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Cao Z, Zhu SJ, Xue ZW, Yao LY, Zhang XX, Guo ZJ. Isoquinoline alkaloids with bioactive constituents from the roots and rhizomes of Hylomecon japonica. Nat Prod Res 2024:1-9. [PMID: 39563611 DOI: 10.1080/14786419.2024.2429122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 10/07/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024]
Abstract
Isoquinoline alkaloids are important effective chemical components separated from the Hylomecon japonica, which were mostly reported as planar structures. By using chiral HPLC, we have concluded that some natural isoquinoline alkaloids exist as enantiomeric mixtures, providing a novel direction for future research on isoquinoline alkaloids. Finally, three pairs of enantiomeric isoquinoline alkaloids (1-3, including five undescribed compounds-1a/1b, 3a/3b and 2b), together with another eight known isoquinoline alkaloids (4-9) were isolated from the roots and rhizomes of Hylomecon japonica. Their structures were elucidated by NMR, HRESIMS, UV, IR, and their absolute configurations were further defined by quantum chemical calculations of ECD spectra. The cytotoxic activities of these isolated compounds in MCF-7 cells were evaluated by MTT methods. Among them, the alkaloids 1a, 1b, 2b, 3b and other known alkaloids 5a and 5b had good inhibitory effects on MCF-7 cells of breast cancer in vitro, with an IC50 lower than 20 μM.
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Affiliation(s)
- Zhen Cao
- College of Biological and Food Engineering, Changshu Institute of Technology, Jiangsu, Changshu, P. R. China
| | - Shang-Jun Zhu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, P. R. China
| | - Zhao-Wei Xue
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, P. R. China
| | - Lu-Ye Yao
- College of Biological and Food Engineering, Changshu Institute of Technology, Jiangsu, Changshu, P. R. China
| | - Xin-Xin Zhang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, P. R. China
| | - Zeng-Jun Guo
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, P. R. China
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2
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El-Readi MZ, Abdulkarim MA, Abdellatif AAH, Elzubeir ME, Refaat B, Althubiti M, Almaimani RA, Mukhtar MH, Al-Moraya IS, Eid SY. Doxorubicin-sanguinarine nanoparticles: formulation and evaluation of breast cancer cell apoptosis and cell cycle. Drug Dev Ind Pharm 2024:1-15. [PMID: 38180322 DOI: 10.1080/03639045.2024.2302557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 12/13/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Therapeutic resistance fails cancer treatment. Drug-nanoparticle combinations overcome resistance. Sanguinarine-conjugated nanoparticles may boost sanguinarine's anticancer effects. METHODS Sanguinarine, HPMC-NPs, and doxorubicin were tested on Adriamycin-resistant MCF-7/ADR breast cancer cells, parent-sensitive MCF-7, and MCR-5 normal cells (DX). RESULTS Regular distribution, 156 nm diameter, <1 μm average size, 100% intensity-SN is therapeutic. Furthermore, the obtained NPs showed PDI = 0.145, zeta-potential=-37.6, and EE%=90.5%. DX sensitized MCF-7 cells (IC50 = 1.4 μM) more than MCF-7/ADR cells (IC50 = 27 μM) with RR = 19.3. SA and SN were more toxic to MCF-7/ADR cells (overexpressed with P-gp) than their sensitive parent MCF-7 cells (IC50 = 4 μM, RR = 0.6 and 0.6 μM, RR = 0.7). MCR-5 normal lung cells were more resistant to SA (IC50 = 7.2 μM) and SN (IC50 = 1.6 μM) with a selection index > 2. Synergistic cytotoxic interactions reduced the IC50 from 27 μM to 1.6 (CI = 0.1) and 0.9 (CI = 0.4) after DX and nontoxic dosages (IC20) of SA and SN. DS and SN killed 27.1% and 39.4% more cells than DX (7.7%), SA (4.9%), SN (5.5%), or untreated control (0.3%). DS and DSN lowered CCND1 and survival in MCF-7/ADR cells while raising p21 and Casp3 gene and protein expression. CONCLUSIONS Cellular and molecular studies suggested adjuvant chemosensitizers SA and SN to reverse MDR in breast cancer cells.
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Affiliation(s)
- Mahmoud Zaki El-Readi
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Majed Abdurhman Abdulkarim
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
- Sulaiman Alhabab Hospital, Alqassim, Saudi Arabia
| | - Ahmed A H Abdellatif
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraydah, Saudi Arabia
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Mohamed E Elzubeir
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammad Althubiti
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Riyad Adnan Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohammed Hasan Mukhtar
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Issa Saad Al-Moraya
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
- Forensic Medicine & Toxicology Center, Abha, Saudi Arabia
| | - Safaa Yehia Eid
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
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Plazas E, Avila M MC, Muñoz DR, Cuca S LE. Natural isoquinoline alkaloids: Pharmacological features and multi-target potential for complex diseases. Pharmacol Res 2022; 177:106126. [DOI: 10.1016/j.phrs.2022.106126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/28/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022]
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Li JY, Huang HB, Wang N, Shi CW, Pan TX, Zhang B, Yang GL, Wang CF. Sanguinarine induces apoptosis in Eimeria tenella sporozoites via the generation of reactive oxygen species. Poult Sci 2022; 101:101771. [PMID: 35272108 PMCID: PMC8913342 DOI: 10.1016/j.psj.2022.101771] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 10/25/2022] Open
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5
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Khan AQ, Rashid K, AlAmodi AA, Agha MV, Akhtar S, Hakeem I, Raza SS, Uddin S. Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids. Biomed Pharmacother 2021; 143:112142. [PMID: 34536761 DOI: 10.1016/j.biopha.2021.112142] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/13/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Khalid Rashid
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | - Maha Victor Agha
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ishrat Hakeem
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Syed Shadab Raza
- Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar.
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6
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Zaw SYM, Kaneko T, Zaw ZCT, Sone PP, Murano H, Gu B, Okada Y, Han P, Katsube KI, Okiji T. Crosstalk between dental pulp stem cells and endothelial cells augments angiogenic factor expression. Oral Dis 2020; 26:1275-1283. [PMID: 32248596 DOI: 10.1111/odi.13341] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/23/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES We aimed to investigate whether the mesenchymal stem cell-endothelial cell crosstalk enhances angiogenic factor expression via nuclear factor-kappa B (NF-κB)-dependent mechanisms. MATERIALS AND METHODS Human dermal microvascular endothelial cells (HDMECs) and stem cells from human exfoliated deciduous teeth (SHEDs) were cocultured for 96 hr, in the presence of NF-κB decoy oligodeoxynucleotides (ODNs) or scramble (control). Vascular endothelial cell growth factor (VEGF) and phospho-NF-κB p65 were measured with enzyme-linked immunosorbent assay. Angiogenesis-related gene expression was analyzed with microarray analysis followed by real-time polymerase chain reaction. Tube formation assay was conducted in the presence of NF-κB decoy. RESULTS The VEGF and phospho-NF-κB p65 levels were significantly higher in the coculture with NF-κB decoy scramble than in single culture and coculture with NF-κB decoy ODN. Microarray analysis of SHEDs and HDMECs with NF-κB decoy scramble showed higher expression of proangiogenic genes, Bcl-2, NF-κB1, VEGFA, CXCL8, and CXCR1, and lower expression of proapoptotic genes, Bax and Caspase 9, compared to cells with NF-κB decoy ODN. Real-time PCR results for Bcl-2 and CXCL8 showed a similar trend. Tube formation assay showed more tube development in the presence of NF-κB decoy scramble. CONCLUSION The SHED-HDMEC crosstalk enhanced proangiogenic factor expression via NF-κB-dependent pathways.
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Affiliation(s)
- Su Yee Myo Zaw
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tomoatsu Kaneko
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Zar Chi Thein Zaw
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Phyo Pyai Sone
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiroki Murano
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Bin Gu
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yamato Okada
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Peifeng Han
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | | | - Takashi Okiji
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Akhtar S, Achkar IW, Siveen KS, Kuttikrishnan S, Prabhu KS, Khan AQ, Ahmed EI, Sahir F, Jerobin J, Raza A, Merhi M, Elsabah HM, Taha R, Omri HE, Zayed H, Dermime S, Steinhoff M, Uddin S. Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling. Front Oncol 2019; 9:285. [PMID: 31058086 PMCID: PMC6478801 DOI: 10.3389/fonc.2019.00285] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 03/29/2019] [Indexed: 12/15/2022] Open
Abstract
Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.
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Affiliation(s)
- Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Iman W Achkar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Kodappully S Siveen
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Eiman I Ahmed
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Fairooz Sahir
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Jayakumar Jerobin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Afsheen Raza
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.,National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.,National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Hesham M Elsabah
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Ruba Taha
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Halima El Omri
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.,National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.,Department of Dermatology Venereology, Hamad Medical Corporation, Doha, Qatar.,Weill Cornell-Medicine, Doha, Qatar.,Weill Cornell-Medicine, Cornell University, New York, NY, United States
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
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8
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Kaneko T, Myo Zaw SY, Sueyama Y, Katsube KI, Kaneko R, Nör JE, Okiji T. Inhibition of Nuclear Factor Kappa B Prevents the Development of Experimental Periapical Lesions. J Endod 2019; 45:168-173. [PMID: 30711173 PMCID: PMC6367709 DOI: 10.1016/j.joen.2018.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/12/2018] [Accepted: 10/18/2018] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Nuclear factor kappa B (NF-κB) is an important transcriptional regulator of angiogenesis involving B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) signaling pathways. Thus, inhibition of NF-κB may suppress the development of periapical lesions via blockage of angiogenesis. Accordingly, we examined the effects of NF-κB decoy oligodeoxynucleotide (ODN) treatment on experimentally induced periapical lesions. METHODS Periapical lesions were induced in the mandibular first molars of 5-week-old male Wistar rats by the application of lipopolysaccharide to the pulp. NF-κB decoy ODN or NF-κB decoy scramble (control) was injected intraperitoneally every 7 days, starting 1 day before pulp exposure. After 28 days, the samples were retrieved, and digital radiographs were taken for radiomorphometry. Samples were processed for (1) immunohistochemistry of CD31, Bcl-2, and Bax; (2) laser capture microdissection to analyze Bcl-2, Bax, chemokine (C-X-C motif) ligand 1 (CXCL1), CXC receptor 2 (CXCR2), and vascular endothelial cell growth factor receptor 2 (VEGFR2) messenger RNA (mRNA) expression in CD31+ endothelial cells; (3) enzyme-linked immunosorbent assay to determine NF-κB/p65 activity; and (4) Western blotting for vascular endothelial growth factor expression. RESULTS NF-κB decoy ODN treatment significantly reduced lesion size, NF-κB/p65 activity, and the density of CD31+ endothelial cells in the lesion. NF-κB decoy ODNs also down-regulated CXCL1, CXCR2, and VEGFR2 mRNAs and up-regulated Bax mRNA in endothelial cells but did not affect Bcl2 mRNA in endothelial cells. Vascular endothelial growth factor protein expression in the lesions was significantly decreased. CONCLUSIONS The inhibition of NF-κB activity by decoy ODN treatment suppressed the development of experimentally induced periapical lesions with a concomitant reduction in angiogenic responses in endothelial cells.
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Affiliation(s)
- Tomoatsu Kaneko
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Su Yee Myo Zaw
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yukiko Sueyama
- Division of Cardiology, Operative Dentistry and Endodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | | | - Reika Kaneko
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Jacques E Nör
- Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan
| | - Takashi Okiji
- Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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9
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Cao FJ, Xu MX, Zhou BH, Du YS, Yao JH, Zhou L. Effects of 2-aryl-1-cyano-1,2,3,4-tetrohydroisoquinolines on apoptosis induction mechanism in NB4 and MKN-45 cells. Toxicol In Vitro 2018; 54:295-303. [PMID: 30342220 DOI: 10.1016/j.tiv.2018.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 09/18/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023]
Abstract
Our previous study found that 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines (CATHIQs) have excellent anti-cancer activity and obvious apoptosis induction phenomenon. As our continuing research, this study further explored their underlying molecular mechanism of apoptosis induction in cancer cells. Flow cytometry analysis showed that the NB4 cells treated by 1-cyano-2-(2-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline or the MKN-45 cells treated by 1-cyano-2-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydroisoquinoline for 48 h were at early stage of apoptosis, and the cell cycle arrest was only slightly affected. Apoptosis rates of the cells significantly increase with the treatment concentration of the compounds. The compounds could significantly decrease the activities of SOD, raise the MDA level and promote the LDH leakage, suggesting that the excessive formation of ROS should be involved in the cell apoptosis. Western blot analysis showed that the compounds improved both Bax/Bcl-2 ratio and cleavages of procaspase-3, promoted efflux of cytochrome c to cytosol and phosphorylation of p38 and JNK, and attenuated phosphorylations of Akt and ERK. Together, inhibitions of PI3K/Akt and ERK and activation of p38 mediated the compounds-induced apoptosis through modulating the mitochondrial pathway and/or ROS production.
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Affiliation(s)
- Fang-Jun Cao
- College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Ming-Xuan Xu
- College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Bo-Hang Zhou
- College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yi-Si Du
- College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jun-Hu Yao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Le Zhou
- College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China.
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Chen Y, Shang H, Zhang S, Zhang X. Retracted
: Ginsenoside Rh2 inhibits proliferation and migration of medulloblastoma Daoy by down‐regulation of microRNA‐31. J Cell Biochem 2018; 119:6527-6534. [DOI: 10.1002/jcb.26716] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/24/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Yan Chen
- Department of PediatricsJining No. 1 People's HospitalJiningShandongChina
| | - Hong Shang
- Department of PediatricsJining No. 1 People's HospitalJiningShandongChina
| | - Shunli Zhang
- Department of PediatricsJining No. 1 People's HospitalJiningShandongChina
| | - Xiaohong Zhang
- Department of PediatricsJining No. 1 People's HospitalJiningShandongChina
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11
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Lin L, Liu YC, Huang JL, Liu XB, Qing ZX, Zeng JG, Liu ZY. Medicinal plants of the genus Macleaya (Macleaya cordata, Macleaya microcarpa): A review of their phytochemistry, pharmacology, and toxicology. Phytother Res 2017; 32:19-48. [PMID: 29130543 DOI: 10.1002/ptr.5952] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 09/16/2017] [Accepted: 09/19/2017] [Indexed: 12/20/2022]
Abstract
In the genus Macleaya, Macleaya cordata and Macleaya microcarpa have been recognized as traditional herbs that are primarily distributed in China, North America, and Europe and have a long history of medicinal usage. These herbs have been long valued and studied for detumescence, detoxification, and insecticidal effect. This review aims to provide comprehensive information on botanical, phytochemical, pharmacological, and toxicological studies on plants in the genus Macleaya. Plants from the genus of Macleaya provide a source of bioactive compounds, primarily alkaloids, with remarkable diversity and complex architectures, thereby having attracted attention from researchers. To date, 291 constituents have been identified and/or isolated from this group. These purified compounds and/or crude extract possess antitumor, anti-inflammatory, insecticidal, and antibacterial activities in addition to certain potential toxicities. Macleaya species hold potential for medicinal applications. However, despite the pharmacological studies on these plants, the mechanisms underlying the biological activities of active ingredients derived from Macleaya have not been thoroughly elucidated to date. Additionally, there is a need for research focusing on in vivo medical effects of Macleaya compounds and, eventually, for clinical trials.
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Affiliation(s)
- Li Lin
- National and Local Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha, 410128, China
| | - Yan-Chun Liu
- National and Local Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha, 410128, China
| | - Jia-Lu Huang
- National and Local Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha, 410128, China
| | - Xiu-Bin Liu
- Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Zhi-Xing Qing
- Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Jian-Guo Zeng
- National and Local Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha, 410128, China.,Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
| | - Zhao-Ying Liu
- National and Local Union Engineering Research Center for the Veterinary Herbal Medicine Resources and Initiative, Hunan Agricultural University, Changsha, 410128, China.,Hunan Co-Innovation Center for Utilization of Botanical Functional Ingredients, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China.,Hunan Engineering Research Center of Veterinary Drug, College of Veterinary Medicine, Hunan Agricultural University, Changsha, 410128, China
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Ma Y, Yu W, Shrivastava A, Alemi F, Lankachandra K, Srivastava RK, Shankar S. Sanguinarine inhibits pancreatic cancer stem cell characteristics by inducing oxidative stress and suppressing sonic hedgehog-Gli-Nanog pathway. Carcinogenesis 2017; 38:1047-1056. [PMID: 28968696 DOI: 10.1093/carcin/bgx070] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Indexed: 12/14/2022] Open
Abstract
Sonic hedgehog pathway is highly activated in pancreatic cancer stem cells (CSC) which play crucial roles in cancer initiation, progression and metastasis. However, the molecular mechanisms by which sanguinarine regulates pancreatic CSC characteristics is not well understood. The objectives of this study were to examine the molecular mechanisms by which sanguinarine regulates pancreatic CSC characteristics. Sanguinarine inhibited cell proliferation and colony formation and induced apoptosis through oxidative damage. Sanguinarine inhibited self-renewal capacity of pancreatic CSCs isolated from human and KrasG12D mice. Furthermore, sanguinarine suppressed epithelial-mesenchymal transition (EMT) by up-regulating E-cadherin and inhibiting N-cadherin. Significant decrease in expression level of Snail, Slug and Zeb1 corroborated the suppression of EMT in sanguinarine treated pancreatic CSCS. The ability of sanguinarine to inhibit pluripotency maintaining factors and CSC markers suggest that sanguinarine can be an effective agent for inhibiting pancreatic cancer growth and development by targeting CSCs. Furthermore, sanguinarine inhibited Shh-Gli pathway leading to modulation of Gli target genes in pancreatic CSCs. Chromatin immunoprecipitation assay demonstrated that Nanog directly binds to promoters of Cdk2, Cdk6, FGF4, c-Myc and Oct4, and sanguinarine inhibits the binding of Nanog with these genes, suggesting the direct involvement of Nanog in cell cycle, pluripotency and self-renewal. To further investigate the role of Shh-Gli-Nanog pathway, we regulated Shh signaling either by Shh protein or Nanog overexpression. Enforced activation of Shh or overexpression of Nanog counteracted the inhibitory effects of sanguinarine on pancreatic CSC proliferation, suggesting the actions of sanguinarine are mediated, at least in part, through Shh-Gli-Nanog pathway. Our studies suggest that sanguinarine can be used for the treatment and/or prevention of pancreatic cancer by targeting CSCs.
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Affiliation(s)
- Yiming Ma
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA
| | - Wei Yu
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA
| | - Anju Shrivastava
- Department of Oncology, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Farzad Alemi
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA.,Department of Surgery, University of Missouri-School of Medicine, Kansas City, MO 64108, USA
| | - Kamani Lankachandra
- Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA.,Department of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA.,Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
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13
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Galadari S, Rahman A, Pallichankandy S, Thayyullathil F. Molecular targets and anticancer potential of sanguinarine-a benzophenanthridine alkaloid. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 34:143-153. [PMID: 28899497 DOI: 10.1016/j.phymed.2017.08.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 07/06/2017] [Accepted: 08/06/2017] [Indexed: 05/03/2023]
Abstract
BACKGROUND Cancer is an enormous global health burden, and should be effectively addressed with better therapeutic strategies. Currently, over 60% of the clinically approved anticancer agents are either directly isolated from natural sources or are modified from natural lead molecules. Sanguinarine (SNG), a quaternary benzophenanthridine alkaloid has gained increasing attention in recent years as a potential anticancer agent. PURPOSE There is a large untapped source of phytochemical-based anticancer agents remaining to be explored. This review article aims to recapitulate different anticancer properties of SNG, and describes some of the molecular targets involved in exerting its effect. It also depicts the pharmacokinetic and toxicological properties of SNG, two parameters important in determining the druggability of a molecule. METHODS Numerous in vivo and in vitro published studies have signified the anticancer properties of SNG. In order to collate and decipher these properties, an extensive literature search was conducted in PubMed, ScienceDirect, and Scopus using keywords followed by the evaluation of the relevant articles where the relevant reports are integrated and analyzed. RESULTS Apart from inducing cell death, SNG inhibits pro-tumorigenic processes such as invasion, angiogenesis, and metastasis in different cancers. Moreover, SNG has been shown to synergistically enhance the sensitivity of several chemotherapeutic agents and is effective against a variety of multi-drug resistant cancers.
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Affiliation(s)
- Sehamuddin Galadari
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Anees Rahman
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Siraj Pallichankandy
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Faisal Thayyullathil
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
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14
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Pandey MK, Gupta SC, Nabavizadeh A, Aggarwal BB. Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin Cancer Biol 2017; 46:158-181. [PMID: 28823533 DOI: 10.1016/j.semcancer.2017.07.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/05/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022]
Abstract
Although it is widely accepted that better food habits do play important role in cancer prevention and treatment, how dietary agents mediate their effects remains poorly understood. More than thousand different polyphenols have been identified from dietary plants. In this review, we discuss the underlying mechanism by which dietary agents can modulate a variety of cell-signaling pathways linked to cancer, including transcription factors, nuclear factor κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein-1 (AP-1), β-catenin/Wnt, peroxisome proliferator activator receptor- gamma (PPAR-γ), Sonic Hedgehog, and nuclear factor erythroid 2 (Nrf2); growth factors receptors (EGFR, VEGFR, IGF1-R); protein Kinases (Ras/Raf, mTOR, PI3K, Bcr-abl and AMPK); and pro-inflammatory mediators (TNF-α, interleukins, COX-2, 5-LOX). In addition, modulation of proteasome and epigenetic changes by the dietary agents also play a major role in their ability to control cancer. Both in vitro and animal based studies support the role of dietary agents in cancer. The efficacy of dietary agents by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against different kinds of cancer. Overall both in vitro and in vivo studies performed with dietary agents strongly support their role in cancer prevention. Thus, the famous quote "Let food be thy medicine and medicine be thy food" made by Hippocrates 25 centuries ago still holds good.
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Affiliation(s)
- Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA.
| | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ali Nabavizadeh
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
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15
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Achkar IW, Mraiche F, Mohammad RM, Uddin S. Anticancer potential of sanguinarine for various human malignancies. Future Med Chem 2017; 9:933-950. [PMID: 28636454 DOI: 10.4155/fmc-2017-0041] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2023] Open
Abstract
Sanguinarine (Sang) - a benzophenanthridine alkaloid extracted from Sanguinaria canadensis - exhibits antioxidant, anti-inflammatory, proapoptotic and growth inhibitory activities on tumor cells of various cancer types as established by in vivo and in vitro studies. Although the underlying mechanism of Sang antitumor activity is yet to be fully elucidated, Sang has displayed multiple biological effects, which remain to suggest its possible use in plant-derived treatments of human malignancies. This review covers the anticancer abilities of Sang including inhibition of aberrantly activated signal transduction pathways, induction of cell death and inhibition of cancer cell proliferation. It also highlights Sang-mediated inhibition of angiogenesis, inducing the expression of tumor suppressors, sensitization of cancer cells to standard chemotherapeutics to enhance their cytotoxic effects, while addressing the present need for further pharmacokinetic-based studies.
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Affiliation(s)
- Iman W Achkar
- Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | | | - Ramzi M Mohammad
- Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
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16
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Lee TK, Park C, Jeong SJ, Jeong MJ, Kim GY, Kim WJ, Choi YH. Sanguinarine Induces Apoptosis of Human Oral Squamous Cell Carcinoma KB Cells via Inactivation of the PI3K/Akt Signaling Pathway. Drug Dev Res 2016; 77:227-40. [PMID: 27363951 DOI: 10.1002/ddr.21315] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 05/25/2016] [Indexed: 01/16/2023]
Abstract
Preclinical Research Sanguinarine, an alkaloid isolated from the root of Sanguinaria canadensis and other plants of the Papaveraceae family, selectively induces apoptotic cell death in a variety of human cancer cells, but its mechanism of action requires further elaboration. The present study investigated the pro-apoptotic effects of sanguinarine in human oral squamous cell carcinoma KB cells. Sanguinarine treatment increased DR5/TRAILR2 (death receptor 5/TRAIL receptor 2) expression and enhanced the activation of caspase-8 and cleavage of its substrate, Bid. Sanguinarine also induced the mitochondrial translocation of pro-apoptotic Bax, mitochondrial dysfunction, cytochrome c release to the cytosol, and activation of caspase-9 and -3. However, a pan-caspase inhibitor, z-VAD-fmk, reversed the growth inhibition and apoptosis induced by sanguinarine. Sanguinarine also suppressed the phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt in KB cells, while co-treatment of cells with sanguinarine and a PI3K inhibitor revealed synergistic apoptotic effects. However, pharmacological inhibition of AMP-activated protein kinase and mitogen-activated protein kinases did not reduce or enhance sanguinarine-induced growth inhibition and apoptosis. Collectively, these findings indicate that the pro-apoptotic effects of sanguinarine in KB cells may be regulated by a caspase-dependent cascade via activation of both intrinsic and extrinsic signaling pathways and inactivation of PI3K/Akt signaling. Drug Dev Res 77 : 227-240, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Tae Kyung Lee
- Department of Biology, New York University, New York, NY, 10012, USA
| | - Cheol Park
- Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan, 614-714, South Korea
| | - Soon-Jeong Jeong
- Department of Dental Hygiene, College of Health Sciences, Youngsan University, Yangsan, 626-790, South Korea
| | - Moon-Jin Jeong
- Department of Oral Histology and Developmental Biology, School of Dentistry, Chosun University, Gwangju, 501-759, South Korea
| | - Gi-Young Kim
- Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju, 690-756, South Korea
| | - Wun-Jae Kim
- Department of Urology, Chungbuk National University, College of Medicine and Institute for Tumor Research, Cheongju, 28644, South Korea
| | - Yung Hyun Choi
- Anti-Aging Research Center, Dongeui University, Busan, 614-714, South Korea.,Department of Biochemistry, Dongeui University College of Korean Medicine, Busan, 614-714, South Korea
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17
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Gaziano R, Moroni G, Buè C, Miele MT, Sinibaldi-Vallebona P, Pica F. Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives. World J Gastrointest Oncol 2016; 8:30-39. [PMID: 26798435 PMCID: PMC4714144 DOI: 10.4251/wjgo.v8.i1.30] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 09/01/2015] [Accepted: 11/04/2015] [Indexed: 02/05/2023] Open
Abstract
Historically, natural products have represented a significant source of anticancer agents, with plant-derived drugs becoming increasingly explored. In particular, sanguinarine is a benzophenanthridine alkaloid obtained from the root of Sanguinaria canadensis, and from other poppy Fumaria species, with recognized anti-microbial, anti-oxidant and anti-inflammatory properties. Recently, increasing evidence that sanguinarine exibits anticancer potential through its capability of inducing apoptosis and/or antiproliferative effects on tumor cells, has been proved. Moreover, its antitumor seems to be due not only to its pro-apoptotic and inhibitory effects on tumor growth, but also to its antiangiogenic and anti-invasive properties. Although the precise mechanisms underlying the antitumor activity of this compound remain not fully understood, in this review we will focus on the most recent findings about the cellular and molecular pathways affected by sanguinarine, together with the rationale of its potential application in clinic. The complex of data currently available suggest the potential application of sanguinarine as an adjuvant in the therapy of cancer, but further pre-clinical studies are needed before such an antitumor strategy can be effectively translated in the clinical practice.
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18
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Liu H, Cao HQ, Ta JB, Zhang W, Liu YH. Knockdown of Peripheral Myelin Protein 22 Inhibits the Progression of Chronic Myeloid Leukemia. Oncol Res 2015; 22:259-65. [PMID: 26629937 PMCID: PMC7842503 DOI: 10.3727/096504015x14410238486603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
We aimed to explore the underlying mechanism of peripheral myelin protein 22 (PMP22) in the development of chronic myeloid leukemia (CML). The level of PMP22 expression in CD34+ cells isolated from CML patients’ bone marrow samples (BMMCs) and peripheral blood samples (PBMCs) was determined by RT-PCR. In addition, PMP22-siRNA and scrambled control siRNA were transfected into human CML cell line K562 with Lipofectamine 2000 reagent. Cell viability and apoptosis were, respectively, determined by MTT assay and flow cytometry. Besides, the level of caspase 3 and Bcl-xL was then detected using Western blot. The level of PMP22 expression in CML patients’ CD34+ cells isolated from both PBMCs and BMMCs was significantly higher than the control group. PMP22 expression in K562 cells was successfully knocked down by siRNA. MTT analysis showed that knockdown of PMP22 inhibited the proliferation of CML cells. Flow cytometry showed that knockdown of PMP22 promoted the apoptosis of CML cells. Besides, Bcl-xL expression markedly decreased, while the expression of caspase 3 in CML cells significantly increased after knockdown of PMP22 expression. Our findings indicate that high expression of PMP22 may promote cell proliferation and inhibit cell apoptosis via upregulation of Bcl-xL or inhibition of caspase 3 activation, and thus may contribute to the development of CML. PMP22 may serve as a novel therapeutic target for the treatment of CML.
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Affiliation(s)
- Hui Liu
- Department of Hematology, The Affiliated Hospital of Yan'an University, Yan'an, Shanxi, China
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19
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Cecen E, Altun Z, Ercetin P, Aktas S, Olgun N. Promoting effects of sanguinarine on apoptotic gene expression in human neuroblastoma cells. Asian Pac J Cancer Prev 2015; 15:9445-51. [PMID: 25422239 DOI: 10.7314/apjcp.2014.15.21.9445] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma is the most common extracranial solid tumor in children. Approximately half of the affected patients are diagnosed with high-risk poor prognosis disease, and novel therapies are needed. Sanguinarine is a benzophenanthridine alkaloid which has anti-microbial, anti-oxidant and anti-inflammatory properties. The aim of this study is whether sanguinarine has in vitro apoptotic effects and which apoptotic genes might be affected in the human neuroblastoma cell lines SH-SY5Y (N-myc negative), Kelly (N-myc positive, ALK positive), and SK- N-BE(2). Cell viability was analysed with WST-1 and apoptotic cell death rates were determined using TUNEL. After RNA isolation and cDNA conversion, expression of 84 custom array genes of apoptosis was determined. Sanguinarine caused cell death in a dose dependent manner in all neuroblastoma cell lines except SK-N-BE(2) with rates of 18% in SH-SY5Y and 21% in Kelly human neuroblastoma cells. Cisplatin caused similar apoptotic cell death rates of 16% in SH-SY5Y and 23% in Kelly cells and sanguinarine-cisplatin combinations caused the same rates (18% and 20%). Sanguinarine treatment did not affect apoptototic gene expression but decreased levels of anti-apoptotic genes NOL3 and BCL2L2 in SH-SY5Y cells. Caspase and TNF related gene expression was affected by the sanguinarine-cisplatin combination in SH-SY5Y cells. The expression of regulation of apoptotic genes were increased with sanguinarine treatment in Kelly cells. From these results, we conclude that sanguinarine is a candidate agent against neuroblastoma.
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Affiliation(s)
- Emre Cecen
- Department of Pediatric Oncology, Adnan Menderes University School of Medicine, Aydin, Turkey E-mail :
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20
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Zhang DS, Li YY, Chen XJ, Li YJ, Liu ZY, Xie WJ, Sun ZL. BCL2 promotor methylation and miR-15a/16-1 upregulation is associated with sanguinarine-induced apoptotic death in rat HSC-T6 cells. J Pharmacol Sci 2015; 127:135-44. [DOI: 10.1016/j.jphs.2014.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 11/14/2014] [Accepted: 11/23/2014] [Indexed: 01/26/2023] Open
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21
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Sandjo LP, Kuete V, Tchangna RS, Efferth T, Ngadjui BT. Cytotoxic Benzophenanthridine and Furoquinoline Alkaloids from Zanthoxylum buesgenii (Rutaceae). Chem Cent J 2014; 8:61. [PMID: 25349626 PMCID: PMC4207896 DOI: 10.1186/s13065-014-0061-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 10/07/2014] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Zanthoxylum buesgenii is a shrub used in Sierra Leone as remedy to cure venereal diseases, arthritis, and rheumatism whereas leaves and barks are employed to treat leprosy and to relieve pain. In South West Region of Cameroon, the plant locally called "Mbem" by Lewoh-Lebang community, is orally given to patients as aphrodisiac decoction and to increase sperm count. Previous chemical studies on Zanthoxylum species reported the identification of lignans, coumarins, diterpenes, sesquiterpenes, steroids, alkaloids and benzopropanoids. Besides, structurally diverse compounds belonging to these classes of secondary metabolites have been reported as trypanocidal, antileishmanial, antimycobacterial and cytotoxic metabolites. RESULTS We therefore investigated the alkaloidal constituents of Z. buesgenii. In the course of the study, two benzophenanthridines [1-methoxy-12-methyl-12,13-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-c]phenanthridine-2,13-diol (1) and isofagaridine (2)] were identified among them one new. Alongside, three known furoquinolines [maculine (3), kokusaginine (4) and teclearverdoornine (5)] were also obtained and their structures were established on the basis of their NMR data and by comparison with those previously reported. Furthermore, the cytotoxicities of metabolites (1-4) isolated in substantial amount were evaluated against a series of multidrugs-resistant cancer cell lines. While compounds 2-4 showed selective cytotoxicities, compound 1 displayed activities against all cancer cells. CONCLUSIONS The observed activities corroborate those previously reported on similar benzophenanthridine alkaloids indicating that compounds 1 and 2 can chemically be explored to develop other chemotherapeutic agents. Graphical abstractCytotoxic Benzophenanthridine and Furoquinoline Alkaloids from Zanthoxylum buesgenii (Rutaceae).
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Affiliation(s)
- Louis P Sandjo
- Department of Organic Chemistry, University of Yaoundé I, P. O. Box 812, Yaoundé, Cameroon
| | - Victor Kuete
- Department of Biochemistry, University of Dschang, P.O. Box 67, Dschang, Cameroon ; Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Rodrigue S Tchangna
- Department of Organic Chemistry, University of Yaoundé I, P. O. Box 812, Yaoundé, Cameroon
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Bonaventure T Ngadjui
- Department of Organic Chemistry, University of Yaoundé I, P. O. Box 812, Yaoundé, Cameroon
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Histopathological features associated with application of black salve to cutaneous lesions: A series of 16 cases and review of the literature. Pathology 2013; 45:670-4. [DOI: 10.1097/pat.0000000000000005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kumar S, Tomar MS, Acharya A. HSF1-mediated regulation of tumor cell apoptosis: a novel target for cancer therapeutics. Future Oncol 2013; 9:1573-86. [PMID: 24106905 DOI: 10.2217/fon.13.106] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Programmed cell death/apoptosis is a genetically conserved phenomenon involved in many biological processes including reconstruction of multicellular organisms and elimination of old or damaged cells. It is regulated by the activation/deactivation of PKC in response to exogenous and endogenous stimuli. PKC is activated under stress by a series of downstream signaling cascades, which ultimately induce HSF1 activation, which results in overexpression of heat shock proteins. Overexpression of heat shock proteins interferes in the apoptotic pathway, while their blocking results in apoptosis. Therefore, HSF1 could be a novel therapeutic target against a variety of tumors. Several pharmacological inhibitors of PKC have been demonstrated to exert inhibitory effects on the activation of HSF1 and, therefore, induce apoptosis in tumor cells. However, studies regarding the role of pharmacological inhibitors in the regulation of apoptosis and possible anti-tumor therapeutic intervention are still unknown or in their infancy. Therefore, an attempt has been made to delineate the precise role of HSF1 in the regulation of apoptosis and its prospects in cancer therapeutics.
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Affiliation(s)
- Sanjay Kumar
- Centre of Advance Study in Zoology, Faculty of Science, Banaras Hindu University, Varanasi–221 005, U.P., India
| | - Munendra Singh Tomar
- Centre of Advance Study in Zoology, Faculty of Science, Banaras Hindu University, Varanasi–221 005, U.P., India
| | - Arbind Acharya
- Centre of Advance Study in Zoology, Faculty of Science, Banaras Hindu University, Varanasi–221 005, U.P., India
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Liu M, Lin YL, Chen XR, Liao CC, Poo WK. In vitro assessment of Macleaya cordata crude extract bioactivity and anticancer properties in normal and cancerous human lung cells. ACTA ACUST UNITED AC 2013; 65:775-87. [DOI: 10.1016/j.etp.2012.11.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 11/08/2012] [Indexed: 10/27/2022]
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25
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WANG CONG, GUO LIUBIN, MA JUNYUAN, LI YONGMEI, LIU HONGMIN. Establishment and characterization of a paclitaxel-resistant human esophageal carcinoma cell line. Int J Oncol 2013; 43:1607-17. [DOI: 10.3892/ijo.2013.2083] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 08/05/2013] [Indexed: 11/05/2022] Open
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Han MH, Kim GY, Yoo YH, Choi YH. Sanguinarine induces apoptosis in human colorectal cancer HCT-116 cells through ROS-mediated Egr-1 activation and mitochondrial dysfunction. Toxicol Lett 2013; 220:157-66. [PMID: 23660334 DOI: 10.1016/j.toxlet.2013.04.020] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 03/27/2013] [Accepted: 04/26/2013] [Indexed: 12/14/2022]
Abstract
We examined the effects of sanguinarine, a benzophenanthridine alkaloid, on reactive oxygen species (ROS) production and the association of these effects with apoptotic cell death in a human colorectal cancer HCT-116 cell line. Sanguinarine generated ROS, which was followed by a decrease in the mitochondrial membrane potential (MMP), the activation of caspase-9 and -3, and the down-regulation of anti-apoptotic proteins, such as Bcl2, XIAP and cIAP-1. Sanguinarine also promoted the activation of caspase-8 and truncation of Bid (tBid). However, the quenching of ROS generation by N-acetyl-l-cysteine, a scavenger of ROS, reversed the sanguinarine-induced apoptosis effects via inhibition of the MMP collapse, tBid expression, and activation of caspases. Sanguinarine also markedly induced the expression of the early growth response gene-1 (Egr-1) during the early period, after which expression level was decreased. In addition, HCT-116 cells transfected with Egr-1 siRNA displayed significant blockage of sanguinarine-induced apoptotic activity in a ROS-dependent manner. These observations clearly indicate that ROS, which are key mediators of Egr-1 activation and MMP collapse, are involved in the early molecular events in the sanguinarine-induced apoptotic pathway acting in HCT-116 cells.
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Affiliation(s)
- Min Ho Han
- Department of Biomaterial Control (BK21 Program), Graduate School, Dongeui University, Busan 614-714, Republic of Korea
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Tang XP, Tang GD, Fang CY, Liang ZH, Zhang LY. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J Gastroenterol 2013; 19:1582-1592. [PMID: 23538603 PMCID: PMC3602475 DOI: 10.3748/wjg.v19.i10.1582] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Revised: 10/17/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of ginsenoside Rh2 on the human pancreatic cancer cell line Bxpc-3.
METHODS: The human pancreatic cancer cell line Bxpc-3 was cultured in vitro and treated with or without ginsenoside Rh2. Growth rates for Bxpc-3 cells were assessed by methyl thiazolyl tetrazolium (MTT) and colony formation assays. Cell cycle changes were analyzed by flow cytometry. Apoptosis was measured by flow cytometry and Hoechst 33258 fluorescence staining. A scratch assay and a Matrigel invasion assay were used to detect cell migration and invasion. Expression of Bax, Bcl-2, survivin, cyclin D1, matrix metalloproteinase (MMP)-2, MMP-9, cleaved caspase-3, caspase-8, and caspase-9 mRNA were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Bax, Bcl-2, survivin, cyclin D1, cleaved caspase-3, caspase-8 and caspase-9 protein levels were examined by western blotting. Expression of MMP-2 and MMP-9 proteins in culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS: Rh2 significantly inhibited Bxpc-3 cell proliferation in a dose- and time-dependent manner, as evaluated by the MTT (P < 0.05) and colony formation assays (P < 0.05). Compared to the control group, Rh2 significantly increased the percentage of Bxpc-3 cells in the G0/G1 phase from 43.32% ± 2.17% to 71.32% ± 1.16%, which was accompanied by a decrease in S phase (from 50.86% ± 1.29% to 28.48% ± 1.18%) and G2/M phase (from 5.81% ± 1.19% to 0.20% ± 0.05%) in a dose-dependent manner (P < 0.05), suggesting that Rh2 arrested cell cycle progression at the G0/G1 phase, as measured by flow cytometry. Compared to the control group, cells treated with Rh2 showed significantly higher apoptosis ratios in a dose-dependent manner (percentage of early apoptotic cells: from 5.29% ± 2.28% to 38.90% ± 3.42% (F = 56.20, P < 0.05); percentage of late apoptotic cells: from 4.58% ± 1.42% to 36.32% ± 2.73% (F = 86.70, P < 0.05). Rh2 inhibited Bxpc-3 cell migration and invasion, as detected by scratch wound healing assay and Matrigel invasion assay [percentages of scratch wound healing for 12 h, 24 h and 48 h (control vs experimental group): 37.3% ± 4.8% vs 18.30% ± 1.65%, 58.7% ± 3.5% vs 38.00% ± 4.09% and 93.83% ± 4.65% vs 65.50% ± 4.09%, respectively; t = 6.489, t = 6.656 and t = 7.926, respectively, P < 0.05; the number of cells invading at various concentrations (0 μmol/L, 35 μmol/L, 45 μmol/L and 55 μmol/L): 81.10 ± 9.55, 46.40 ± 6.95, 24.70 ± 6.88 and 8.70 ± 3.34, respectively (F = 502.713, P < 0.05)]. RT-PCR, western blotting or ELISA showed that mRNA and protein expression of Bax, cleaved caspase-3 and caspase-9 were upregulated (P < 0.05), while mRNA and protein expression of Bcl-2, survivin, cyclin D1, MMP-2 and MMP-9 were downregulated (P < 0.05).
CONCLUSION: Ginsenoside Rh2 inhibits proliferation, migration and invasion and induces apoptosis of the human pancreatic cancer cell line Bxpc-3.
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Rapid human melanoma cell death induced by sanguinarine through oxidative stress. Eur J Pharmacol 2013; 705:109-18. [PMID: 23499690 DOI: 10.1016/j.ejphar.2013.02.035] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Revised: 02/06/2013] [Accepted: 02/13/2013] [Indexed: 12/14/2022]
Abstract
Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Here we have found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Time-lapse videomicroscopy showed rapid morphological changes compatible with an apoptotic cell death, which was further supported by biochemical markers, including caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage and DNA breakdown. Pan-caspase inhibition blocked sanguinarine-induced cell death. Sanguinarine treatment also induced an increase in intracellular calcium concentration, which was inhibited by dantrolene, and promoted cleavage of BAP-31, thus suggesting a putative role for Ca(2+) release from endoplasmic reticulum and a cross-talk between endoplasmic reticulum and mitochondria in the anti-melanoma action of sanguinarine. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨm), released cytochrome c and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Overexpression of Bcl-XL by gene transfer did not prevent sanguinarine-mediated cell death, oxidative stress or release of mitochondrial apoptogenic proteins. However, preincubation with N-acetyl-l-cysteine (NAC) prevented sanguinarine-induced oxidative stress, PARP cleavage, release of apoptogenic mitochondrial proteins, and cell death. Pretreatment with glutathione (GSH) also inhibited the anti-melanoma activity of sanguinarine. Thus, pretreatment with the thiol antioxidants NAC and GSH abrogated the killing activity of sanguinarine. Taking together, our data indicate that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress.
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Balasubramanian K, Padma PR. Anticancer activity of Zea mays leaf extracts on oxidative stress-induced Hep2 cells. J Acupunct Meridian Stud 2013; 6:149-58. [PMID: 23787284 DOI: 10.1016/j.jams.2013.01.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 11/23/2012] [Accepted: 11/28/2012] [Indexed: 01/05/2023] Open
Abstract
Cancer is one of the leading causes of death in humans. It is believed that plants can provide potential bioactive compounds for the development of "new leads" to combat cancer and other diseases. The present study focuses on the ability of the different extracts (aqueous, methanol, and chloroform) of the leaves of Zea mays in influencing the process of apoptosis induced by hydrogen peroxide (H2O2) in Hep2 (laryngeal carcinoma) cells. Various apoptosis-related parameters, such as cell viability, morphological changes, nuclear changes, and apoptotic index were characterized. sulforhodamine B and MTT assays were used to quantify the extent of cell death in the group exposed to H2O2, plant extracts, and their combination. Treatment with H2O2 caused cytotoxicity in cancer cells. The administration of leaf extract also caused an increase in the death of cancer cells. Oxidatively stressed cancer cells co-treated with all the Z. mays leaf extracts (except the chloroform extract) demonstrated cytotoxicity on a par with the H2O2-treated groups. This indicated that the aqueous and methanol leaf extracts did not influence the cytotoxic action of H2O2 in the cancer cells. Thus, various apoptosis-related events in Hep2 cells exposed to leaf extract throw light on the potential anticancer activity of the Z. mays leaves. The maximum activity was exerted by the methanolic extract followed by the aqueous and chloroform extracts.
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Affiliation(s)
- Kiruthika Balasubramanian
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Deemed University, Tamil Nadu, India
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Artemisia absinthium (AA): a novel potential complementary and alternative medicine for breast cancer. Mol Biol Rep 2012; 39:7373-9. [DOI: 10.1007/s11033-012-1569-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 01/25/2012] [Indexed: 10/14/2022]
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Lee JS, Jung WK, Jeong MH, Yoon TR, Kim HK. Sanguinarine induces apoptosis of HT-29 human colon cancer cells via the regulation of Bax/Bcl-2 ratio and caspase-9-dependent pathway. Int J Toxicol 2012; 31:70-7. [PMID: 22215411 DOI: 10.1177/1091581811423845] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Sanguinarine is an alkaloid obtained from the bloodroot plant Sanguinaria canadensis and has beneficial effects on oxidative stress and inflammatory disorders. Previous reports have demonstrated that sanguinarine also exhibit anticancer properties. In the current study, we investigated the effects of sanguinarine on HT-29 human colon cancer cells. It was observed that sanguinarine treatment induces a dose-dependent increase in apoptosis of human colon cancer cells. We also investigated the effects of sanguinarine on the expression of apoptosis-associated proteins, and the results revealed that there was an increase in Bax and a decrease in B-cell lymphoma 2 (Bcl-2) protein levels. Moreover, sanguinarine treatment significantly increases the activation of caspases 3 and 9 that are the key executioners in apoptosis. Our results suggest that sanguinarine induces apoptosis of HT-29 human colon cancer cells and may have a potential therapeutic use in the treatment of human colon cancer.
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Affiliation(s)
- Jun Sik Lee
- Heart Research Center of Chonnam National University Hospital, Cardiovascular Research Institute of Chonnam National University, Gwangju 501-757, Korea.
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Sun M, Liu C, Nadiminty N, Lou W, Zhu Y, Yang J, Evans CP, Zhou Q, Gao AC. Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion. Prostate 2012; 72:82-9. [PMID: 21538419 PMCID: PMC3938016 DOI: 10.1002/pros.21409] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 04/05/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a potential therapeutic target. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. METHODS DU145, C4-2B, and LNCaP cells were treated with sanguinarine. The phosphorylation status of Stat3 and related proteins were measured with Western blots. Activation of transcription by Stat3 was measured with luciferase reporter assay. The effect of sanguinarine on anchorage-independent growth was examined with soft agar assay, and on cell migration and invasion of DU145 cells were measured with scratch assay and invasion assay, respectively. RESULTS In this study, we identified sanguinarine as a potent inhibitor of Stat3 activation which was able to suppress prostate cancer growth, migration, and invasion. Sanguinarine inhibits constitutive as well as IL6-induced phosphorylation of Stat3 at both Tyr705 and Ser727 in prostate cancer cells. The inhibition of Stat3 phosphorylation by sanguinarine correlates with reduction of Janus-activated Kinase 2 (Jak2) and Src phosphorylation. Sanguinarine downregulates the expression of Stat3-mediated genes such as c-myc and survivin and inhibits the Stat3 responsive element luciferase reporter activity. Sanguinarine inhibits the anchorage-independent growth of DU145 and LN-S17 cells expressing constitutively activated Stat3. Migration and invasion abilities of DU145 cells were also inhibited by sanguinarine in a manner similar to the dominant negative form of Stat3. CONCLUSIONS These data demonstrate that sanguinarine is a potent Stat3 inhibitor and it could be developed as a therapeutic agent for prostate cancer with constitutive activation of Stat3.
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Affiliation(s)
- Meng Sun
- Department of Urology, University of California at Davis, Sacramento, California
- Graduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California
| | - Chengfei Liu
- Department of Urology, University of California at Davis, Sacramento, California
| | | | - Wei Lou
- Department of Urology, University of California at Davis, Sacramento, California
| | - Yezi Zhu
- Department of Urology, University of California at Davis, Sacramento, California
- Graduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California
| | - Joy Yang
- Department of Urology, University of California at Davis, Sacramento, California
| | - Christopher P. Evans
- Department of Urology, University of California at Davis, Sacramento, California
| | - Qinghua Zhou
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Allen C. Gao
- Department of Urology, University of California at Davis, Sacramento, California
- Graduate Program of Pharmacology and Toxicology and Cancer Center, University of California at Davis, Sacramento, California
- Correspondence to: Allen C. Gao, Department of Urology and Cancer Center, University of California Davis Medical Center, 4645 2nd Ave, Research III, Suite 1300, Sacramento, CA 95817,
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Jiang JW, Chen XM, Chen XH, Zheng SS. Ginsenoside Rg3 inhibit hepatocellular carcinoma growth via intrinsic apoptotic pathway. World J Gastroenterol 2011; 17:3605-13. [PMID: 21987607 PMCID: PMC3180017 DOI: 10.3748/wjg.v17.i31.3605] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Revised: 07/06/2011] [Accepted: 07/13/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the anti-tumor function of ginsenoside Rg3 on hepatocellular carcinoma (HCC) in vitro and in vivo, and its mechanism.
METHODS: Hep1-6 and HepG2 cells were treated by Rg3 in different concentrations (0, 50, 100 and 200 μg/mL) in vitro. After incubation for 0, 6, 12, 24 and 48 h, cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Apoptosis was identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. Caspase-3 activity was measured by chromophore p-nitroanilide and flow cytometry. Bcl-2 family proteins were ascertained by Western-blotting. Mitochondria membrane potential was detected by 5, 5’, 6’ 6’ - tetrachloro-1, 1’, 3, 3’ - tetraethylbenzimidazolylcarbocyanine iodide. Forty liver tumor-bearing C57Bl6 mice were divided randomly into 4 groups for intra-tumor injection of saline, ginsenoside Rg3, cyclophosphamide (CTX) and ginsenoside Rg3 + CTX combination.
RESULTS: The survival time was followed up to 102 d. The mice in the Rg3 + CTX group showed significant increased survival time compared with those in the control group (P < 0.05). Rg3 could inhibit HCC cell proliferation and induce cell apoptosis in vitro in the concentration and time dependent manner. It also induced mitochondria membrane potential to decrease. Caspase-3 activation can be blocked by the inhibitor z-DEVD-FMK. Bax was up-regulated while Bcl-2 and Bcl-XL were down-regulated after Rg3 treatment.
CONCLUSION: Our data suggested that Rg3 alone or combined with CTX inhibited tumor growth in vivo and prolonged mouse survival time by inducing HCC cell apoptosis via intrinsic pathway by expression alterations of Bcl-2 family proteins.
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Sun JG, Chen CY, Luo KW, Yeung CLA, Tsang TY, Huang ZZ, Wu P, Fung KP, Kwok TT, Liu FY. 3,5-Dimethyl-H-furo[3,2-g]chromen-7-one as a potential anticancer drug by inducing p53-dependent apoptosis in human hepatoma HepG2 cells. Chemotherapy 2011; 57:162-72. [PMID: 21454974 DOI: 10.1159/000326915] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 12/06/2010] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS Coumarins are natural compounds found in many plants that possess medical value by itself and its modified derivatives. METHOD Six novel coumarin derivatives were synthesized and examined for their potential anticancer cytotoxicity. RESULT Among the 6 derivatives, 3,5-dimethyl-(7)H-furo[3,2-g]chromen-7-one (DMFC) presented the strongest cytotoxicity against human hepatoma HepG2 cells in vitro with an IC(50) value of 8.46 ± 0.28 μM in a 48-hour treatment. Further experiments revealed that DMFC induced apoptosis in HepG2 cells through both extrinsic and intrinsic apoptotic pathways in a p53-dependent manner. Mechanistically, DMFC activated caspases 3, 8 and 9, depolarized mitochondrial membrane potential and induced cytochrome c and apoptosis-inducing factor release. DMFC-induced apoptosis was also characterized by DNA fragmentation, phosphatidylserine externalization and sub-G1 peak in DNA histograms. Moreover, both caspase 8 and 9 inhibitors suppressed the apoptosis induced by DMFC. Western blot analyses revealed that DMFC also significantly increased the expression levels of p53, Fas death receptor, Fas-associated death domain protein and proapoptotic Bcl-2 family members such as Bax, Bad and tBid, as well as decreased the levels of pro-survival members such as Bcl-2 and Bcl-xl. CONCLUSION DMFC is potentially an effective therapeutic agent in liver cancer therapy.
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Affiliation(s)
- Jian-guo Sun
- Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Zhejiang University, Hangzhou, PR China
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Hammerová J, Uldrijan S, Táborská E, Slaninová I. Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. J Dermatol Sci 2011; 62:22-35. [PMID: 21324654 DOI: 10.1016/j.jdermsci.2011.01.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 01/11/2011] [Accepted: 01/14/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Search for new substances with antiproliferative activity towards melanoma cells is important since malignant melanoma is notoriously resistant to conventional chemotherapy. Benzo[c]phenanthridine alkaloids (BAs) are natural products with significant anti-proliferative activities, therefore they are considered as agents promising for cancer therapy. OBJECTIVES The effects of five BAs (sanguinarine, chelerythrine, chelidonine, sanguilutine, and chelilutine) on human malignant melanoma cell lines were compared. The study focused on BAs effects on DNA, anti-apoptotic and p53 protein levels; and the involvement of p53 in cellular responses to alkaloids treatment. METHODS Melanoma cell lines, two wild types and two with dysfunctional p53 derived from one of them were used. The mechanism of anti-proliferative and pro-apoptotic effects and the effect on DNA was investigated using MTT assay, flow cytometry, Western blot analysis, fluorescence and electron microscopy. RESULTS All tested alkaloids exhibit strong anti-proliferative activity. CHL, CHE and SA induced apoptosis, which was probably mediated by decreasing levels of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP) and was accompanied by mitochondrial membrane potential decrease as well as caspase-3 and PARP cleavage. Although all alkaloids caused DNA damage, which was demonstrated by induction of H2AX phosphorylation, none of the tested alkaloids stabilised p53 and their toxicity in cells with non-functional p53 was comparable to wild type cells. CONCLUSION Despite the profound similarity of BAs molecular structures, it is clear that the mechanism of cell death induction is different for each alkaloid. Our results indicate that BAs could be effective in malignant melanoma treatment, including tumours which have lost wild type p53.
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Affiliation(s)
- Jindřiška Hammerová
- Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A16, 62500 Brno, Czech Republic
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Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 2010; 29:405-34. [PMID: 20737283 DOI: 10.1007/s10555-010-9235-2] [Citation(s) in RCA: 544] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed "Let food be thy medicine and medicine be thy food." Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, gamma-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.
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Affiliation(s)
- Subash C Gupta
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Najim N, Bathich Y, Zain MM, Hamzah AS, Shaameri Z. Evaluation of the bioactivity of novel spiroisoxazoline typecompounds against normal and cancer cell lines. Molecules 2010; 15:9340-53. [PMID: 21169884 PMCID: PMC6259157 DOI: 10.3390/molecules15129340] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Revised: 11/03/2010] [Accepted: 12/02/2010] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to investigate the in vitro cellular activity of novel spiroisoxazoline type compounds against normal and cancer cell lines from lung tissue (Hs888Lu), neuron-phenotypic cells (SH-SY5Y), neuroblastoma (SH-SY5Y), human histiocytic lymphoma (U937), lung cancer (A549), and leukaemia (HL-60). Our bioassay program revealed that the spiroisoxazoline type compounds show cytotoxicity only in lymphoma cell lines, which is in contrast with the pyrrolidine precursor of these spiroisoxazoline compounds, where significant cytotoxicity is seen in all normal and cancer cell lines. These data suggest a tumour-specific mechanism of action. In addition these data also show that spiroisoxazoline compounds are non-toxic in the human neuronphenotypic neuroblastoma SH-SY5Y cell line, and furthermore that they might protect cells from neurodegenerative disease.
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Affiliation(s)
- Nigar Najim
- Tissue Culture Research Laboratory, Centre of Synthesis and Chemical Biology, Institute of Science, University Technology MARA, 40450 Shah Alam, Malaysia; E-Mail: (M.M.Z.)
| | - Yaser Bathich
- Organic Synthesis Research Laboratory, Centre of Synthesis and Chemical Biology, Institute of Science, University Technology MARA, 40450 Shah Alam, Malaysia; E-Mails: (Y.B.); (A.S.H.); (Z.S.)
| | - Mazatulikhma Mat Zain
- Tissue Culture Research Laboratory, Centre of Synthesis and Chemical Biology, Institute of Science, University Technology MARA, 40450 Shah Alam, Malaysia; E-Mail: (M.M.Z.)
| | - Ahmad Sazali Hamzah
- Organic Synthesis Research Laboratory, Centre of Synthesis and Chemical Biology, Institute of Science, University Technology MARA, 40450 Shah Alam, Malaysia; E-Mails: (Y.B.); (A.S.H.); (Z.S.)
| | - Zurina Shaameri
- Organic Synthesis Research Laboratory, Centre of Synthesis and Chemical Biology, Institute of Science, University Technology MARA, 40450 Shah Alam, Malaysia; E-Mails: (Y.B.); (A.S.H.); (Z.S.)
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Shafi G, Munshi A, Hasan TN, Alshatwi AA, Jyothy A, Lei DKY. Induction of apoptosis in HeLa cells by chloroform fraction of seed extracts of Nigella sativa. Cancer Cell Int 2009; 9:29. [PMID: 19943925 PMCID: PMC2794855 DOI: 10.1186/1475-2867-9-29] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Accepted: 11/27/2009] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Cancer remains one of the most dreaded diseases causing an astonishingly high death rate, second only to cardiac arrest. The fact that conventional and newly emerging treatment procedures like chemotherapy, catalytic therapy, photodynamic therapy and radiotherapy have not succeeded in reverting the outcome of the disease to any drastic extent, has made researchers investigate alternative treatment options. The extensive repertoire of traditional medicinal knowledge systems from various parts of the world are being re-investigated for their healing properties. This study progresses in the direction of identifying component(s) from Nigella sativa with anti cancer activity. In the present study we investigated the efficacy of Organic extracts of Nigella sativa seed powder for its clonogenic inhibition and induction of apoptosis in HeLa cancer cell. RESULTS Methanolic, n-Hexane and chloroform extracts of Nigella sativa seedz effectively killed HeLa cells. The IC50 values of methanolic, n-hexane, and chloroform extracts of Nigella sativa were 2.28 microg/ml, 2.20 microg/ml and 0.41 ng/ml, respectively. All three extracts induced apoptosis in HeLa cells. Apoptosis was confirmed by DNA fragmentation, western blot and terminal transferase-mediated dUTP-digoxigenin-end labeling (TUNEL) assay. CONCLUSION Western Blot and TUNEL results suggested that Nigella sativa seed extracts regulated the expression of pro- and anti- apoptotic genes, indicating its possible development as a potential therapeutic agent for cervical cancer upon further investigation.
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Affiliation(s)
- Gowhar Shafi
- Molecular Cancer Biology Lab, Department of Food Science and Nutrition, King Saud University, Riyadh, Saudi Arabia
- Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Hyderabad, India
| | - Anjana Munshi
- Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Hyderabad, India
| | - Tarique N Hasan
- Molecular Cancer Biology Lab, Department of Food Science and Nutrition, King Saud University, Riyadh, Saudi Arabia
| | - Ali A Alshatwi
- Molecular Cancer Biology Lab, Department of Food Science and Nutrition, King Saud University, Riyadh, Saudi Arabia
| | - A Jyothy
- Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Hyderabad, India
| | - David KY Lei
- Department of Nutrition and Food Science, University of Maryland, College Park, Maryland, USA
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Lim HK, Moon JY, Kim H, Cho M, Cho SK. Induction of apoptosis in U937 human leukaemia cells by the hexane fraction of an extract of immature Citrus grandis Osbeck fruits. Food Chem 2009. [DOI: 10.1016/j.foodchem.2008.10.088] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Choi YH, Choi WY, Hong SH, Kim SO, Kim GY, Lee WH, Yoo YH. Anti-invasive activity of sanguinarine through modulation of tight junctions and matrix metalloproteinase activities in MDA-MB-231 human breast carcinoma cells. Chem Biol Interact 2008; 179:185-91. [PMID: 19063874 DOI: 10.1016/j.cbi.2008.11.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 11/08/2008] [Accepted: 11/11/2008] [Indexed: 10/21/2022]
Abstract
Tight junctions (TJs) are critical structures for the maintenance of cellular polarity, acting as paracellular permeability barriers and playing an essential role in regulation of the diffusion of fluid, electrolytes and macromolecules through the paracellular pathway. Matrix metalloproteinases (MMPs) have been implicated as possible mediators of invasiveness and metastasis in some cancers. In this study, it was investigated the effect of sanguinarine, a benzophenanthridine alkaloid, on the correlation between the tightening of TJs and the anti-invasive activity in human breast carcinoma MDA-MB-231 cells. The inhibitory effects of sanguinarine on cell proliferation, motility and invasiveness were found to be associated with the increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance (TER). Additionally, immunoblotting results indicated that sanguinarine repressed the levels of the claudin proteins, major components of TJs that play a key role in the control and selectivity of paracellular transport. Furthermore, the activities of MMP-2 and -9 in MDA-MB-231 cells were dose-dependently inhibited by treatment with sanguinarine, and this was also correlated with a decrease in the expression of their mRNA and proteins.
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Affiliation(s)
- Yung Hyun Choi
- Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, South Korea.
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