|
1
|
Zhang H, Liu Y, Dong Y, Li G, Wang S. Thymoquinone: An Effective Natural Compound for Kidney Protection. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:775-797. [PMID: 38715182 DOI: 10.1142/s0192415x24500319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Kidney disease is a common health problem worldwide. Acute or chronic injuries may interfere with kidney functions, eventually resulting in irreversible kidney damage. A number of recent studies have shown that the plant-derived natural products have an extensive potential for renal protection. Thymoquinone (TQ) is an essential compound derived from Nigella Sativa (NS), which is widely applied in the Middle East as a folk medicine. Previous experiments have demonstrated that TQ has a variety of potential pharmacological effects, including anti-oxidant, antibacterial, antitumor, immunomodulatory, and neuroprotective activities. In particular, the prominent renal protective efficacy of TQ has been demonstrated in both in vivo and in vitro experiments. TQ can prevent acute kidney injuries from various xenobiotics through anti-oxidation, anti-inflammatory, and anti-apoptosis effects. In addition, TQ exhibited significant pharmacological effects on renal cell carcinoma, renal fibrosis, and urinary calculi. The essential mechanisms involve scavenging ROS and increasing anti-oxidant activity, decreasing inflammatory mediators, inducing apoptosis, and inhibiting migration and invasion. The purpose of this review is to conclude the pharmacological effects and the potential mechanisms of TQ in renal protection, shedding new light on the exploration of medicinal phyto-protective agents targeting kidneys.
Collapse
Affiliation(s)
- Huijing Zhang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Yuanqing Liu
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Yanjun Dong
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Gebin Li
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Shuaiyu Wang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
- Center of Research and Innovation of Chinese Traditional Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| |
Collapse
|
|
2
|
Kurowska N, Madej M, Strzalka-Mrozik B. Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer. Curr Issues Mol Biol 2023; 46:121-139. [PMID: 38248312 PMCID: PMC10814900 DOI: 10.3390/cimb46010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and is responsible for approximately one million deaths each year. The current standard of care is surgical resection of the lesion and chemotherapy with 5-fluorouracil (5-FU). However, of concern is the increasing incidence in an increasingly younger patient population and the ability of CRC cells to develop resistance to 5-FU. In this review, we discuss the effects of thymoquinone (TQ), one of the main bioactive components of Nigella sativa seeds, on CRC, with a particular focus on the use of TQ in combination therapy with other chemotherapeutic agents. TQ exhibits anti-CRC activity by inducing a proapoptotic effect and inhibiting proliferation, primarily through its effect on the regulation of signaling pathways crucial for tumor progression and oxidative stress. TQ can be used synergistically with chemotherapeutic agents to enhance their anticancer effects and to influence the expression of signaling pathways and other genes important in cancer development. These data appear to be most relevant for co-treatment with 5-FU. We believe that TQ is a suitable candidate for consideration in the chemoprevention and adjuvant therapy for CRC, but further studies, including clinical trials, are needed to confirm its safety and efficacy in the treatment of cancer.
Collapse
Affiliation(s)
- Natalia Kurowska
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (N.K.); (M.M.)
| | - Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (N.K.); (M.M.)
- Silesia LabMed, Centre for Research and Implementation, Medical University of Silesia, 40-752 Katowice, Poland
| | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (N.K.); (M.M.)
| |
Collapse
|
|
3
|
Sheikhnia F, Rashidi V, Maghsoudi H, Majidinia M. Potential anticancer properties and mechanisms of thymoquinone in colorectal cancer. Cancer Cell Int 2023; 23:320. [PMID: 38087345 PMCID: PMC10717210 DOI: 10.1186/s12935-023-03174-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 12/04/2023] [Indexed: 10/14/2024] Open
Abstract
Colorectal neoplasms are one of the deadliest diseases among all cancers worldwide. Thymoquinone (TQ) is a natural compound of Nigella sativa that has been used in traditional medicine against a variety of acute/chronic diseases such as asthma, bronchitis, rheumatism, headache, back pain, anorexia, amenorrhea, paralysis, inflammation, mental disability, eczema, obesity, infections, depression, dysentery, hypertension, gastrointestinal, cardiovascular, hepatic, and renal disorders. This review aims to present a detailed report on the studies conducted on the anti-cancer properties of TQ against colorectal cancer, both in vitro and in vivo. TQ stands as a promising natural therapeutic agent that can enhance the efficacy of existing cancer treatments while minimizing the associated adverse effects. The combination of TQ with other anti-neoplastic agents promoted the efficacy of existing cancer treatments. Further research is needed to acquire a more comprehensive understanding of its exact molecular targets and pathways and maximize its clinical usefulness. These investigations may potentially aid in the development of novel techniques to combat drug resistance and surmount the obstacles presented by chemotherapy and radiotherapy.
Collapse
Affiliation(s)
- Farhad Sheikhnia
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Vahid Rashidi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Maghsoudi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| |
Collapse
|
|
4
|
Kłos P, Perużyńska M, Baśkiewicz-Hałasa M, Skupin-Mrugalska P, Majcher M, Sawczuk M, Szostak B, Droździk M, Machaliński B, Chlubek D. Response of Skin-Derived and Metastatic Human Malignant Melanoma Cell Lines to Thymoquinone and Thymoquinone-Loaded Liposomes. Pharmaceutics 2022; 14:2309. [PMID: 36365127 PMCID: PMC9698994 DOI: 10.3390/pharmaceutics14112309] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 09/29/2023] Open
Abstract
Thymoquinone has been proved to be effective against neoplasms, including skin cancer. Its high lipophilicity, however, may limit its potential use as a drug. Melanoma remains the deadliest of all skin cancers worldwide, due to its high heterogeneity, depending on the stage of the disease. Our goal was to compare the anti-cancer activity of free thymoquinone and thymoquinone-loaded liposomes on two melanoma cell lines that originated from different stages of this cancer: skin-derived A375 and metastatic WM9. We evaluated the proapoptotic effects of free thymoquinone by flow cytometry and Western blot, and its mitotoxicity by means of JC-1 assay. Additionally, we compared the cytotoxicity of free thymoquinone and thymoquinone in liposomes by WST-1 assay. Our results revealed a higher antiproliferative effect of TQ in WM9 cells, whereas its higher proapoptotic activity was observed in the A375 cell line. Moreover, the thymoquinone-loaded liposome was proved to exert stronger cytotoxic effect on both cell lines studied than free thymoquinone. Differences in the response of melanoma cells derived from different stages of the disease to thymoquinone, as well as their different responses to free and carrier-delivered thymoquinone, are essential for the development of new anti-melanoma therapies. However, further research is required to fully understand them.
Collapse
Affiliation(s)
- Patrycja Kłos
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Magdalena Perużyńska
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Magdalena Baśkiewicz-Hałasa
- Department of General Pathology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Paulina Skupin-Mrugalska
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Małgorzata Majcher
- Faculty of Food Science and Nutrition, Poznań University of Life Sciences, Wojska Polskiego 31, 60-624 Poznan, Poland
| | - Magdalena Sawczuk
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Bartosz Szostak
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| |
Collapse
|
|
5
|
Renal cell carcinoma management: A step to nano-chemoprevention. Life Sci 2022; 308:120922. [PMID: 36058262 DOI: 10.1016/j.lfs.2022.120922] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/12/2022] [Accepted: 08/26/2022] [Indexed: 11/21/2022]
Abstract
Renal cell carcinoma (RCC) is one of the most common kidney cancers, responsible for nearly 90 % of all renal malignancies. Despite the availability of many treatment strategies, RCC still remains to be an incurable disease due to its resistivity towards conventional therapies. Nanotechnology is an emerging field of science that offers newer possibilities in therapeutics including cancer medicine, specifically by targeted delivery of anticancer drugs. Several phytochemicals are known for their anti-cancer properties and have been regarded as chemopreventive agents. However, the hydrophobic nature of many phytochemicals decreases its bioavailability and distribution, thus showing limited therapeutic effect. Application of nanotechnology to enhance chemoprevention is an effective strategy to increase the bioavailability of phytochemicals and thereby its therapeutic efficacy. The present review focuses on the utility of nanotechnology in RCC treatment and chemopreventive agents of RCC. We have also visualized the future prospects of nanomolecules in the prevention and cure of RCC.
Collapse
|
|
6
|
Park MY, Kim Y, Ha SE, Kim HH, Bhosale PB, Abusaliya A, Jeong SH, Kim GS. Function and Application of Flavonoids in the Breast Cancer. Int J Mol Sci 2022; 23:7732. [PMID: 35887080 PMCID: PMC9323071 DOI: 10.3390/ijms23147732] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/23/2022] [Accepted: 07/09/2022] [Indexed: 11/28/2022] Open
Abstract
Breast cancer is one of the top causes of death, particularly among women, and it affects many women. Cancer can also be caused by various factors, including acquiring genetic alteration. Doctors use radiation to detect and treat breast cancer. As a result, breast cancer becomes radiation-resistant, necessitating a new strategy for its treatment. The approach discovered by the researchers is a flavonoid, which is being researched to see if it might help treat radiation-resistant breast cancer more safely than an approved medicine already being used in the field. As a result, this study focuses on the role of flavonoids in breast cancer suppression, breast cancer gene anomalies, and the resulting apoptotic mechanism.
Collapse
Affiliation(s)
- Min Yeong Park
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| | - Yoonjung Kim
- College of Nursing, Konyang University Medical Campus, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea;
| | - Sang Eun Ha
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Korea
| | - Hun Hwan Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| | - Pritam Bhangwan Bhosale
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| | - Abuyaseer Abusaliya
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| | - Se Hyo Jeong
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| | - Gon Sup Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (M.Y.P.); (S.E.H.); (H.H.K.); (P.B.B.); (A.A.); (S.H.J.)
| |
Collapse
|
|
7
|
Bajalia EM, Azzouz FB, Chism DA, Giansiracusa DM, Wong CG, Plaskett KN, Bishayee A. Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms. Cancers (Basel) 2022; 14:3278. [PMID: 35805049 PMCID: PMC9265746 DOI: 10.3390/cancers14133278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/26/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
Renal cell carcinoma (RCC) is associated with about 90% of renal malignancies, and its incidence is increasing globally. Plant-derived compounds have gained significant attention in the scientific community for their preventative and therapeutic effects on cancer. To evaluate the anticancer potential of phytocompounds for RCC, we compiled a comprehensive and systematic review of the available literature. Our work was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. The literature search was performed using scholarly databases such as PubMed, Scopus, and ScienceDirect and keywords such as renal cell carcinoma, phytochemicals, cancer, tumor, proliferation, apoptosis, prevention, treatment, in vitro, in vivo, and clinical studies. Based on in vitro results, various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, suppressed cell viability, proliferation and growth, showed cytotoxic activity, inhibited invasion and migration, and enhanced the efficacy of chemotherapeutic drugs in RCC. In various animal tumor models, phytochemicals suppressed renal tumor growth, reduced tumor size, and hindered angiogenesis and metastasis. The relevant antineoplastic mechanisms involved upregulation of caspases, reduction in cyclin activity, induction of cell cycle arrest and apoptosis via modulation of a plethora of cell signaling pathways. Clinical studies demonstrated a reduced risk for the development of kidney cancer and enhancement of the efficacy of chemotherapeutic drugs. Both preclinical and clinical studies displayed significant promise of utilizing phytochemicals for the prevention and treatment of RCC. Further research, confirming the mechanisms and regulatory pathways, along with randomized controlled trials, are needed to establish the use of phytochemicals in clinical practice.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; (E.M.B.); (F.B.A.); (D.A.C.); (D.M.G.); (C.G.W.); (K.N.P.)
| |
Collapse
|
|
8
|
Alam M, Alam S, Shamsi A, Adnan M, Elasbali AM, Al-Soud WA, Alreshidi M, Hawsawi YM, Tippana A, Pasupuleti VR, Hassan MI. Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer. Front Oncol 2022; 12:869672. [PMID: 35402265 PMCID: PMC8990771 DOI: 10.3389/fonc.2022.869672] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Non-small cell lung carcinoma (NSCLC) comprises 80%-85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC.
Collapse
Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
| | - Shoaib Alam
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, India
| | - Anas Shamsi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Abdelbaset Mohamed Elasbali
- Department of Clinical Laboratory Science, College of Applied Sciences-Qurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Waleed Abu Al-Soud
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
- Health Sciences Research Unit, Jouf University, Sakaka, Saudi Arabia
| | - Mousa Alreshidi
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
- Molecular Diagnostics and Personalized Therapeutics Unit, University of Hail, Hail, Saudi Arabia
| | | | - Anitha Tippana
- Regional Agricultural Research Station, Acharya N. G. Ranga Agricultural University (ANGRAU), Tirupati, India
| | - Visweswara Rao Pasupuleti
- Department of Biomedical Sciences and Therapeutics, Faculty of Medicine & Health Sciences, University Malaysia Sabah, Kota Kinabalu, Malaysia
- Department of Biochemistry, Faculty of Medicine and Health Sciences, Abdurrab University, Pekanbaru, Indonesia
- Centre for International Collaboration and Research, Reva University, Rukmini Knowledge Park, Bangalore, India
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
| |
Collapse
|
|
9
|
Alhakamy NA, Okbazghi SZ, A. Alfaleh M, H. Abdulaal W, Bakhaidar RB, Alselami MO, Zahrani MAL, Alqarni HM, F. Alghaith A, Alshehri S, Badr-Eldin SM, Aldawsari HM, Al-hejaili OD, Aldhabi BM, Mahdi WA. Wasp venom peptide improves the proapoptotic activity of alendronate sodium in A549 lung cancer cells. PLoS One 2022; 17:e0264093. [PMID: 35202419 PMCID: PMC8872391 DOI: 10.1371/journal.pone.0264093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/02/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Lung cancer in men and women is considered the leading cause for cancer-related mortality worldwide. Anti-cancer peptides represent a potential untapped reservoir of effective cancer therapy. METHODOLOGY Box-Behnken response surface design was applied for formulating Alendronate sodium (ALS)-mastoparan peptide (MP) nanoconjugates using Design-Expert software. The optimization process aimed at minimizing the size of the prepared ALS-MP nanoconjugates. ALS-MP nanoconjugates' particle size, encapsulation efficiency and the release profile were determined. Cytotoxicity, cell cycle, annexin V staining and caspase 3 analyses on A549 cells were carried out for the optimized formula. RESULTS The results revealed that the optimized formula was of 134.91±5.1 nm particle size. The novel ALS-MP demonstrated the lowest IC50 (1.3 ± 0.34 μM) in comparison to ALS-Raw (37.6 ± 1.79 μM). Thus, the results indicated that when optimized ALS-MP nanoconjugate was used, the IC50 of ALS was also reduced by half. Cell cycle analysis demonstrated a significantly higher percentage of cells in the G2-M phase following the treatment with optimized ALS-MP nanoconjugates. CONCLUSION The optimized ALS-MP formula had significantly improved the parameters related to the cytotoxic activity towards A549 cells, compared to control, MP and ALS-Raw.
Collapse
Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Solomon Z. Okbazghi
- Global Analytical and Pharmaceutical Development, Alexion Pharmaceuticals, New Haven, Connecticut, United States of America
| | - Mohamed A. Alfaleh
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wesam H. Abdulaal
- Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rana B. Bakhaidar
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed O. Alselami
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Majed AL Zahrani
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani M. Alqarni
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adel F. Alghaith
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Pharmaceutical Sciences, College of Pharmacy, Almaarefa University, Ad Diriyah, Saudi Arabia
| | - Shaimaa M. Badr-Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hibah M. Aldawsari
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Omar D. Al-hejaili
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Bander M. Aldhabi
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wael A. Mahdi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
10
|
Phua CYH, Teoh ZL, Goh BH, Yap WH, Tang YQ. Triangulating the pharmacological properties of thymoquinone in regulating reactive oxygen species, inflammation, and cancer: Therapeutic applications and mechanistic pathways. Life Sci 2021; 287:120120. [PMID: 34762903 DOI: 10.1016/j.lfs.2021.120120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/24/2021] [Accepted: 11/01/2021] [Indexed: 12/29/2022]
Abstract
Cancer is a heterogeneous disease with high morbidity and mortality rate involving changes in redox balance and deregulation of redox signalling. For decades, studies have involved developing an effective cancer treatment to combat treatment resistance. As natural products such as thymoquinone have numerous health benefits, studies are also focusing on using them as a viable method for cancer treatment, as they have minimal toxic effects compared with standard cancer treatments. Thymoquinone studies have shown numerous mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signalling pathways as well as immunomodulatory effects in vitro and in vivo. Thymoquinone's anti-cancer effect is mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-tumour cell proliferation, ROS regulation, hypoxia and anti-metastasis. Insight into thymoquinone's potential as an alternative treatment for chemoprevention and inflammation can be accomplished via compiling these studies, to provide a better understanding on how and why it works, as well as its interactions with common chemotherapeutic treatments.
Collapse
Affiliation(s)
- Caroline Yuin Hueii Phua
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia
| | - Zhi Ling Teoh
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia; College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, PR China
| | - Wei Hsum Yap
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia; Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
| | - Yin-Quan Tang
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia; Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
| |
Collapse
|
|
11
|
Asfour HZ, Fahmy UA, Alharbi WS, Almehmady AM, Alamoudi AJ, Tima S, Mansouri RA, Omar UM, Ahmed OAA, Zakai SA, Aldarmahi AA, Bagalagel A, Diri R, Alhakamy NA. Phyto-Phospholipid Conjugated Scorpion Venom Nanovesicles as Promising Carrier That Improves Efficacy of Thymoquinone against Adenocarcinoma Human Alveolar Basal Epithelial Cells. Pharmaceutics 2021; 13:2144. [PMID: 34959424 PMCID: PMC8709205 DOI: 10.3390/pharmaceutics13122144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/05/2021] [Accepted: 12/10/2021] [Indexed: 01/15/2023] Open
Abstract
Lung cancer is a dangerous type of cancer in men and the third leading cause of cancer-related death in women, behind breast and colorectal cancers. Thymoquinone (THQ), a main compound in black seed essential oils, has a variety of beneficial effects, including antiproliferative, anti-inflammatory, and antioxidant properties. On the other hand, scorpion venom peptides (SV) induce apoptosis in the cancer cells, making it a promising anticancer agent. THQ, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess THQ's cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human alveolar epithelial cells (A549). Several nanovesicles were prepared and optimized using factorial experimental design. The optimized phytosome formulation contained 79.0 mg of PL and 170.0 mg of SV, with vesicle size and zeta potential of 209.9 nm and 21.1 mV, respectively. The IC50 values revealed that A549 cells were significantly more sensitive to the THQ formula than the plain formula and THQ. Cell cycle analysis revealed that THQ formula treatment resulted in significant cell cycle arrest at the S phase, increasing cell population in this phase by 22.1%. Furthermore, the THQ formula greatly increased cell apoptosis (25.17%) when compared to the untreated control (1.76%), plain formula (11.96%), or THQ alone (13.18%). The results also indicated that treatment with THQ formula significantly increased caspase-3, Bax, Bcl-2, and p53 mRNA expression compared to plain formula and THQ. In terms of the inflammatory markers, THQ formula significantly reduced the activity of TNF-α and NF-κB in comparison with the plain formula and THQ only. Overall, the findings from the study proved that a phytosome formulation of THQ could be a promising therapeutic approach for the treatment of lung adenocarcinoma.
Collapse
Affiliation(s)
- Hani Z. Asfour
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (H.Z.A.); (S.A.Z.)
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
| | - Waleed S. Alharbi
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Alshaimaa M. Almehmady
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
| | - Abdulmohsin J. Alamoudi
- Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Singkome Tima
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Rasha A. Mansouri
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (R.A.M.); (U.M.O.)
| | - Ulfat M. Omar
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (R.A.M.); (U.M.O.)
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Shadi A. Zakai
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (H.Z.A.); (S.A.Z.)
| | - Ahmed A. Aldarmahi
- College of Sciences and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia;
| | - Alaa Bagalagel
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.B.); (R.D.)
| | - Reem Diri
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (A.B.); (R.D.)
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (W.S.A.); (A.M.A.); (O.A.A.A.); (N.A.A.)
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| |
Collapse
|
|
12
|
A Fast Ubiquitination of UHRF1 Oncogene Is a Unique Feature and a Common Mechanism of Thymoquinone in Cancer Cells. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11167633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Downregulation of the ubiquitin-like containing PHD and ring finger 1 (UHRF1) oncogene in cancer cells in response to natural anticancer drugs, including thymoquinone (TQ), is a key event that induces apoptosis. TQ can induce UHRF1 autoubiquitination via the E3 ligase activity of its RING domain, most likely through the downregulation of herpes virus-associated ubiquitin-specific protease (HAUSP). In this study, we evaluated whether HAUSP downregulation and fast ubiquitination of UHRF1 are prerequisites for UHRF1 degradation in response to TQ in cancer cells and whether doxorubicin can mimic the effects of TQ on UHRF1 ubiquitination. RNA sequencing was performed to investigate differentially expressed genes in TQ-treated Jurkat cells. The protein expression of UHRF1, HAUSP and Bcl-2 was detected by means of Western blot analysis. The proliferation of human colon cancer (HCT-116) and Jurkat cells was analyzed via the WST-1 assay. RNA sequencing data revealed that TQ significantly decreased HAUSP expression. TQ triggered UHRF1 to undergo rapid ubiquitination as the first step in its degradation and the inhibition of its cell proliferation. TQ-induced UHRF1 ubiquitination is associated with HAUSP downregulation. Like TQ, doxorubicin induced a similar dose- and time-dependent downregulation of UHRF1 in cancer cells, but UHRF1 did not undergo ubiquitination as detected in response to TQ. Furthermore, TQ decreased Bcl-2 expression without triggering its ubiquitination. A fast UHRF1 ubiquitination is an indispensable event for its degradation in response to TQ but not for its responses to doxorubicin. TQ appears to trigger ubiquitination of UHRF1 but not of the Bcl-2 oncogene, thereby identifying UHRF1 as a specific target of TQ for cancer therapy.
Collapse
|
|
13
|
Fatfat Z, Fatfat M, Gali-Muhtasib H. Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells. World J Clin Oncol 2021; 12:522-543. [PMID: 34367926 PMCID: PMC8317652 DOI: 10.5306/wjco.v12.i7.522] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects, resistance to treatment and cancer relapse. These monotherapeutic strategies shrink the tumor bulk but do not effectively eliminate the population of self-renewing cancer stem cells (CSCs) that are normally present within the tumor. These surviving CSCs develop mechanisms of resistance to treatment and refuel the tumor, thus causing cancer relapse. To ensure durable tumor control, research has moved away from adopting the monotreatment paradigm towards developing and using combination therapy. Combining different therapeutic modalities has demonstrated significant therapeutic outcomes by strengthening the anti-tumor potential of monotreatment against cancer and cancer stem cells, mitigating their toxic adverse effects, and ultimately overcoming resistance. Recently, there has been growing interest in combining natural products from different sources or with clinically used chemotherapeutics to further improve treatment efficacy and tolerability. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention in combination therapy research after demonstrating its low toxicity to normal cells and remarkable anticancer efficacy in extensive preclinical studies in addition to its ability to target chemoresistant CSCs. Here, we provide an overview of the therapeutic responses resulting from combining TQ with conventional therapeutic agents such as alkylating agents, antimetabolites and antimicrotubules as well as with topoisomerase inhibitors and non-coding RNA. We also review data on anticancer effects of TQ when combined with ionizing radiation and several natural products such as vitamin D3, melatonin and other compounds derived from Chinese medicinal plants. The focus of this review is on two outcomes of TQ combination therapy, namely eradicating CSCs and treating various types of cancers. In conclusion, the ability of TQ to potentiate the anticancer activity of many chemotherapeutic agents and sensitize cancer cells to radiotherapy makes it a promising molecule that could be used in combination therapy to overcome resistance to standard chemotherapeutic agents and reduce their associated toxicities.
Collapse
Affiliation(s)
- Zaynab Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Maamoun Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
- Center for Drug Discovery, American University of Beirut, Beirut 1107 2020, Lebanon
| |
Collapse
|
|
14
|
Sarkar C, Jamaddar S, Islam T, Mondal M, Islam MT, Mubarak MS. Therapeutic perspectives of the black cumin component thymoquinone: A review. Food Funct 2021; 12:6167-6213. [PMID: 34085672 DOI: 10.1039/d1fo00401h] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The dietary phytochemical thymoquinone (TQ), belonging to the family of quinones, mainly obtained from the black and angular seeds of Nigella sativa, is one of the promising monoterpenoid hydrocarbons, which has been receiving massive attention for its therapeutic potential and pharmacological properties. It plays an important role as a chemopreventive and therapeutic agent in the treatment of various diseases and illnesses. The aim of this review is to present a summary of the most recent literature pertaining to the use of TQ for the prevention and treatment of various diseases along with possible mechanisms of action, and the potential use of this natural product as a complementary or alternative medicine. Research findings indicated that TQ exhibits numerous pharmacological activities including antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, antidiabetic, neuroprotective, and anticancer, among others. Conclusions of this review on the therapeutic aspects of TQ highlight the medicinal and folk values of this compound against various diseases and ailments. In short, TQ could be a novel drug in clinical trials, as we hope.
Collapse
Affiliation(s)
- Chandan Sarkar
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh.
| | | | | | | | | | | |
Collapse
|
|
15
|
Zhang R, Wu T, Zheng P, Liu M, Xu G, Xi M, Yu J. Thymoquinone sensitizes human hepatocarcinoma cells to TRAIL-induced apoptosis via oxidative DNA damage. DNA Repair (Amst) 2021; 103:103117. [PMID: 33990030 DOI: 10.1016/j.dnarep.2021.103117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/23/2021] [Accepted: 04/06/2021] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) remains one of the most predominant types of digestive system malignancies worldwide. TNF-related apoptosis-inducing ligand (TRAIL) is a biological cytokine with the mentioned specificity, but some tumor cells' resistance limits its use as a therapeutic approach. The present study aimed to investigate thymoquinone (TQ) and TRAIL's combined effect and the potential mechanisms in human hepatic HepG2 carcinoma cells. METHODS Cell viability and IC50 dose for TQ and TRAIL, alone and in combination, were determined using the MTT method. ELISA evaluated the expression levels of 8-Hydroxy-2'-deoxyguanosine. The apoptosis rate was assessed by flow cytometry, ELISA cell death assay, and caspase 8 activity assays. The mRNA and protein evaluation of candidate genes, including survivin, Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP, were accomplished before and after the treatment using qRT-PCR and Western blot analysis, respectively. RESULTS Our results showed that TQ synergistically increased TRAIL's cell toxic effects as follows: TQ plus TRAIL > TRAIL > TQ. TQ could sensitize the HepG2 cells against the TRAIL-induced apoptosis and amplify the caspase 8 activity. This outcome is achieved by decreasing the mRNA and protein expression levels of anti-apoptotic genes. CONCLUSIONS Our findings suggest that TQ can sensitize the human HCC cell line HepG2 against TRAIL by inducing the death receptor pathway. Moreover, these agents' combinational therapy might promise a therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with HCC.
Collapse
Affiliation(s)
- Ruikui Zhang
- Department of Special Emergency Surgery, Special Medical Center of Chinese People 's Armed Police Forces, Tianjin, 300162, China
| | - Tao Wu
- Department of Infectious Disease, Hainan General Hospital, Haikou, Hainan, 570311, China
| | - Peipei Zheng
- Department of General Surgery, the First Hospital Affiliated of Shandong First Medical University (Qianfoshan Hospital), Jinan, Shandong, 250014, China
| | - Ming Liu
- Department of Infectious Disease, Hainan General Hospital, Haikou, Hainan, 570311, China
| | - Guixiang Xu
- Department of General Surgery, Qingdao Fuwai Hospital Qingdao, Shandong, 266034, China
| | - Ming Xi
- Department of Urology, Huadu District People's Hospital, Southern Medical University, Guangzhou, Guangdong, 510800, China
| | - Jian Yu
- Department of General Surgery, the First Hospital Affiliated of Shandong First Medical University (Qianfoshan Hospital), Jinan, Shandong, 250014, China.
| |
Collapse
|
|
16
|
Ansary J, Giampieri F, Forbes-Hernandez TY, Regolo L, Quinzi D, Gracia Villar S, Garcia Villena E, Tutusaus Pifarre K, Alvarez-Suarez JM, Battino M, Cianciosi D. Nutritional Value and Preventive Role of Nigella sativa L. and Its Main Component Thymoquinone in Cancer: An Evidenced-Based Review of Preclinical and Clinical Studies. Molecules 2021; 26:molecules26082108. [PMID: 33916916 PMCID: PMC8067617 DOI: 10.3390/molecules26082108] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/31/2021] [Accepted: 04/03/2021] [Indexed: 11/16/2022] Open
Abstract
In recent times, scientific attention has been paid to different foods and their bioactive components for the ability to inhibit the onset and progress of different types of cancer. Nigella sativa extract, powder and seed oil and its main components, thymoquinone and α-hederin, have showed potent anticancer and chemosensitizing effects against various types of cancer, such as liver, colon, breast, renal, cervical, lung, ovarian, pancreatic, prostate and skin tumors, through the modulation of various molecular signaling pathways. Herein, the purpose of this review was to highlight the anticancer activity of Nigella sativa and it constitutes, focusing on different in vitro, in vivo and clinical studies and projects, in order to underline their antiproliferative, proapoptotic, cytotoxic and antimetastatic effects. Particular attention has been also given to the synergistic effect of Nigella sativa and it constitutes with chemotherapeutic drugs, and to the synthesized analogs of thymoquinone that seem to enhance the chemo-sensitizing potential. This review could be a useful step towards new research on N. sativa and cancer, to include this plant in the dietary treatments in support to conventional therapies, for the best achievement of therapeutic goals.
Collapse
Affiliation(s)
- Johura Ansary
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
| | - Francesca Giampieri
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Tamara Y. Forbes-Hernandez
- Nutrition and Food Science Group, Department of Analytical and Food Chemistry, CITACA, CACTI, University of Vigo, 36310 Vigo, Spain;
| | - Lucia Regolo
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
| | - Denise Quinzi
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
| | - Santos Gracia Villar
- Research Center for Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain; (S.G.V.); (E.G.V.); (K.T.P.)
- Research Center for Foods, Nutritional Biochemistry and Health, Universidad Internacional Iberoamericana, Campeche 24560, Mexico
| | - Eduardo Garcia Villena
- Research Center for Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain; (S.G.V.); (E.G.V.); (K.T.P.)
| | - Kilian Tutusaus Pifarre
- Research Center for Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain; (S.G.V.); (E.G.V.); (K.T.P.)
- Research Center for Foods, Nutritional Biochemistry and Health, Universidad Internacional Iberoamericana, Campeche 24560, Mexico
| | - José M. Alvarez-Suarez
- Departamento de Ingeniería en Alimentos, Colegio de Ciencias e Ingenierías, Universidad San Francisco de Quito, Quito 170157, Ecuador
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: (J.M.A.-S.); (M.B.); (D.C.); Tel.: +593-2-297-1700 (J.M.A.-S.); +339-071-220-4646 (M.B.); +339-071-220-4136 (D.C.)
| | - Maurizio Battino
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
- Correspondence: (J.M.A.-S.); (M.B.); (D.C.); Tel.: +593-2-297-1700 (J.M.A.-S.); +339-071-220-4646 (M.B.); +339-071-220-4136 (D.C.)
| | - Danila Cianciosi
- Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (J.A.); (F.G.); (L.R.); (D.Q.)
- Correspondence: (J.M.A.-S.); (M.B.); (D.C.); Tel.: +593-2-297-1700 (J.M.A.-S.); +339-071-220-4646 (M.B.); +339-071-220-4136 (D.C.)
| |
Collapse
|
|
17
|
Elgohary S, Elkhodiry AA, Amin NS, Stein U, El Tayebi HM. Thymoquinone: A Tie-Breaker in SARS-CoV2-Infected Cancer Patients? Cells 2021; 10:302. [PMID: 33540625 PMCID: PMC7912962 DOI: 10.3390/cells10020302] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022] Open
Abstract
Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-2) pandemic, arace to develop a vaccine has been initiated, considering the massive and rather significant economic and healthcare hits that this virus has caused. The pathophysiology occurring following COVID-19(coronavirus disease-2019) infection has givenhints regarding the supportive and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications. Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients are at higher risk of viral infection and more likely to develop serious complications due to their immunocompromised state, the fact that they are already administering multiple medications, as well as combined comorbidity compared to the general population. It may seem impossible to find a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19 infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive COVID-19 therapy and cancer therapy, and finally, its anticancer effects.
Collapse
Affiliation(s)
- Sawsan Elgohary
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Aya A. Elkhodiry
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Nada S. Amin
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Hend M. El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| |
Collapse
|
|
18
|
Mehanna MM, Sarieddine R, Alwattar JK, Chouaib R, Gali-Muhtasib H. Anticancer Activity of Thymoquinone Cubic Phase Nanoparticles Against Human Breast Cancer: Formulation, Cytotoxicity and Subcellular Localization. Int J Nanomedicine 2020; 15:9557-9570. [PMID: 33293807 PMCID: PMC7718962 DOI: 10.2147/ijn.s263797] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/15/2020] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Triple negative breast cancer is an aggressive disorder which accounts for at least 15% of breast cancer diagnosis and a high percentage of breast cancer morbidity, hence intensive research efforts are focused on the development of effective therapies to overcome the disease. Thymoquinone (TQ), the bioactive constituent of Nigella sativa, exhibits anticancer activity, yet its translation to the clinic is hindered by its poor bioavailability and lack of quantification method in blood and tissues. To overcome these limitations, cubosomes were utilized for the encapsulation and delivery of this anticancer molecule. METHODS Thymoquinone loaded cubosomes were prepared through the emulsification homogenization method. The physicochemical characteristics, including particle size, zeta potential, morphology and entrapment efficiency, were studied. Moreover, the in vitro antitumor activity was tested on breast cancer cell lines (MCF-7 and MDA-MB-231) and compared to non-tumorigenic cell line (MCF-10A). Subcellular localization, cellular uptake and apoptotic effects of the formulations were assessed. RESULTS The results revealed that the TQ loaded cubosomal formulation exhibited a mean particle size of 98.0 ± 4.10 nm with narrow unimodal distribution. The high entrapment efficiency (96.60 ± 3.58%) and zeta potential (31.50 ±4.20 mV) conceived the effectiveness of this nanosystem for TQ encapsulation. Cell viability in both breast cancer cell lines demonstrated a dose-dependent decrease in response to treatment with free TQ or TQ-loaded cubosomes, with enhanced antitumor activity upon treating with the latter formulation. A significant increase in apoptotic bodies and cleaved caspase 3 was observed upon treatment of MDA-MB-231 cells with either TQ or TQ-loaded cubosomes. Localization and trafficking studies unveiled that cubosomes accumulate in the cytoplasm of the studied breast cancer cell lines. DISCUSSION Our results show that thymoquinone encapsulation in cubosomal nanoparticles provides a promising anticancer drug delivery system with the ability to label, detect and subsequently trace it within the human cells.
Collapse
Affiliation(s)
- Mohammed M Mehanna
- Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon
| | - Rana Sarieddine
- Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| | - Jana K Alwattar
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon
| | - Racha Chouaib
- Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| |
Collapse
|
|
19
|
Almatroodi SA, Almatroudi A, Alsahli MA, Khan AA, Rahmani AH. Thymoquinone, an Active Compound of Nigella sativa: Role in Prevention and Treatment of Cancer. Curr Pharm Biotechnol 2020; 21:1028-1041. [DOI: 10.2174/1389201021666200416092743] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 11/30/2019] [Accepted: 02/11/2020] [Indexed: 12/18/2022]
Abstract
Background:
Cancer is the leading cause of death worldwide and the current mode of cancer
treatment causes side effects on normal cells and are still the key challenges in its’ treatment. However,
natural products or active compounds of medicinal plants have shown to be safe, affordable, and
effective in diseases cure.
Methods:
In this context, scientific studies evidence the health-promoting effects of natural products,
which work through its anti-oxidant, anti-inflammatory, and anti-cancer activity. Thymoquinone (TM),
a predominant active compound of Nigella sativa, has confirmed anti-neoplastic activity through its
ability to regulate various genetic pathways. In addition, thymoquinone has established anti-cancerous
effects through killing of various cancerous cells,and inhibiting the initiation, migration, invasion, and
progression of the cancer. The anti-cancer effects of TM are chiefly mediated via regulating various
cell signaling pathways such as VEGF, bcl2/bax ratio, p53, NF-kB, and oncogenes.
Results:
The anti-cancer drugs have limitations in efficacy and also causes adverse side effects on
normal cells. The combination of anti-cancer drugs and thymoquinone improves the efficacy of drugs
which is evident by decrease resistance to drugs and regulation of various cell signaling pathways.
Moreover, combination of anti-cancer drugs as well as thymoquinone shows synergistic effect on killing
of cancer cells and cells viability. Thus, TM, in combination with anti-cancer drugs, can be a good
strategy in the management of various types of cancer.
Conclusion:
In this review article, we deliver an outline of thymoquinone role in cancer inhibition and
prevention of cancer-based on in vivo and in vitro studies. Further studies on thymoquinone based on
clinical trials are highly required to explore the benefits of thymoquinone in cancer management.
Collapse
Affiliation(s)
- Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Mohammed A. Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Amjad A. Khan
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| | - Arshad H. Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraidah, Saudi Arabia
| |
Collapse
|
|
20
|
A. Fahmy U, A.A. Ahmed O, A. El-mose M, Asfour HZ, Alhakamy NA. Thymoquinone Loaded Zein Nanoparticles Improves the Cytotoxicity against Breast Cancer Cells. INT J PHARMACOL 2020. [DOI: 10.3923/ijp.2020.554.561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
|
21
|
Alhakamy NA, Badr-Eldin SM, Fahmy UA, Alruwaili NK, Awan ZA, Caruso G, Alfaleh MA, Alaofi AL, Arif FO, Ahmed OAA, Alghaith AF. Thymoquinone-Loaded Soy-Phospholipid-Based Phytosomes Exhibit Anticancer Potential against Human Lung Cancer Cells. Pharmaceutics 2020; 12:E761. [PMID: 32806507 PMCID: PMC7463966 DOI: 10.3390/pharmaceutics12080761] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022] Open
Abstract
Thymoquinone (TQ), a natural polyphenol, has been associated with various pharmacological responses; however, low bioavailability of TQ limits its clinical application. Thus, a novel phytosomal delivery system of TQ-Phospholipon® 90H complex (TQ-phytosome) was developed by refluxing combined with anti-solvent precipitation. This TQ delivery system was optimized by a three-factor, three-level Box-Behnken design. The optimized TQ-phytosome size was (45.59 ± 1.82 nm) and the vesicle size was confirmed by transmission electron microscopy. The in vitro release pattern of the formulation indicated a biphasic release pattern, where an initial burst release was observed within 2 h, followed by a prolonged release. A remarkable increase in dose-dependent cytotoxicity was evident from the significant decrease in IC50 value of TQ-phytosomes (4.31 ± 2.21 µM) against the A549 cell line. The differential effect of TQ-phytosomes in cell cycle analysis was observed, where cancer cells were accumulated on G2-M and pre-G1 phases. Furthermore, increased apoptotic induction and cell necrosis of TQ-phytosomes were revealed with the annexin V staining technique via activation of caspase-3. In reactive oxygen species (ROS) analysis, TQ-phytosomes acted to significantly increase ROS generation in A549 cells. In conclusion, the sustained release profile with significantly-improved anticancer potential could be obtained with TQ by this phytosomal nanocarrier platform.
Collapse
Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.)
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Shaimaa M. Badr-Eldin
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.)
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.)
| | - Nabil K. Alruwaili
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Al-Jouf 2014, Saudi Arabia;
| | - Zuhier A. Awan
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Giuseppe Caruso
- Oasi Research Institute—IRCCS, Via Conte Ruggero, 73, 94018 Troina (EN), Italy;
| | - Mohamed A. Alfaleh
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Ahmed L. Alaofi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (A.L.A.); (A.F.A.)
| | - Faris O Arif
- General Surgery KAUH, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia;
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (S.M.B.-E.); (O.A.A.A.)
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Adel F. Alghaith
- Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (A.L.A.); (A.F.A.)
| |
Collapse
|
|
22
|
Novel thymoquinone lipidic core nanocapsules with anisamide-polymethacrylate shell for colon cancer cells overexpressing sigma receptors. Sci Rep 2020; 10:10987. [PMID: 32620860 PMCID: PMC7335198 DOI: 10.1038/s41598-020-67748-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/12/2020] [Indexed: 12/18/2022] Open
Abstract
The biggest challenge in colorectal cancer therapy is to avoid intestinal drug absorption before reaching the colon, while focusing on tumor specific delivery with high local concentration and minimal toxicity. In our work, thymoquinone (TQ)-loaded polymeric nanocapsules were prepared using the nanoprecipitation technique using Eudragit S100 as polymeric shell. Conjugation of anisamide as a targeting ligand for sigma receptors overexpressed by colon cancer cells to Eudragit S100 was carried out via carbodiimide coupling reaction, and was confirmed by thin layer chromatography and 1H-NMR. TQ nanocapsules were characterized for particle size, surface morphology, zeta potential, entrapment efficiency % (EE%), in vitro drug release and physical stability. A cytotoxicity study on three colon cancer cell lines (HT-29, HCT-116, Caco-2) was performed. Results revealed that the polymeric nanocapsules were successfully prepared, and the in vitro characterization showed a suitable size, zeta potential, EE% and physical stability. TQ exhibited a delayed release pattern from the nanocapsules in vitro. Anisamide-targeted TQ nanocapsules showed higher cytotoxicity against HT-29 cells overexpressing sigma receptors compared to their non-targeted counterparts and free TQ after incubation for 48 h, hence delineating anisamide as a promising ligand for active colon cancer targeting.
Collapse
|
|
23
|
Houssein M, Fatfat M, Habli Z, Ghazal N, Moodad S, Khalife H, Khalil M, Gali-Muhtasib H. Thymoquinone synergizes with arsenic and interferon alpha to target human T-cell leukemia/lymphoma. Life Sci 2020; 251:117639. [PMID: 32272181 DOI: 10.1016/j.lfs.2020.117639] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 04/01/2020] [Accepted: 04/01/2020] [Indexed: 12/11/2022]
Abstract
AIMS To reduce the dose of arsenic used against human T-cell leukemia/lymphoma and to sensitize cells to drug treatment, we combined arsenic/interferon-alpha (As/IFN-α) with thymoquinone (TQ) in HTLV-I positive (HuT-102 and C91) and HTLV-1 negative (CEM and Jurkat) cell lines. MAIN METHODS Cells were treated with TQ, As/IFN-α and combinations. Trypan blue and flow cytometry were used to investigate viability and cell cycle effects. Annexin-V staining, rhodamine assay and western blotting were used to determine apoptosis induction and changes in protein expression. Efficacy of single drugs and combinations were tested in adult T-cell leukemia (HuT-102) mouse xenograft model. KEY FINDINGS TQ/As/IFN-α led to a more pronounced and synergistic time-dependent inhibitory effect on HTLV-I positive cells in comparison to As/IFN-α. While As/IFN-α combination was not effective against CEM or Jurkat cells, the triple combination TQ/As/IFN-α sensitized these two cell lines and led to a pronounced time-dependent inhibition of cell viability. TQ/As/IFN-α significantly induced apoptosis in all four cell lines and disrupted the mitochondrial membrane potential. Apoptosis was confirmed by the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), downregulation of Bcl-2 and XIAP and upregulation of Bax. TQ alone or in combination activated p53 in HTLV-1 positive cell lines. Strikingly, TQ/As/IFN-α resulted in a pronounced significant decrease in tumor volume in HuT-102 xenograft mouse model, as compared to separate treatments or double combination therapy. SIGNIFICANCE Our results suggest a strong potential for TQ to enhance the drug targeting effects of the standard clinical drugs As and IFN-α against CD4+ malignant T-cells.
Collapse
Affiliation(s)
- Marwa Houssein
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Lebanon
| | - Maamoun Fatfat
- Center for Drug Discovery, American University of Beirut, Lebanon
| | - Zeina Habli
- Center for Drug Discovery, American University of Beirut, Lebanon
| | - Nasab Ghazal
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon
| | - Sara Moodad
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon; Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Lebanon
| | - Hala Khalife
- Rammal Laboratory (ATAC), Faculty of Sciences I, Lebanese University Hadath, Beirut, Lebanon
| | - Mahmoud Khalil
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon; Center for Drug Discovery, American University of Beirut, Lebanon.
| |
Collapse
|
|
24
|
Stelmashook EV, Chetverikov NS, Golyshev SA, Genrikhs EE, Isaev NK. Thymoquinone Induces Mitochondrial Damage and Death of Cerebellar Granule Neurons. BIOCHEMISTRY (MOSCOW) 2020; 85:205-212. [PMID: 32093596 DOI: 10.1134/s0006297920020078] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Thymoquinone (TQ) exhibits a wide spectrum of biological activities. Most studies on the neurotoxic action of TQ have been carried out in cancer cell lines. Here, we studied the toxic effect of TQ in primary neuronal cultures in vitro. Incubation with 0.04-0.05 mM TQ for 24 h induced the death of cultured cerebellar granule neurons (CGNs) in a dose-dependent manner. Neuronal death was preceded by an increase in the reactive oxygen species (ROS) generation, as demonstrated using CellROX Green and MitoSOX Red. Confocal and electron microscopy showed that incubation with 0.05 mM TQ for 5 h induced changes in the intracellular localization of mitochondria and mitochondria hypertrophy and cell swelling. The antioxidant N-acetyl-L-cysteine (2 mM) protected CGNs from the toxic action of TQ. Taken together, these facts suggest that TQ is toxic for normal neurons, while ROS-induced changes in the mitochondria can be one of the major causes of the TQ-induced neuronal damage and death.
Collapse
Affiliation(s)
| | - N S Chetverikov
- Lomonosov Moscow State University, Biological Faculty, Moscow, 119234, Russia
| | - S A Golyshev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - E E Genrikhs
- Research Center of Neurology, Moscow, 125367, Russia
| | - N K Isaev
- Research Center of Neurology, Moscow, 125367, Russia. .,Lomonosov Moscow State University, Biological Faculty, Moscow, 119234, Russia
| |
Collapse
|
|
25
|
Sheng W, Yang H, Niu Z, Yin H. Anti-apoptosis effect of heme oxygenase-1 on lung injury after cardiopulmonary bypass. J Thorac Dis 2020; 12:1393-1403. [PMID: 32395277 PMCID: PMC7212168 DOI: 10.21037/jtd.2020.03.48] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Background This study aimed to investigate the anti-apoptosis effects of heme oxygenase-1 (HO-1) on lung injury (LI) after cardiopulmonary bypass (CPB) and its probable mechanisms. Methods One hundred and forty-four male Wistar rats were divided into 3 groups randomly: group A (control group), group B (cobalt protoporphyrin, CoPP), and group C [CoPP plus zinc protoporphyrin (ZnPP)]. Lung tissues were harvested at different time: before CPB (T0), 0 min after CPB (T1), 2 h after CPB (T2), 6 h (T3), 12 h (T4), and 24 h (T5). Results The HO-1 protein expressions in lung tissue in group B were higher than those in group A and group C in any given time, and the same as HO-1 activity (P<0.05). The expressions of Bcl-2 protein in group B at all time point after bypass were higher than those in group A and group C, and the difference was statistically significant (P<0.05). Apoptosis index (AI) in group B at any time point after bypass were lower than those in group A and group C (P<0.05). Conclusions CoPP can significantly increase the expression of HO-1 protein in lung tissue. HO-1 is still highly expressed after CPB, so as to play an important part in anti-apoptosis, and reduce LI.
Collapse
Affiliation(s)
- Wei Sheng
- Department of Cardiovascular Surgery, Qingdao Municipal Hospital, Medical College of Qingdao University, Qingdao 266071, China
| | - Haiqin Yang
- Department of Mental Intervention, Qingdao Preferential Hospital, Qingdao 266071, China
| | - Zhaozhuo Niu
- Department of Cardiovascular Surgery, Qingdao Municipal Hospital, Medical College of Qingdao University, Qingdao 266071, China
| | - Hong Yin
- Department of Cardiovascular Surgery, Qingdao Municipal Hospital, Medical College of Qingdao University, Qingdao 266071, China
| |
Collapse
|
|
26
|
Chae IG, Song NY, Kim DH, Lee MY, Park JM, Chun KS. Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect. Food Chem Toxicol 2020; 139:111253. [PMID: 32165235 DOI: 10.1016/j.fct.2020.111253] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 12/15/2022]
Abstract
Currently, there are limited effective treatment options for renal cell carcinoma (RCC), due to its poor responses to conventional therapies. Instead of using extrinsic anti-cancer drugs, cancer cell-intrinsic reactive oxygen species (ROS) can be a weapon of RCC treatment. In the present study, we found that the phytochemical thymoquinone (TQ), a bioactive natural product obtained from the black cumin seeds of Nigella sativa, generates intracellular ROS in human renal cancer Caki-1 cells. Treatment of Caki-1 cells with high concentration of TQ up-regulated pro-apoptotic p53 and Bax expression, while downregulated anti-apoptotic Bcl-2 and Bcl-xl expression. Simultaneously, TQ suppressed the pro-oncogenic JAK2/STAT3 pathway, resulting in decreased expression of Bcl-2, Bcl-xl, cyclin D1, cyclin D2, and survivin. Thus, TQ can integrate between apoptosis and the pro-survival JAK2/STAT3 pathway through the Bcl family members, collectively magnifying Caki-1 cell apoptosis. However, treatment with the ROS scavenger N-acetyl cysteine significantly blocked TQ-induced apoptosis as well as incorporated signaling pathways, supporting that its pro-oxidant property is crucial for Caki-1 cell apoptosis. Moreover, TQ reduced the tumor xenograft growth of Caki-1 cells in nude mice. Taken together, these data suggest that TQ is a prominent anti-cancer drug to treat human RCC by enhancing apoptosis through its pro-oxidant nature.
Collapse
Affiliation(s)
- In Gyeong Chae
- College of Pharmacy, Keimyung University, Daegu, 42601, South Korea
| | - Na-Young Song
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, 03722, South Korea
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do, 16227, South Korea
| | - Moo-Yeol Lee
- College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, 410-820, South Korea
| | - Jung-Min Park
- College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, 410-820, South Korea
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu, 42601, South Korea.
| |
Collapse
|
|
27
|
A multiple endpoint approach reveals potential in vitro anticancer properties of thymoquinone in human renal carcinoma cells. Food Chem Toxicol 2019; 136:111076. [PMID: 31883990 DOI: 10.1016/j.fct.2019.111076] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/28/2022]
Abstract
Thymoquinone (TQ) is a monoterpene isolated from the oil of Nigella sativa seeds. The aim of this work was to evaluate the cytotoxic effects induced by TQ and its impact on the migration and invasion potential of 786-O human renal cancer cells. These cells were exposed to TQ (1-100 μM) for 24 and 48 h and cell viability assessed using the Crystal Violet and MTS assays. TQ treatment clearly decreased cell viability in a concentration- and time-dependent manner. TQ exposure moderately increased intracellular ROS levels and co-incubation with reduced glutathione markedly increased cell viability. Moreover, the effect of TQ in the cell cycle distribution was evaluated using flow cytometry, and an increase in the sub-G1 population was observed, especially at 30 μM, along with an increase in the % of apoptotic cells. TQ did not show genotoxic effects at a non-cytotoxic concentration (1.0 μM). At this concentration level, TQ significantly decreased the collective migration of 786-O cells, whereas it had no effect in chemotactic migration. TQ also decreased the invasiveness potential of 786-O cells, as evaluated by the transwell invasion assay. Overall, these results suggest that TQ presents an anticancer potential in the context of renal cancer, warranting further investigation.
Collapse
|
|
28
|
Razmpoosh E, Safi S, Mazaheri M, Salehi-Abargouei A, Abdollahi N, Nazari M, Fallahzadeh H, Nadjarzadeh A. Effects of oral Nigella sativa oil on the expression levels and serum concentrations of adiponectin, PPAR-γ, and TNF-α in overweight and obese women: a study protocol for a crossover-designed, double-blind, placebo-controlled randomized clinical trial. Trials 2019; 20:512. [PMID: 31420057 PMCID: PMC6698025 DOI: 10.1186/s13063-019-3568-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 07/10/2019] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Obesity is a major public health problem in recent decades. The accumulation of excessive fat promotes inflammatory status. Meanwhile, herbal products are marketed for their weight-loss properties, such as Nigella sativa (N. Sativa) which has been used for centuries to treat rheumatoid arthritis, diabetes, and asthma; recently, the anti-obesity characteristics of N. sativa have also been indicated. However, the exact mechanisms and cellular-related pathways are still unclear. Thus, we will aim to assess the effects of oral N. sativa on the gene expression of inflammatory and adipogenesis-related factors, including TNF-α, PPAR-γ, and adiponectin as well as assessing their serum concentrations among obese and overweight individuals. METHODS Obese and overweight women aged 25-55 years with a body mass index (BMI) of 25-35 kg/m2 will be recruited from the Obesity Clinic in Shahid Sadoughi University of Medical Sciences and will be assessed for eligibility against inclusion criteria. They will be randomly assigned into two groups to receive either two capsules of N. sativa or two capsules of placebo per day for eight weeks (each capsule contains 1000 mg of N. sativa or placebo). There will be a four-week wash-out period and then participants will receive the reverse supplements for another eight weeks. Biochemical assessments and gene expressions (using real-time polymerase chain reaction) will be conducted at the beginning and at the end of every intervention period. DISCUSSION The present study will investigate the probable cellular pathways for the anti-obesity effects of N. sativa in overweight/obese women. TRIAL REGISTRATION Iranian Registry of Clinical Trials, IRCT20180528039884N1 . Registered on 2nd of July, 2018.
Collapse
Affiliation(s)
- Elham Razmpoosh
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sara Safi
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahta Mazaheri
- Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Amin Salehi-Abargouei
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nooshin Abdollahi
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Majid Nazari
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Fallahzadeh
- Department of Biostatistics and Epidemiology, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Azadeh Nadjarzadeh
- Department of Nutrition, Faculty of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. .,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| |
Collapse
|
|
29
|
Shahein SA, Aboul-Enein AM, Higazy IM, Abou-Elella F, Lojkowski W, Ahmed ER, Mousa SA, AbouAitah K. Targeted anticancer potential against glioma cells of thymoquinone delivered by mesoporous silica core-shell nanoformulations with pH-dependent release. Int J Nanomedicine 2019; 14:5503-5526. [PMID: 31410001 PMCID: PMC6650459 DOI: 10.2147/ijn.s206899] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/10/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND AND PURPOSE Glioma is one of the most aggressive primary brain tumors and is incurable. Surgical resection, radiation, and chemotherapies have been the standard treatments for brain tumors, however, they damage healthy tissue. Therefore, there is a need for safe anticancer drug delivery systems. This is particularly true for natural prodrugs such as thymoquinone (TQ), which has a high therapeutic potential for cancers but has poor water solubility and insufficient targeting capacity. We have tailored novel core-shell nanoformulations for TQ delivery against glioma cells using mesoporous silica nanoparticles (MSNs) as a carrier. METHODS The core-shell nanoformulations were prepared with a core of MSNs loaded with TQ (MSNTQ), and the shell consisted of whey protein and gum Arabic (MSNTQ-WA), or chitosan and stearic acid (MSNTQ-CS). Nanoformulations were characterized, studied for release kinetics and evaluated for anticancer activity on brain cancer cells (SW1088 and A172) and cortical neuronal cells-2 (HCN2) as normal cells. Furthermore, they were evaluated for caspase-3, cytochrome c, cell cycle arrest, and apoptosis to understand the possible anticancer mechanism. RESULTS TQ release was pH-dependent and different for core and core-shell nanoformulations. A high TQ release from MSNTQ was detected at neutral pH 7.4, while a high TQ release from MSNTQ-WA and MSNTQ-CS was obtained at acidic pH 5.5 and 6.8, respectively; thus, TQ release in acidic tumor environment was enhanced. The release kinetics fitted with the Korsmeyer-Peppas kinetic model corresponding to diffusion-controlled release. Comparative in vitro tests with cancer and normal cells indicated a high anticancer efficiency for MSNTQ-WA compared to free TQ, and low cytotoxicity in the case of normal cells. The core-shell nanoformulations significantly improved caspase-3 activation, cytochrome c triggers, cell cycle arrest at G2/M, and apoptosis induction compared to TQ. CONCLUSION Use of MSNs loaded with TQ permit improved cancer targeting and opens the door to translating TQ into clinical application. Particularly good results were obtained for MSNTQ-WA.
Collapse
Affiliation(s)
- Samar A Shahein
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza, Egypt
| | - Ahmed M Aboul-Enein
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza, Egypt
| | - Iman M Higazy
- Department of Pharmaceutical Technology, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt
| | - Faten Abou-Elella
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza, Egypt
| | - Witold Lojkowski
- Laboratory of Nanostructures, Institute of High Pressure Physics, Polish Academy of Sciences, Warsaw, Poland
| | - Esam R Ahmed
- Confirmatory Diagnostic Unit, Egyptian Organization for Vaccine, Sera and Biological Products (VACSERA), Giza, Egypt
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, New York, NY, USA
| | - Khaled AbouAitah
- Laboratory of Nanostructures, Institute of High Pressure Physics, Polish Academy of Sciences, Warsaw, Poland
- Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), Giza, Egypt
| |
Collapse
|
|
30
|
Zhang Y, Fan Y, Huang S, Wang G, Han R, Lei F, Luo A, Jing X, Zhao L, Gu S, Zhao X. Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci 2018; 109:3865-3873. [PMID: 30259603 PMCID: PMC6272120 DOI: 10.1111/cas.13808] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 12/19/2022] Open
Abstract
Thymoquinone (TQ, 2-methyl-5-isopropyl-1,4-benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti-tumor efficiency in various cancers. Autophagy is a self-digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786-O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ-treated RCC cells, and then found that autophagy was induced by TQ in 786-O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy-dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ-induced autophagy in RCC treatment.
Collapse
Affiliation(s)
- Yujiao Zhang
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yizeng Fan
- Department of Urologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shangke Huang
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Guanying Wang
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Rui Han
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Fuxi Lei
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Anqi Luo
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xin Jing
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Lin Zhao
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Shanzhi Gu
- Department of College of Forensic MedicineXi'an Jiaotong University Health Science CenterXi'anChina
| | - Xinhan Zhao
- Department of Medical Oncologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| |
Collapse
|
|
31
|
Imran M, Rauf A, Khan IA, Shahbaz M, Qaisrani TB, Fatmawati S, Abu-Izneid T, Imran A, Rahman KU, Gondal TA. Thymoquinone: A novel strategy to combat cancer: A review. Biomed Pharmacother 2018; 106:390-402. [PMID: 29966985 DOI: 10.1016/j.biopha.2018.06.159] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/25/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
The higher consumption of fruit, herbs, spices, and vegetables is well known and practical strategy to cure human cancers owing to their presence of bioactive compounds. Among these, Nigella sativa is a promising source of bioactive compounds including thymoquinone, monoterpenes, p-cymene and α-piene etc. Thymoquinone has been found effective to inhibit the different cancer stages such as proliferation, migration and invasion. It also acts as anticancer agent against different human cancers such as breast, pancreatic, prostate, blood, oral, bone, head and neck, cervical, liver and lung. It significantly mediated miR-34a up-regulation, enhanced the levels of miR-34a through p53, and down controlled Rac1 expression. Thymoquinone induces apoptosis, regulates the levels of pro- and anti- apoptotic genes. It also has been known to lower the phosphorylation of NF-κB and IKKα/β and reduces the metastasis as well as also lowered the ERK1/2 and PI3K activities. Thymoquinone inhibits the metastasis through activation of JNK and p38. The present review article highlights the anticancer perspectives of thymoquinone in human by various pathways and use of this compound as diet based therapy has proven new pharmacological agent against several types of cancers.
Collapse
Affiliation(s)
- Muhammad Imran
- University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore, Pakistan
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan.
| | - Imtiaz Ali Khan
- Department ofAgriculture, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Shahbaz
- Department of Food science and Technology, Muhammad Nawaz Shareef University of Agriculture, Multan, Pakistan
| | | | - Sri Fatmawati
- Department of Chemistry,Faculty of Mathematics and Natural Sciences, Institut Teknologi Sepuluh Nopember, Kampus ITS-Sukolilo, Surabaya, Indonesia
| | - Tareq Abu-Izneid
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, P.O.Box 42, Saudi Arabia
| | - Ali Imran
- Institute of Home and Food Sciences, Faculty of Science and Technology, Government College University, Faisalabad, Pakistan
| | - Khaliq Ur Rahman
- Department of Chemistry, University of Swabi, Anbar-23561, Khyber Pakhtunkhwa, Pakistan
| | - Tanweer Aslam Gondal
- School of Exercise and Nutrition, Centre of Advanced Sensory Science, Deakin University, Australia
| |
Collapse
|
|
32
|
Bashmail HA, Alamoudi AA, Noorwali A, Hegazy GA, AJabnoor G, Choudhry H, Al-Abd AM. Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities. Sci Rep 2018; 8:11674. [PMID: 30076320 PMCID: PMC6076303 DOI: 10.1038/s41598-018-30046-z] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/20/2018] [Indexed: 12/11/2022] Open
Abstract
The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy, and/or protecting from major side effects of chemotherapeutics. Thymoquinone (TQ) is a naturally occurring compound with cumulative evidence of anti-cancer properties. In this study, we assessed the chemomodulatory potential of TQ to gemcitabine (GCB) against human breast adenocarcinoma (MCF-7), and ductal carcinoma (T47D) cells. TQ showed cytotoxic effects against MCF-7 and T47D with IC50's of 64.9 ± 14 µM and 165 ± 2 µM, respectively. The IC50's of GCB against MCF-7 and T47D were 0.9 ± 0.18 µM and 14.3 ± 2.8 µM and were significantly reduced after combination with TQ to 0.058 ± 12 µM and 2.3 ± 0.2 µM, respectively. The CI- values were indicative of synergism in MCF-7 and T47D cells (0.15 and 0.30, respectively). Further investigation showed that GCB caused significant anti-proliferative effect reflected by increasing cell population in S-phase in both cell lines. TQ potentiated GCB-induced anti-proliferative activity in both cell lines. GCB induced considerable apoptosis in T47D cell line, and TQ significantly increased GCB-induced apoptotic effects by 1.5 to 3.6 folds. Interestingly, GCB, TQ and their combination induced significant autophagic cell death in the apoptosis defected MCF-7 cells. In addition, TQ, GCB and their combination depleted breast cancer associated stem cell (CD44(+)/CD24(-)/(low)) clone within MCF-7 and T47D cells by 3.8% to 27.5%. In conclusion, TQ showed promising chemomodulatory effects to GCB against breast cancer cells via inducing apoptosis, necrosis and autophagy, in addition to depleting tumor associated resistant stem cell fraction.
Collapse
Affiliation(s)
- Hanan A Bashmail
- Departement of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aliaa A Alamoudi
- Departement of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Stem Cell Research Unit, King Fahad Medical Research Center, Jeddah, Saudi Arabia
| | - Abdulwahab Noorwali
- Departement of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Stem Cell Research Unit, King Fahad Medical Research Center, Jeddah, Saudi Arabia
| | - Gehan A Hegazy
- Departement of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Hormones, Medical Division, National Research Centre, Giza, Egypt
| | - Ghada AJabnoor
- Departement of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed M Al-Abd
- Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt.
- Biomedical Research Section, Nawah Scientific, Mokkatam, Cairo, Egypt.
- Depaertment of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates.
| |
Collapse
|
|
33
|
Beker M, Dallı T, Elibol B. Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons. Mol Nutr Food Res 2018; 62. [PMID: 29277983 DOI: 10.1002/mnfr.201700768] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 12/11/2017] [Indexed: 12/11/2022]
Abstract
SCOPE Thymoquinone (TQ) has been used as a potential therapeutic for diseases such as cancer and diabetes. Herein, we aim to investigate the effect of TQ on behavioral and molecular parameters in healthy rat hippocampus. METHODS TQ (20 mg kg-1 d-1 ) is administered intragastrically for 15 days to adult rats. After behavioral tests, the hippocampal tissues are investigated at the histological and molecular levels. RESULTS In both dentate gyrus and cornu ammonis 1, TQ significantly increases the number of hippocampal neurons. This increase is supported by a significant increase in the doublecortin expression on both gene and protein levels. In addition, TQ significantly decreases the amount of Caspase-3 expression and the cleavage of poly ADP ribose polymerase, indicating a decrease in apoptosis. Further, ERK, GSK-3, JNK, CREB, and iNOS proteins are found to be positively regulated by TQ. However, the gene expression of synapsin, synaptophysin, NGF, AKT, Bax, NFkB, and p53 and the protein expression of BDNF and nNOS are not affected by TQ. CONCLUSION These findings suggest that TQ has an enhancing effect on cell survival and neurogenesis in healthy hippocampus, rather inducing apoptosis in damaged neurons. This may proceed via ERK/JNK and CREB signaling pathways as a candidate acting mechanism for TQ.
Collapse
Affiliation(s)
- Merve Beker
- Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Tuğçe Dallı
- Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Birsen Elibol
- Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| |
Collapse
|
|
34
|
The Role of Compounds Derived from Natural Supplement as Anticancer Agents in Renal Cell Carcinoma: A Review. Int J Mol Sci 2017; 19:ijms19010107. [PMID: 29301217 PMCID: PMC5796057 DOI: 10.3390/ijms19010107] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 12/24/2017] [Accepted: 12/28/2017] [Indexed: 12/24/2022] Open
Abstract
Renal Cell Carcinoma (RCC) is the most prominent kidney cancer derived from renal tubules and accounts for roughly 85% of all malignant kidney cancer. Every year, over 60,000 new cases are registered, and about 14,000 people die from RCC. The incidence of this has been increasing significantly in the U.S. and other countries. An increased understanding of molecular biology and the genomics of RCC has uncovered several signaling pathways involved in the progression of this cancer. Significant advances in the treatment of RCC have been reported from agents approved by the Food and Drug Administration (FDA) that target these pathways. These agents have become drugs of choice because they demonstrate clinical benefit and increased survival in patients with metastatic disease. However, the patients eventually relapse and develop resistance to these drugs. To improve outcomes and seek approaches for producing long-term durable remission, the search for more effective therapies and preventative strategies are warranted. Treatment of RCC using natural products is one of these strategies to reduce the incidence. However, recent studies have focused on these chemoprevention agents as anti-cancer therapies given they can inhibit tumor cell grow and lack the severe side effects common to synthetic compounds. This review elaborates on the current understanding of natural products and their mechanisms of action as anti-cancer agents. The present review will provide information for possible use of these products alone or in combination with chemotherapy for the prevention and treatment of RCC.
Collapse
|
|
35
|
Shanmugam MK, Arfuso F, Kumar AP, Wang L, Goh BC, Ahn KS, Bishayee A, Sethi G. Modulation of diverse oncogenic transcription factors by thymoquinone, an essential oil compound isolated from the seeds of Nigella sativa Linn. Pharmacol Res 2017; 129:357-364. [PMID: 29162539 DOI: 10.1016/j.phrs.2017.11.023] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/17/2017] [Accepted: 11/17/2017] [Indexed: 12/14/2022]
Abstract
Thymoquinone (TQ), isolated almost fifty years ago, is the main bioactive constituent of black seed essential oil extracted from the seed of Nigella sativa. TQ has been shown to have promising effects against a variety of inflammatory diseases and cancer. Cancer development is a multistep process where normal cells acquire qualities that enable the cells to proliferate continuously and migrate to distant sites in the human body. Drugs that interfere with this process are considered potential anti-cancer therapeutics, which may ultimately result in their clinical usage. TQ is once such compound which has been reported to modulate several major signaling pathways and key oncogenic molecules that play a prominent role in cancer initiation, progression, invasion, metastasis, and angiogenesis. Various studies have reported that TQ can enhance the anti-cancer potential when co-administered with several chemotherapeutic agents while reducing their toxic side effects. In addition, TQ has been shown to inhibit the growth of breast, prostate, pancreatic, colon, lung, and hematological malignancies in different mouse models of cancer. This review focuses on TQ's chemical and pharmacological properties, its diverse molecular targets and also provides clear evidence on its promising potential under preclinical and clinical settings.
Collapse
Affiliation(s)
- Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6009, Australia
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore; Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6009, Australia; National University Cancer Institute, National University Health System, 117600, Singapore; Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore
| | - Boon Cher Goh
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117600, Singapore; Department of Haematology-Oncology, National University Health System, 119228, Singapore
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, Kyungheedae-gil, Dongdaemoon-gu, Seoul 130-701, South Korea, South Korea
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, 18301 N. Miami Avenue, Miami, FL 33169, USA
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6009, Australia.
| |
Collapse
|
|
36
|
El-Ashmawy NE, Khedr EG, Ebeid EZM, Salem ML, Zidan AAA, Mosalam EM. Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma. Eur J Pharm Sci 2017; 109:525-532. [PMID: 28890201 DOI: 10.1016/j.ejps.2017.09.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/04/2017] [Accepted: 09/06/2017] [Indexed: 02/07/2023]
Abstract
The incidence of breast cancer remarkably increases all over the world. Therefore, there is a great demand to introduce new approaches into cancer treatment field. The current study was designated to evaluate the role of doxorubicin (DOX) and/or thymoquinone (TQ) nanomatrix in potentiating the cytotoxicity of either drug, and to investigate the ability of TQ to reduce cardiotoxicity of DOX in solid Ehrlich carcinoma (SEC)-bearing mice. DOX and TQ were loaded into F2 gel, which is a fully-acetylated poly-N-acetyl glucosamine nanofiber. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10): normal control, tumor control, F2 gel, free DOX, DOX+F2 gel, free TQ, TQ+F2 gel, and DOX+TQ+F2 gel. On day 28th from tumor inoculation, mice were sacrificed and blood samples were collected for measurement of the cardiac markers; lactate dehydrogenase (LDH) and creatine kinase (CK-MB). In addition, cardiac tissue was utilized for determination of lipid peroxide, and tumor tissue was used for measurement of anti-apoptotic protein Bcl-2 as well as gene expression of the tumor suppressor gene P53. DOX and/or TQ showed a significant reduction in tumor volume, cardiac markers, tumor Bcl-2, and P53 upregulation compared to free conventional therapies. Co-treatment with DOX+TQ+F2 gel was superior to all other groups in exerting beneficial effects. Use of TQ as an adjuvant therapy with DOX could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, loading of DOX and/or TQ into F2 gel showed a remarkable anti-cancer activity.
Collapse
MESH Headings
- Acetylglucosamine/administration & dosage
- Animals
- Antibiotics, Antineoplastic/administration & dosage
- Benzoquinones/administration & dosage
- Carcinoma, Ehrlich Tumor/drug therapy
- Carcinoma, Ehrlich Tumor/metabolism
- Carcinoma, Ehrlich Tumor/pathology
- Chemotherapy, Adjuvant
- Creatine Kinase/blood
- Creatine Kinase, MB Form/blood
- Doxorubicin/administration & dosage
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, p53
- L-Lactate Dehydrogenase/blood
- Malondialdehyde/metabolism
- Mice
- Microscopy, Electron, Transmission
- Myocardium/metabolism
- Nanostructures/administration & dosage
- Nanostructures/ultrastructure
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Tumor Burden/drug effects
Collapse
Affiliation(s)
| | - Eman G Khedr
- Biochemistry Department, Faculty of Pharmacy, Tanta University, Egypt
| | - El-Zeiny M Ebeid
- Physical Chemistry Department, Faculty of Science, Tanta University, Egypt
| | - Mohamed L Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science Tanta University, Egypt
| | | | - Esraa M Mosalam
- Biochemistry Department, Faculty of Pharmacy, Menoufia University, Egypt.
| |
Collapse
|
|
37
|
Miyata Y, Matsuo T, Sagara Y, Ohba K, Ohyama K, Sakai H. A Mini-Review of Reactive Oxygen Species in Urological Cancer: Correlation with NADPH Oxidases, Angiogenesis, and Apoptosis. Int J Mol Sci 2017; 18:ijms18102214. [PMID: 29065504 PMCID: PMC5666894 DOI: 10.3390/ijms18102214] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 10/17/2017] [Accepted: 10/17/2017] [Indexed: 12/24/2022] Open
Abstract
Oxidative stress refers to elevated reactive oxygen species (ROS) levels, and NADPH oxidases (NOXs), which are one of the most important sources of ROS. Oxidative stress plays important roles in the etiologies, pathological mechanisms, and treatment strategies of vascular diseases. Additionally, oxidative stress affects mechanisms of carcinogenesis, tumor growth, and prognosis in malignancies. Nearly all solid tumors show stimulation of neo-vascularity, termed angiogenesis, which is closely associated with malignant aggressiveness. Thus, cancers can be seen as a type of vascular disease. Oxidative stress-induced functions are regulated by complex endogenous mechanisms and exogenous factors, such as medication and diet. Although understanding these regulatory mechanisms is important for improving the prognosis of urothelial cancer, it is not sufficient, because there are controversial and conflicting opinions. Therefore, we believe that this knowledge is essential to discuss observations and treatment strategies in urothelial cancer. In this review, we describe the relationships between members of the NOX family and tumorigenesis, tumor growth, and pathological mechanisms in urological cancers including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, we introduce natural compounds and chemical agents that are associated with ROS-induced angiogenesis or apoptosis.
Collapse
Affiliation(s)
- Yasuyoshi Miyata
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Tomohiro Matsuo
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Yuji Sagara
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Kojiro Ohba
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Kaname Ohyama
- Department of Pharmaceutical Science, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Hideki Sakai
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| |
Collapse
|
|
38
|
Liu X, Dong J, Cai W, Pan Y, Li R, Li B. The Effect of Thymoquinone on Apoptosis of SK-OV-3 Ovarian Cancer Cell by Regulation of Bcl-2 and Bax. Int J Gynecol Cancer 2017; 27:1596-1601. [PMID: 28692636 DOI: 10.1097/igc.0000000000001064] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE We aim to determine how cisplatin, thymoquinone (TQ), and combination regimen can affect apoptosis of cultured SK-OV-3 cells. We also want to explore the mechanism of these influences on the cells' apoptosis by Bcl-2 and Bax gene. METHOD/MATERIALS Cell Counting Kit-8 assay was used to measure the viability of cultured ovarian cancer cells. Propidium iodide with flow cytometry was used in cell cycle analysis. Thereafter, we used fluorescein isothiocyanate-stained annexin V and propidium iodide to detect the effect of cisplatin, TQ, and combination regimen on apoptosis. Real-time PCR was used to measure the Bcl-2 and Bax levels. Western blotting was used to measure on protein expression levels of Bcl-2 and Bax. RESULTS In Cell Counting Kit-8 assay, we found that inhibitory effect of TQ was even better than cisplatin, and combination regimen had best inhibitory effect on cell proliferation. In cell cycle analysis, we found all regimens had obvious effect to stop cell cycle in S phase. In apoptosis assay, we found that combination regimen was better to activate cell apoptosis than cisplatin alone. Combination regimen could decrease expression of Bcl-2 and increase expression of Bax more than cisplatin or TQ alone. CONCLUSIONS Thymoquinone and cisplatin had comparable antitumoric effects on SK-OV-3 cells, and combination regimen was even better. Thymoquinone could also activate apoptosis by regulating Bcl-2 and Bax genes. These indicated potential advantage of TQ for ovarian cancer in clinical practice and suggested future clinical trials to confirm its effectiveness.
Collapse
Affiliation(s)
- Xiaoli Liu
- *Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou; †Nan Yang the First People's Hospital, Nanyang; ‡Heilongjiang University of Chinese Medicine, Harbin; §The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang; ∥Henan University of Chinese Medicine, Zhengzhou; and ¶Jinshan Hospital Affiliated to Fudan University, Shanghai, China
| | | | | | | | | | | |
Collapse
|