and angiogenesis can be blocked; therefore, IL-1-blockade provides an interesting therapy target for chondrosarcoma.
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Affiliation(s)
- T Kalinski
- Institut für Pathologie, Otto-von-Guericke-Universität, Leipziger Str. 44, 39120, Magdeburg, Deutschland,
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37
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Dai F, Liu GY, Li Y, Yan WJ, Wang Q, Yang J, Lu DL, Ding DJ, Lin D, Zhou B. Insights into the importance for designing curcumin-inspired anticancer agents by a prooxidant strategy: The case of diarylpentanoids. Free Radic Biol Med 2015; 85:127-37. [PMID: 25912482 DOI: 10.1016/j.freeradbiomed.2015.04.017] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 04/09/2015] [Accepted: 04/13/2015] [Indexed: 12/20/2022]
Abstract
Developing anticancer agents by a prooxidant strategy has attracted increasing attention in recent years, although it is not conventional in medicinal chemistry and is completely opposite to antioxidant therapy. In this work, a panel of diarylpentanoids as the curcumin mono-carbonyl analogs were designed and synthesized, and their cytotoxic and proapoptotic mechanisms against human lung cancer A549 cells were investigated at the frontiers of chemistry and biology. It was found that compared with curcumin, the compounds (A1, B1, and C1) bearing two ortho substituents on the aromatic rings, especially A1, exhibit significantly increased cytotoxic and proapoptotic activities through a Michael acceptor unit-dependent prooxidant-mediated mechanism. The prooxidative ability is governed not only by their electrophilicity but also by their geometry, cellular uptake and metabolic stability, and TrxR-inhibitory activity. Mechanistic investigation reveals that the compound A1 could effectively and irreversibly modify the TrxR by virtue of the above optimal biochemical parameters, and convert this antioxidant enzyme into a reactive oxygen species (ROS) promoter, resulting in a burst of the intracellular ROS including H2O2 and O2(-)•. The ROS generation is associated with falling apart in the redox buffering system, and subsequently induces increases in Ca(2+) influx and oxidative stress, collapse of mitochondrial membrane potential, and activation of caspase-9 and caspase-3, ultimately leading to cell apoptosis. This work highlights the feasibility in designing curcumin-inspired anticancer agents by a prooxidant strategy, and gives us useful information on how to design them.
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Affiliation(s)
- Fang Dai
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Guo-Yun Liu
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Yan Li
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Wen-Jing Yan
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Qi Wang
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Jie Yang
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Dong-Liang Lu
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - De-Jun Ding
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Dong Lin
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China
| | - Bo Zhou
- State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
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38
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Paulraj F, Abas F, Lajis NH, Othman I, Hassan SS, Naidu R. The Curcumin Analogue 1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one Induces Apoptosis and Downregulates E6 and E7 Oncogene Expression in HPV16 and HPV18-Infected Cervical Cancer Cells. Molecules 2015; 20:11830-60. [PMID: 26132907 PMCID: PMC6331910 DOI: 10.3390/molecules200711830] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 06/16/2015] [Indexed: 01/01/2023] Open
Abstract
In an effort to study curcumin analogues as an alternative to improve the therapeutic efficacy of curcumin, we screened the cytotoxic potential of four diarylpentanoids using the HeLa and CaSki cervical cancer cell lines. Determination of their EC50 values indicated relatively higher potency of 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one (MS17, 1.03 ± 0.5 μM; 2.6 ± 0.9 μM) and 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13, 2.8 ± 0.4; 6.7 ± 2.4 μM) in CaSki and HeLa, respectively, with significantly greater growth inhibition at 48 and 72 h of treatment compared to the other analogues or curcumin. Based on cytotoxic and anti-proliferative activity, MS17 was selected for comprehensive apoptotic studies. At 24 h of treatment, fluorescence microscopy detected that MS17-exposed cells exhibited significant morphological changes consistent with apoptosis, corroborated by an increase in nucleosomal enrichment due to DNA fragmentation in HeLa and CaSki cells and activation of caspase-3 activity in CaSki cells. Quantitative real-time PCR also detected significant down-regulation of HPV18- and HPV16-associated E6 and E7 oncogene expression following treatment. The overall data suggests that MS17 treatment has cytotoxic, anti-proliferative and apoptosis-inducing potential in HPV-positive cervical cancer cells. Furthermore, its role in down-regulation of HPV-associated oncogenes responsible for cancer progression merits further investigation into its chemotherapeutic role for cervical cancer.
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Affiliation(s)
- Felicia Paulraj
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia.
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
| | - Nordin H Lajis
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia.
| | - Sharifah Syed Hassan
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia.
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor, Malaysia.
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A Novel Approach for Overcoming Drug Resistance in Breast Cancer Chemotherapy by Targeting new Synthetic Curcumin Analogues Against Aldehyde Dehydrogenase 1 (ALDH1A1) and Glycogen Synthase Kinase-3 β (GSK-3β). Appl Biochem Biotechnol 2015; 176:1996-2017. [DOI: 10.1007/s12010-015-1696-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 05/28/2015] [Indexed: 12/16/2022]
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40
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Raghavan S, Manogaran P, Gadepalli Narasimha KK, Kalpattu Kuppusami B, Mariyappan P, Gopalakrishnan A, Venkatraman G. Synthesis and anticancer activity of novel curcumin-quinolone hybrids. Bioorg Med Chem Lett 2015; 25:3601-5. [PMID: 26174555 DOI: 10.1016/j.bmcl.2015.06.068] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 06/04/2015] [Accepted: 06/19/2015] [Indexed: 12/25/2022]
Abstract
A number of new curcumin-quinolone hybrids were synthesised from differently substituted 3-formyl-2-quinolones and vanillin and their in vitro cytotoxicity was determined on a panel of representative cell lines (A549, MCF7, SKOV3 and H460) using MTT assay. The most potent compound 14, was analysed for its mode of action using various cell biology experiments. SKOV3 cells treated with compound 14 showed distorted cell morphology under phase contrast imaging and induction of apoptosis was confirmed by Annexin V/PE assay. Further experiments on generation of reactive oxygen species (ROS) and cell cycle analysis revealed that these hybrids induce apoptosis by ROS generation and arrest cell cycle progression in S and G2/M phase.
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Affiliation(s)
- Saiharish Raghavan
- Department of Medicinal Chemistry, Sri Ramachandra University, Chennai 600 116, India
| | - Prasath Manogaran
- Department of Human Genetics, Sri Ramachandra University, Chennai 600 116, India
| | | | | | - Palanivelu Mariyappan
- Department of Medicinal Chemistry, Sri Ramachandra University, Chennai 600 116, India
| | | | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra University, Chennai 600 116, India.
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41
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Makarov MV, Rybalkina EY, Klemenkova ZS, Röschenthaler GV. 3,5-Bis(arylidene)-4-piperidinones modified with bisphosphonate groups using a 1,2,3-triazole ring: Synthesis and antitumor properties. Russ Chem Bull 2015. [DOI: 10.1007/s11172-014-0752-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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42
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Rodrigues JL, Prather KLJ, Kluskens LD, Rodrigues LR. Heterologous production of curcuminoids. Microbiol Mol Biol Rev 2015; 79:39-60. [PMID: 25631288 PMCID: PMC4402967 DOI: 10.1128/mmbr.00031-14] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
SUMMARY Curcuminoids, components of the rhizome of turmeric, show several beneficial biological activities, including anticarcinogenic, antioxidant, anti-inflammatory, and antitumor activities. Despite their numerous pharmaceutically important properties, the low natural abundance of curcuminoids represents a major drawback for their use as therapeutic agents. Therefore, they represent attractive targets for heterologous production and metabolic engineering. The understanding of biosynthesis of curcuminoids in turmeric made remarkable advances in the last decade, and as a result, several efforts to produce them in heterologous organisms have been reported. The artificial biosynthetic pathway (e.g., in Escherichia coli) can start with the supplementation of the amino acid tyrosine or phenylalanine or of carboxylic acids and lead to the production of several natural curcuminoids. Unnatural carboxylic acids can also be supplemented as precursors and lead to the production of unnatural compounds with possibly novel therapeutic properties. In this paper, we review the natural conversion of curcuminoids in turmeric and their production by E. coli using an artificial biosynthetic pathway. We also explore the potential of other enzymes discovered recently or already used in other similar biosynthetic pathways, such as flavonoids and stilbenoids, to increase curcuminoid yield and activity.
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Affiliation(s)
- J L Rodrigues
- Centre of Biological Engineering, University of Minho, Braga, Portugal MIT-Portugal Program, Cambridge, Massachusetts, USA, and Lisbon, Portugal
| | - K L J Prather
- Department of Chemical Engineering, Synthetic Biology Engineering Research Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA MIT-Portugal Program, Cambridge, Massachusetts, USA, and Lisbon, Portugal
| | - L D Kluskens
- Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - L R Rodrigues
- Centre of Biological Engineering, University of Minho, Braga, Portugal MIT-Portugal Program, Cambridge, Massachusetts, USA, and Lisbon, Portugal
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43
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Sintov AC. Transdermal delivery of curcumin via microemulsion. Int J Pharm 2015; 481:97-103. [DOI: 10.1016/j.ijpharm.2015.02.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 02/01/2015] [Indexed: 12/19/2022]
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Fridlender M, Kapulnik Y, Koltai H. Plant derived substances with anti-cancer activity: from folklore to practice. FRONTIERS IN PLANT SCIENCE 2015; 6:799. [PMID: 26483815 PMCID: PMC4589652 DOI: 10.3389/fpls.2015.00799] [Citation(s) in RCA: 221] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 09/14/2015] [Indexed: 05/20/2023]
Abstract
Plants have had an essential role in the folklore of ancient cultures. In addition to the use as food and spices, plants have also been utilized as medicines for over 5000 years. It is estimated that 70-95% of the population in developing countries continues to use traditional medicines even today. A new trend, that involved the isolation of plant active compounds begun during the early nineteenth century. This trend led to the discovery of different active compounds that are derived from plants. In the last decades, more and more new materials derived from plants have been authorized and subscribed as medicines, including those with anti-cancer activity. Cancer is among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next two decades. Thus, there is a real need for new efficient anti-cancer drugs with reduced side effects, and plants are a promising source for such entities. Here we focus on some plant-derived substances exhibiting anti-cancer and chemoprevention activity, their mode of action and bioavailability. These include paclitaxel, curcumin, and cannabinoids. In addition, development and use of their synthetic analogs, and those of strigolactones, are discussed. Also discussed are commercial considerations and future prospects for development of plant derived substances with anti-cancer activity.
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Affiliation(s)
| | | | - Hinanit Koltai
- *Correspondence: Hinanit Koltai, Institute of Plant Sciences, Agricultural Research Organization, Volcani Center, POB6, Bet Dagan 50250, Israel,
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45
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Makarov MV, Rybalkina EY, Khrustalev VN, Röschenthaler GV. Modification of 3,5-bis(arylidene)-4-piperidone pharmacophore by phosphonate group using 1,2,3-triazole cycle as a linker for the synthesis of new cytostatics. Med Chem Res 2014. [DOI: 10.1007/s00044-014-1262-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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46
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Kumar N, Dhamija I, Vasanth Raj P, Jayashree B, Parihar V, Manjula S, Thomas S, Gopalan Kutty N, Mallikarjuna Rao C. Preliminary investigation of cytotoxic potential of 2-quinolone derivatives using in vitro and in vivo (solid tumor and liquid tumor) models of cancer. ARAB J CHEM 2014. [DOI: 10.1016/j.arabjc.2012.12.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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47
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Yerdelen KO, Gul HI, Sakagami H, Umemura N. Synthesis and biological evaluation of 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one and its aminomethyl derivatives. J Enzyme Inhib Med Chem 2014; 30:383-8. [DOI: 10.3109/14756366.2014.940934] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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48
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Kanai M. Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol 2014; 20:9384-9391. [PMID: 25071333 PMCID: PMC4110570 DOI: 10.3748/wjg.v20.i28.9384] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
A number of preclinical studies have demonstrated anticancer effects for curcumin in various types of tumors, including pancreatic cancer. Curcumin has anticancer effects both alone and in combination with other anticancer drugs (e.g., gemcitabine, 5-fluorouracil, and oxaliplatin), and it has been shown to modulate a variety of molecular targets in preclinical models, with more than 30 molecular targets identified to date. Of these various molecules, NF-κB is thought to be one of the primary targets of curcumin activity. Based on these promising preclinical results, several research groups, including our own, have progressed to testing the anticancer effects of curcumin in clinical trials; however, the poor bioavailability of this agent has been the major challenge for its clinical application. Despite the ingestion of gram-level doses of curcumin, plasma curcumin levels remain at low (ng/mL) levels in patients, which is insufficient to yield the anticancer benefits of curcumin. This problem has been solved by the development of highly bioavailable forms of curcumin (THERACURMIN®), and higher plasma curcumin levels can now be achieved without increased toxicity in patients with pancreatic cancer. In this article, we review possible therapeutic applications of curcumin in patients with pancreatic cancer.
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49
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Singh DV, Bharti SK, Agarwal S, Roy R, Misra K. Study of interaction of human serum albumin with curcumin by NMR and docking. J Mol Model 2014; 20:2365. [DOI: 10.1007/s00894-014-2365-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 06/22/2014] [Indexed: 10/25/2022]
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50
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Kalinski T, Sel S, Hütten H, Röpke M, Roessner A, Nass N. Curcumin blocks interleukin-1 signaling in chondrosarcoma cells. PLoS One 2014; 9:e99296. [PMID: 24901233 PMCID: PMC4047106 DOI: 10.1371/journal.pone.0099296] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 05/13/2014] [Indexed: 02/07/2023] Open
Abstract
Interleukin (IL)-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF)-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK) to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents.
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Affiliation(s)
- Thomas Kalinski
- Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany
- * E-mail:
| | - Saadettin Sel
- Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany
| | - Heiko Hütten
- Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany
| | - Martin Röpke
- Department of Orthopedics, Otto-von-Guericke-University, Magdeburg, Germany
| | - Albert Roessner
- Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany
| | - Norbert Nass
- Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany
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