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Lee E, Yang D, Hong JH. Prominent Naturally Derived Oxidative-Stress-Targeting Drugs and Their Applications in Cancer Treatment. Antioxidants (Basel) 2025; 14:49. [PMID: 39857383 PMCID: PMC11760868 DOI: 10.3390/antiox14010049] [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: 11/27/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
The relationship between oxidative stress and cancer has been extensively studied and highlighted, along with its role in various aspects of angiogenesis. The modulation of oxidative levels and the adaptive mechanisms of oxidative stress in cancer systems are attractive research themes for developing anti-cancer strategies. Reactive oxygen species (ROS) are involved in various pathophysiological processes and play crucial roles in DNA damage and angiogenesis. Although cancer cells have developed various adaptive defense mechanisms against oxidative stress, excessive ROS production has been proposed as an anti-cancer strategy to induce cellular apoptosis. In particular, natural-source-based antioxidants have been identified as effective against cancers, and various delivery platforms have been developed to enhance their efficacy. In this review, we highlighted the anti-cancer components (plumbagin, quercetin, resveratrol, curcumin, xanthatin, carvacrol, telmisartan, and sulforaphane) that modulate ROS levels and the recent targeting platforms used to increase the application of anti-cancer drugs and the developed delivery platforms with diverse mechanisms of action. Further, we summarized the actual doses used and the effects of these drug candidates in various cancer systems. Overall, this review provides beneficial research themes for expanding cancer-targeting fields and addressing limited applications in diverse cancer types.
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Affiliation(s)
| | - Dongki Yang
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
| | - Jeong Hee Hong
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Republic of Korea;
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Baladi A, Fadli ME, Tafenzi HA, Bouaouidi KE, Benhima N, Afani L, Essâdi I, Belbaraka R. Prevalence and associated factors of herbal medicine use among breast cancer patients: a cross-sectional study in Morocco. Ecancermedicalscience 2024; 18:1786. [PMID: 39816400 PMCID: PMC11735139 DOI: 10.3332/ecancer.2024.1786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Indexed: 01/18/2025] Open
Abstract
Background Despite advances in modern medicine, an increasing number of breast cancer (BC) patients are turning to complementary and alternative medicine, such as phytotherapy. Instead of being prescribed by breast medical oncologists, patients are often seeking out phytotherapy themselves. They typically resort to herbal medicine as an alternative treatment to alleviate symptoms and side effects and enhance their quality of life during cancer treatment. This study, conducted in Morocco, aimed to investigate the prevalence and associated factors of herbal medicine use among BC patients. Methods A cross-sectional study of 170 patients with BC was carried out from October 2021 to January 2022 at the Mohamed VI University Hospital in Marrakech. Participants were selected using convenience sampling based on specific criteria such as being over 18 years old, having a histological diagnosis of BC, and being in active treatment. Data were collected through a structured questionnaire administered by trained clinicians, and medical records were reviewed for clinical data. Statistical analysis was conducted using Microsoft Forms for data collection and SPSS version 26 for statistical analysis. Descriptive statistics summarised demographic and health-related characteristics. Associations between herbal medicine use and categorical variables were assessed using chi-square and Fisher exact tests. Logistic regression analyses were performed to identify predictors of herbal medicine use, with statistical significance set at p < 0.05. Results Among the 170 BC patients included in the study, 37% reported using phytotherapeutics. One of the significant findings of this study was that nearly half of the BC patients surveyed believed herbal remedies to be harmless. None of the patients received information about herbal medicine use from their attending physicians. The use of herbal medication was significantly associated with marital status adjusted odds ratio (AOR: NR, p = 0.019), residence (AOR: 2.291, 95% confidence interval (CI): 1.214-4.324, p = 0.019), education levels (AOR: NR, p = 0.04) and receipt of radiotherapy (AOR: 0.128, 95% CI: 0.016-1.007, p = 0.023). Widowed women had a four times higher probability of using medicinal herbs than single or divorced women (AOR: 4.95, 95% CI: 1.16-20.90, p = 0.03). Illiterate women (AOR: 0.18, 95% CI: 0.052-0.65, p = 0.009) or those who attended Koranic school (AOR: 0.04, 95% CI: 0.004-0.47, p = 0.01) were less likely to use herbal medicine. Urban women were about twice as likely to use herbal remedies as women from rural areas (AOR: 2.02, 95% CI: 1.002-4.09, p = 0.049). Conclusion This study highlights the need for healthcare professionals to be aware of their patients' possible use of herbal medicine, be familiar with commonly used herbal treatments, and take proactive steps to explain any potential drug interaction and associated benefits. The findings of this study also provide insight into information on the sociodemographic and health-related factors associated with the use of herbal medicines among BC patients.
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Affiliation(s)
- Anass Baladi
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Mohammed El Fadli
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Hassan Abdelilah Tafenzi
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
- Laboratory of Biosciences and Health, Faculty of Medicine and Pharmacy of Marrakech, Marrakech 40000, Morocco
| | - Kawtar El Bouaouidi
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Nada Benhima
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Leila Afani
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Ismail Essâdi
- Laboratory of Biosciences and Health, Faculty of Medicine and Pharmacy of Marrakech, Marrakech 40000, Morocco
- Department of Medical Oncology, Avicenna Military Hospital of Marrakech, Marrakesh 40000, Morocco
| | - Rhizlane Belbaraka
- Department of Medical Oncology, Mohammed VI University Hospital of Marrakech, Marrakesh 40000, Morocco
- Laboratory of Biosciences and Health, Faculty of Medicine and Pharmacy of Marrakech, Marrakech 40000, Morocco
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Razali NSC, Lam KW, Rajab NF, Jamal ARA, Kamaludin NF, Chan KM. Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells. Genes Environ 2024; 46:4. [PMID: 38303058 PMCID: PMC10832295 DOI: 10.1186/s41021-023-00297-y] [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: 07/22/2023] [Accepted: 12/27/2023] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Previously, we have reported on the two curcuminoid analogues with piperidone derivatives, namely FLDP-5 and FLDP-8 have more potent anti-proliferative and anti-migration effects than curcumin. In this study, we further investigated the mode of cell death and the mechanism involved in the cell death process induced by these analogues on human glioblastoma LN-18 cells. RESULTS The FLDP-5 and FLDP-8 curcuminoid analogues induced LN-18 cell death through apoptosis in a concentration-dependent manner following 24 h of treatment. These analogues induced apoptosis in LN-18 cells through significant loss of mitochondrial mass and mitochondrial membrane potential (MMP) as early as 1-hour of treatment. Interestingly, N-acetyl-l-cysteine (NAC) pretreatment did not abolish the apoptosis induced by these analogues, further confirming the cell death process is independent of ROS. However, the apoptosis induced by the analogues is caspases-dependent, whereby pan-caspase pretreatment inhibited the curcuminoid analogues-induced apoptosis. The apoptotic cell death progressed with the activation of both caspase-8 and caspase-9, which eventually led to the activation of caspase-3, as confirmed by immunoblotting. Moreover, the existing over-expression of miRNA-21 in LN-18 cells was suppressed following treatment with both analogues, which suggested the down-regulation of the miRNA-21 facilitates the cell death process. CONCLUSION The FLDP-5 and FLDP-8 curcuminoid analogues downregulate the miRNA-21 expression and induce extrinsic and intrinsic apoptotic pathways in LN-18 cells.
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Affiliation(s)
- Nur Syahirah Che Razali
- Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
| | - Kok Wai Lam
- Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
| | - Nor Fadilah Rajab
- Center for Health Ageing and Wellness Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
| | - A Rahman A Jamal
- UKM Medical Molecular Biology Institute, UKM Medical Centre, Cheras, 56000, Malaysia
| | - Nurul Farahana Kamaludin
- Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia
| | - Kok Meng Chan
- Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia.
- Product Stewardship and Toxicology, Group Health, Safety and Environment (GHSE), Petroliam Nasional Berhad (PETRONAS), Kuala Lumpur, 50088, Malaysia.
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Wang Y, Xu S, Han C, Huang Y, Wei J, Wei S, Qin Q. Modulatory effects of curcumin on Singapore grouper iridovirus infection-associated apoptosis and autophagy in vitro. FISH & SHELLFISH IMMUNOLOGY 2022; 131:84-94. [PMID: 36206994 DOI: 10.1016/j.fsi.2022.09.074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/30/2022] [Accepted: 09/30/2022] [Indexed: 06/16/2023]
Abstract
Singapore grouper iridovirus (SGIV) with high pathogenicity can cause great economic losses to aquaculture industry. Thus, it is of urgency to find effective antiviral strategies to combat SGIV. Curcumin has been demonstrated effective antiviral activity on SGIV infection. However, the molecular mechanism behind this action needs to be further explanations. In view of the fact that apoptosis (type I programmed cell death) and autophagy (type II programmed cell death) were key regulators during SGIV infection, we aimed to investigate the relevance between antiviral activity of curcumin and SGIV-associated programmed and clarify the role of potential signaling pathways. Our results showed that curcumin suppressed SGIV-induced apoptosis. At the same time, the activities of caspase-3/8/9 and activating protein-1 (AP-1), P53, nuclear factor-κB (NF-ΚB) promoters were inhibited. Besides, the activation of extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen activate protein kinase (p38 MAPK) signal pathways were suppressed in curcumin-treated cells. On the other hand, curcumin down-regulated protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway to promote autophagy representing by increased LC3 II and Beclin1 expression. Curcumin also hindered the transition of cells from G1 to S phase, as well as down-regulating the expression of CyclinD1. Our findings revealed the resistance curcumin induced to the effects of DNA virus on cell apoptosis and autophagy and the insights gained from this study may be of assistance to understand the molecular mechanism of curcumin against DNA virus infection.
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Affiliation(s)
- Yuexuan Wang
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China
| | - Suifeng Xu
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China
| | - Chengzong Han
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China
| | - Youhua Huang
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China
| | - Jingguang Wei
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China
| | - Shina Wei
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China.
| | - Qiwei Qin
- College of Marine Sciences, South China Agricultural University, Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, 528478, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, China.
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Mitra S, Tareq AM, Das R, Emran TB, Nainu F, Chakraborty AJ, Ahmad I, Tallei TE, Idris AM, Simal-Gandara J. Polyphenols: A first evidence in the synergism and bioactivities. FOOD REVIEWS INTERNATIONAL 2022. [DOI: 10.1080/87559129.2022.2026376] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Abu Montakim Tareq
- Department of Pharmacy, International Islamic University Chittagong, Chittagong, Bangladesh
| | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, Bgc Trust University Bangladesh, Chittagong, Bangladesh
| | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar, Indonesia
| | | | - Islamudin Ahmad
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Mulawarman, Samarinda, Indonesia
| | - Trina E. Tallei
- Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado, Indonesia
| | - Abubakr M. Idris
- Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia
- Research Center for Advanced Materials Science (Rcams), King Khalid University, Abha, Saudi Arabia
| | - Jesus Simal-Gandara
- Department of Analytical Chemistry and Food Science, Faculty of Science, Universidade de Vigo, Nutrition and Bromatology Group, Ourense, E32004, Spain
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Hao M, Chu Y, Lei J, Yao Z, Wang P, Chen Z, Wang K, Sang X, Han X, Wang L, Cao G. Pharmacological Mechanisms and Clinical Applications of Curcumin: Update. Aging Dis 2022; 14:716-749. [PMID: 37191432 DOI: 10.14336/ad.2022.1101] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Curcumin, a well-known hydrophobic polyphenol extracted from the rhizomes of turmeric (Curcuma longa L.), has attracted great interest in the last ten years due to its multiple pharmacological activities. A growing body of evidence has manifested that curcumin has extensive pharmacological activities including anti-inflammatory, anti-oxygenation, lipid regulation, antiviral, and anticancer with hypotoxicity and minor adverse reactions. However, the disadvantages of low bioavailability, short half-life in plasma, low drug concentration in blood, and poor oral absorption severely limited the clinical application of curcumin. Pharmaceutical researchers have carried out plenty of dosage form transformations to improve the druggability of curcumin and have achieved remarkable results. Therefore, the objective of this review summarizes the pharmacological research progress, problems in clinical application and the improvement methods of curcumin's druggability. By reviewing the latest research progress of curcumin, we believe that curcumin has a broad clinical application prospect for its wide range of pharmacological activities with few side effects. The deficiencies of lower bioavailability of curcumin could be improved by dosage form transformation. However, curcumin in the clinical application still requires further study regarding the underlying mechanism and clinical trial verification.
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Costea T, Vlad OC, Miclea LC, Ganea C, Szöllősi J, Mocanu MM. Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer. Int J Mol Sci 2020; 21:E401. [PMID: 31936346 PMCID: PMC7013436 DOI: 10.3390/ijms21020401] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.
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Affiliation(s)
- Teodora Costea
- Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Oana Cezara Vlad
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
| | - Luminita-Claudia Miclea
- Department of Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Research Excellence Center in Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Constanta Ganea
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
| | - János Szöllősi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Maria-Magdalena Mocanu
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
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Wan Mohd Tajuddin WNB, Lajis NH, Abas F, Othman I, Naidu R. Mechanistic Understanding of Curcumin's Therapeutic Effects in Lung Cancer. Nutrients 2019; 11:E2989. [PMID: 31817718 PMCID: PMC6950067 DOI: 10.3390/nu11122989] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/22/2019] [Accepted: 11/30/2019] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is among the most common cancers with a high mortality rate worldwide. Despite the significant advances in diagnostic and therapeutic approaches, lung cancer prognoses and survival rates remain poor due to late diagnosis, drug resistance, and adverse effects. Therefore, new intervention therapies, such as the use of natural compounds with decreased toxicities, have been considered in lung cancer therapy. Curcumin, a natural occurring polyphenol derived from turmeric (Curcuma longa) has been studied extensively in recent years for its therapeutic effects. It has been shown that curcumin demonstrates anti-cancer effects in lung cancer through various mechanisms, including inhibition of cell proliferation, invasion, and metastasis, induction of apoptosis, epigenetic alterations, and regulation of microRNA expression. Several in vitro and in vivo studies have shown that these mechanisms are modulated by multiple molecular targets such as STAT3, EGFR, FOXO3a, TGF-β, eIF2α, COX-2, Bcl-2, PI3KAkt/mTOR, ROS, Fas/FasL, Cdc42, E-cadherin, MMPs, and adiponectin. In addition, limitations, strategies to overcome curcumin bioavailability, and potential side effects as well as clinical trials were also reviewed.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Nordin H. Lajis
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia; (N.H.L.); (F.A.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia; (N.H.L.); (F.A.)
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; (W.N.B.W.M.T.); (I.O.)
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Peng F, Xie X, Peng C. Chinese Herbal Medicine-Based Cancer Therapy: Novel Anticancer Agents Targeting MicroRNAs to Regulate Tumor Growth and Metastasis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:1711-1735. [PMID: 31801358 DOI: 10.1142/s0192415x19500873] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
MicroRNAs, small non-coding RNA molecules, have gained a reputation of the most substantial regulators in gene network with the ability to down-regulate their targets. Accumulating evidence shifted insight toward microRNAs regulation as the key element of cancer initiation, development, and aggression. Recent studies have attached the importance of traditional Chinese medicine (TCM) to the treatment of various cancers, and the functional natural compounds have been considered as novel anticancer agents to directly inhibit tumor progression. In more recent decades, a wide range of biologically active components of TCM has gained increasing attention to their applications in the modulation of microRNAs. This review is on the purpose of demonstrating the significance of TCM bioactive ingredients in microRNAs regulation for cancer treatment according to the reports mainly in the recent six years, providing the evidence of efficient Chinese herbal medicine-based therapy and effective pro-diagnosis focusing on microRNAs expression of cancer patients.
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Affiliation(s)
- Fu Peng
- West China School of Pharmacy, Sichuan University, Chengdu, P. R. China
| | - Xiaofang Xie
- Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.,State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu, P. R. China
| | - Cheng Peng
- Chengdu University of Traditional Chinese Medicine, Chengdu, P. R. China.,State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu, P. R. China
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Golonko A, Lewandowska H, Świsłocka R, Jasińska U, Priebe W, Lewandowski W. Curcumin as tyrosine kinase inhibitor in cancer treatment. Eur J Med Chem 2019; 181:111512. [DOI: 10.1016/j.ejmech.2019.07.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/12/2022]
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Monroe JD, Hodzic D, Millay MH, Patty BG, Smith ME. Anti-Cancer and Ototoxicity Characteristics of the Curcuminoids, CLEFMA and EF24, in Combination with Cisplatin. Molecules 2019; 24:molecules24213889. [PMID: 31671767 PMCID: PMC6864451 DOI: 10.3390/molecules24213889] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 12/23/2022] Open
Abstract
In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC50 values: 2-16 μM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75-0.85-fold). Combination treatments reduced A549 migration (0.51-0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin's effect against A549 migration, but may counteract cisplatin's effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.
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Affiliation(s)
- Jerry D Monroe
- Department of Biology, Western Kentucky University, 1906 College Heights Boulevard, #11080, Bowling Green, KY 42101-1080, USA.
| | - Denis Hodzic
- Department of Biology, Western Kentucky University, 1906 College Heights Boulevard, #11080, Bowling Green, KY 42101-1080, USA.
| | - Matthew H Millay
- Department of Biology, Western Kentucky University, 1906 College Heights Boulevard, #11080, Bowling Green, KY 42101-1080, USA.
| | - Blaine G Patty
- Department of Biology, Western Kentucky University, 1906 College Heights Boulevard, #11080, Bowling Green, KY 42101-1080, USA.
| | - Michael E Smith
- Department of Biology, Western Kentucky University, 1906 College Heights Boulevard, #11080, Bowling Green, KY 42101-1080, USA.
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Yang Y, Huang Z, Pu X, Yin G, Wang L, Gao F. Fabrication of magnetic nanochains linked with CTX and curcumin for dual modal imaging detection and limitation of early tumour. Cell Prolif 2018; 51:e12486. [PMID: 30133050 PMCID: PMC6528879 DOI: 10.1111/cpr.12486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/02/2018] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Five-year survival rate at early lung tumour was about 70%; however, its early diagnosis rate was still at a low level, so the enhancement of diagnosis level for early lung tumour is the key factor to increase the survival rate. Diagnosis and therapy of early lung tumour are still challenged. METHODS The magnetic nanochains (NCs) with biocompatibility and transverse relaxivity (r2 = 231 Fe mmol l-1 s-1 ) were fabricated through a co-precipitation method in the assistance of dextran, and then, linked with chlorotoxin (CTX) and curcumin (Cur) via the PEGylation and carbodiimide technique (named as CTX-NCs-Cur). RESULTS The results of cell test indicated that CTX-conjugated NCs could obviously target non-small-cell lung cancer cells and limit their growth. The in vivo results of magnetic resonance imaging and fluorescence imaging indicated that the CTX-NCs-Cur significantly targeted the tumour site and enhanced images contrast of the small-size tumour. Moreover, the results of everyday tail-vein injection confirmed that CTX-NCs-Cur could significantly limit the growth of early tumour, due to blocking Cl ion channels from CTX-NCs-Cur-MMP-2 composite and intracellular ROS increase from Cur treatment. CONCLUSIONS We provided a mechanism about the effect of CTX-NCs-Cur on the targeting and limiting early tumour, and these results indicated the application foreground of CTX-NCs-Cur in tumour diagnosis and therapy.
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Affiliation(s)
- Yuedi Yang
- College of Materials Science and EngineeringSichuan UniversityChengduChina
| | - Zhongbing Huang
- College of Materials Science and EngineeringSichuan UniversityChengduChina
| | - Ximing Pu
- College of Materials Science and EngineeringSichuan UniversityChengduChina
| | - Guangfu Yin
- College of Materials Science and EngineeringSichuan UniversityChengduChina
| | - Lei Wang
- Department of RadiologyMolecular Imaging CenterWest China Hospital of Sichuan UniversityChengduChina
| | - Fabao Gao
- Department of RadiologyMolecular Imaging CenterWest China Hospital of Sichuan UniversityChengduChina
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13
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Curcumin composite particles prepared by spray drying and in vitro anti-cancer activity on lung cancer cell line. J Drug Deliv Sci Technol 2018. [DOI: 10.1016/j.jddst.2018.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Moghtaderi H, Sepehri H, Delphi L, Attari F. Gallic acid and curcumin induce cytotoxicity and apoptosis in human breast cancer cell MDA-MB-231. ACTA ACUST UNITED AC 2018; 8:185-194. [PMID: 30211078 PMCID: PMC6128975 DOI: 10.15171/bi.2018.21] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 02/26/2018] [Accepted: 03/01/2018] [Indexed: 12/28/2022]
Abstract
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Introduction: Gallic acid (GA) and curcumin (Cur) are natural phenolic compounds that their anti-tumor effects on many types of cancers have been proved. In the current study, the effect of the combination of these agents on MDA-MB-231 breast cancer cells was investigated.
Methods: Inhibition of cell proliferation (MTT assay), light microscopy, fluorescence microscopy, cell cycle analysis, nitrite detection, ROS levels, measurement of the mitochondrial membrane potential, GSH level, Annexin V assay, RT-PCR and Western blotting methods were applied.
Results: The results revealed the combination of GA and Cur strongly decreased MDA-MB-231 cell growth. Moreover, this combination increased ROS level and cytotoxic activity along with the glutathione depletion in MDA-MB-231 cells. Flow cytometry analysis showed the combination of GA and Cur increased sub-G1 cell population. Furthermore, fluorescent staining and Annexin V/PI assay showed that apoptotic cells were significantly increased in the presence of GA and Cur. At last, protein expression evaluation showed that the combination of GA and Cur significantly decreased Bcl-2 level while increased Bax, cleaved-caspase3 and PARP levels in MDA-MB-231 cells.
Conclusion: These results suggest that GA in combination with Cur could be a possible candidate for chemoprevention agent of triple negative breast cancer.
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Affiliation(s)
- Hassan Moghtaderi
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Houri Sepehri
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Ladan Delphi
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farnoosh Attari
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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15
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Tang L, Liu J, Zhu L, Chen Q, Meng Z, Sun L, Hu J, Ni Z, Wang X. Curcumin Inhibits Growth of Human NCI-H292 Lung Squamous Cell Carcinoma Cells by Increasing FOXA2 Expression. Front Pharmacol 2018; 9:60. [PMID: 29456509 PMCID: PMC5801542 DOI: 10.3389/fphar.2018.00060] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/17/2018] [Indexed: 12/11/2022] Open
Abstract
Lung squamous cell carcinoma (LSCC) is a common histological lung cancer subtype, but unlike lung adenocarcinoma, limited therapeutic options are available for treatment. Curcumin, a natural compound, may have anticancer effects in various cancer cells, but how it may be used to treat LSCC has not been well studied. Here, we applied curcumin to a human NCI-H292 LSCC cell line to test anticancer effects and explored underlying potential mechanisms of action. Curcumin treatment inhibited NCI-H292 cell growth and increased FOXA2 expression in a time-dependent manner. FOXA2 expression was decreased in LSCC tissues compared with adjacent normal tissues and knockdown of FOXA2 increased NCI-H292 cells proliferation. Inhibition of cell proliferation by curcumin was attenuated by FOXA2 knockdown. Moreover inhibition of STAT3 pathways by curcumin increased FOXA2 expression in NCI-H292 cells whereas a STAT3 activator (IL-6) significantly inhibited curcumin-induced FOXA2 expression. Also, SOCS1 and SOCS3, negative regulators of STAT3 activity, were upregulated by curcumin treatment. Thus, curcumin inhibited human NCI-H292 cells growth by increasing FOXA2 expression via regulation of STAT3 signaling pathways.
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Affiliation(s)
- Lingling Tang
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinjin Liu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Linyun Zhu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qingge Chen
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziyu Meng
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Sun
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Junsheng Hu
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenhua Ni
- Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiongbiao Wang
- Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kangarlou S, Ramezanpour S, Balalaie S, Roudbar Mohammadi S, Haririan I. Curcumin-loaded nanoliposomes linked to homing peptides for integrin targeting and neuropilin-1-mediated internalization. PHARMACEUTICAL BIOLOGY 2017; 55:277-285. [PMID: 27937055 PMCID: PMC6130459 DOI: 10.1080/13880209.2016.1261301] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 08/17/2016] [Accepted: 11/07/2016] [Indexed: 06/06/2023]
Abstract
CONTEXT Curcumin, a naturally occurring polyphenol, has been extensively studied for its broad-spectrum anticancer effects. The potential benefits are, however, limited due to its poor water solubility and rapid degradation which result in low bioavailability on administration. OBJECTIVES This study encapsulates curcumin in nanoliposomes including an integrin-homing peptide combined with a C end R neuropilin-1 targeting motif for targeted delivery and receptor-mediated internalization, respectively. MATERIALS AND METHODS The linear GHHNGR (Glycine-Histidine-Histidine-Asparagine-Glycine-Arginine) was synthesized through F-moc chemistry on 2-chlorotrityl chloride resin and conjugated to oleic acid. The lipoyl-peptide units were then co-assembled with lecithin and 0-75 mole % Tween-80 into liposomes. Curcumin was passively entrapped using a film hydration technique and its degradation profile was examined within seven consecutive days. The cytotoxic effects of the curcumin-loaded liposomes were studied on MCF-7 and MDA-MB-468, during 24 h exposure in MTT assay. RESULTS The maximum curcumin entrapment (15.5% W/W) and minimum degradation (< 23%) were obtained in a pH switch loading method from 5.7 to 8, in nanoliposomes (< 50 nm) containing oleyl-peptide, lecithin and Tween-80 (1:1:0.75 mole ratio). The oleyl-peptide did not prove any haemolytic activity (< 1.5%) up to 10-fold of its experimental concentration. The curcumin-loaded liposomes displayed significant reduction in the viabilities of MCF-7 (IC50 3.8 μM) and MDA-MB-468 (IC50 5.4 μM). DISCUSSION AND CONCLUSION This study indicated potential advantages of the peptide-conjugated liposomes in drug transport to the cancer cells. This feature might be an outcome of probable interactions between the targeted nanoliposomes with the integrin and neuropilin-1 receptors.
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Affiliation(s)
- Sogol Kangarlou
- Department of Pharmaceutical Biomaterials School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Sorour Ramezanpour
- Peptide Chemistry Research Center, K.N. Toosi University of Technology, Tehran, Iran
| | - Saeed Balalaie
- Peptide Chemistry Research Center, K.N. Toosi University of Technology, Tehran, Iran
| | - Shahla Roudbar Mohammadi
- Department of Medical Mycology School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ismaeil Haririan
- Department of Pharmaceutical Biomaterials School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Medical Biomaterials Research Center, Tehran University of Medical Sciences, Tehran, Iran
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17
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Zhan JW, Jiao DM, Wang Y, Song J, Wu JH, Wu LJ, Chen QY, Ma SL. Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. Thorac Cancer 2017; 8:461-470. [PMID: 28660665 PMCID: PMC5582578 DOI: 10.1111/1759-7714.12467] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/29/2017] [Accepted: 06/01/2017] [Indexed: 12/11/2022] Open
Abstract
Background Curcumin (diferuloylmethane) has chemopreventive and therapeutic properties against many types of tumors, both in vitro and in vivo. Previous reports have shown that curcumin exhibits anti‐invasive activities, but the mechanisms remain largely unclear. Methods In this study, both microRNA (miRNA) and messenger RNA (mRNA) expression profiles were used to characterize the anti‐metastasis mechanisms of curcumin in human non‐small cell lung cancer A549 cell line. Results Microarray analysis revealed that 36 miRNAs were differentially expressed between the curcumin‐treated and control groups. miR‐330‐5p exhibited maximum upregulation, while miR‐25‐5p exhibited maximum downregulation in the curcumin treatment group. mRNA expression profiles and functional analysis indicated that 226 differentially expressed mRNAs belonged to different functional categories. Significant pathway analysis showed that mitogen‐activated protein kinase, transforming growth factor‐β, and Wnt signaling pathways were significantly downregulated. At the same time, axon guidance, glioma, and ErbB tyrosine kinase receptor signaling pathways were significantly upregulated. We constructed a miRNA gene network that contributed to the curcumin inhibition of metastasis in lung cancer cells. let‐7a‐3p, miR‐1262, miR‐499a‐5p, miR‐1276, miR‐331‐5p, and miR‐330‐5p were identified as key microRNA regulators in the network. Finally, using miR‐330‐5p as an example, we confirmed the role of miR‐330‐5p in mediating the anti‐migration effect of curcumin, suggesting the importance of miRNAs in the regulation of curcumin biological activity. Conclusion Our findings provide new insights into the anti‐metastasis mechanism of curcumin in lung cancer.
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Affiliation(s)
- Jian-Wei Zhan
- Department of Emergency Disease, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China
| | - De-Min Jiao
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, China
| | - Yi Wang
- Department of Emergency Disease, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China
| | - Jia Song
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, China
| | - Jin-Hong Wu
- Department of Emergency Disease, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China
| | - Li-Jun Wu
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, China
| | - Qing-Yong Chen
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, China
| | - Sheng-Lin Ma
- Department of Emergency Disease, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China
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18
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Tunc D, Dere E, Karakas D, Cevatemre B, Yilmaz VT, Ulukaya E. Cytotoxic and apoptotic effects of the combination of palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine and curcumin on non small lung cancer cell lines. Bioorg Med Chem 2017; 25:1717-1723. [PMID: 28187956 DOI: 10.1016/j.bmc.2017.01.043] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 01/25/2017] [Indexed: 11/29/2022]
Abstract
Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100μM) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50μM) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48h, compared to single use of each agent, only in H1299 cell line (combination index <1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSF10A and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect.
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Affiliation(s)
- Duygu Tunc
- Uludag University, Faculty of Science and Art, Department of Biology, Bursa, Turkey
| | - Egemen Dere
- Uludag University, Faculty of Science and Art, Department of Biology, Bursa, Turkey
| | - Didem Karakas
- Uludag University, Faculty of Science and Art, Department of Biology, Bursa, Turkey
| | - Buse Cevatemre
- Uludag University, Faculty of Science and Art, Department of Biology, Bursa, Turkey
| | - Veysel Turan Yilmaz
- Uludag University, Faculty of Science and Art, Department of Chemistry, Bursa, Turkey
| | - Engin Ulukaya
- Istinye University, Faculty of Medical School, Department of Medical Biochemistry, Istanbul, Turkey.
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Allegra A, Innao V, Russo S, Gerace D, Alonci A, Musolino C. Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies. Cancer Invest 2016; 35:1-22. [PMID: 27996308 DOI: 10.1080/07357907.2016.1247166] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.
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Affiliation(s)
- Alessandro Allegra
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
| | - Vanessa Innao
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
| | - Sabina Russo
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
| | - Demetrio Gerace
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
| | - Andrea Alonci
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
| | - Caterina Musolino
- a Division of Hematology, Department of General Surgery, Oncology and Pathological Anatomy , University of Messina , Messina , Italy
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Park EJ, Chauhan AK, Min KJ, Park DC, Kwon TK. Thymoquinone induces apoptosis through downregulation of c-FLIP and Bcl-2 in renal carcinoma Caki cells. Oncol Rep 2016; 36:2261-7. [PMID: 27573448 DOI: 10.3892/or.2016.5019] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 08/04/2016] [Indexed: 12/15/2022] Open
Abstract
Renal carcinoma is a common and frequently fatal carcinoma occurring worldwide and death rates due to this carcinoma are increasing with time. In the present study, we investigated the potential of thymoquinone a natural compound to induce apoptosis in renal carcinoma Caki cells. Thymoquinone efficiently enhanced the apoptotic population of Caki cells in a dose-dependent manner. Moreover, thymoquinone-mediated apoptosis caused downregulation of c-FLIP and Bcl-2, the master regulators of the anti-apoptotic mechanism. However, we did not find any changes in mRNA expression level of c-FLIP, therefore; this regulation of c-FLIP was a result of post-translation modification by thymoquinone. In contrast, expression of the Bcl-2 protein was observed at both transcriptional and translational level. However, we also observed that thymoquinone enhanced the level of intracellular reactive oxygen species (ROS) in Caki cells, which resulted in reduction of mitochondrial membrane potential (MMP) and cytochrome c release into cytoplasm. Our results postulate that thymoquinone induces apoptosis through downregulating c-FLIP and Bcl-2 which can be utilized as a chemotherapeutic agent to treat renal carcinoma.
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Affiliation(s)
- Eun Jung Park
- Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea
| | - Anil Kumar Chauhan
- Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea
| | - Kyoung-Jin Min
- Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea
| | - Dong Cheol Park
- Department of Hotel Cuisine and Food Service Management, Gimcheon University, Gimcheon 39528, Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea
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21
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Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer. MOLECULAR THERAPY-ONCOLYTICS 2016; 3:16018. [PMID: 27525306 PMCID: PMC4972091 DOI: 10.1038/mto.2016.18] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/27/2016] [Accepted: 05/27/2016] [Indexed: 01/12/2023]
Abstract
The epithelial-mesenchymal transition (EMT) and angiogenesis have emerged as two pivotal events in cancer progression. Curcumin has been extensively studied in preclinical models and clinical trials of cancer prevention due to its favorable toxicity profile. However, the possible involvement of curcumin in the EMT and angiogenesis in lung cancer remains unclear. This study found that curcumin inhibited hepatocyte growth factor (HGF)-induced migration and EMT-related morphological changes in A549 and PC-9 cells. Moreover, pretreatment with curcumin blocked HGF-induced c-Met phosphorylation and downstream activation of Akt, mTOR, and S6. These effects mimicked that of c-Met inhibitor SU11274 or PI3 kinase inhibitor LY294002 or mTOR inhibitor rapamycin treatment. c-Met gene overexpression analysis further demonstrated that curcumin suppressed lung cancer cell EMT by inhibiting c-Met/Akt/mTOR signaling pathways. In human umbilical vein endothelial cells (HUVECs), we found that curcumin also significantly inhibited PI3K/Akt/mTOR signaling and induced apoptosis and reduced migration and tube formation of HGF-treated HUVEC. Finally, in the experimental mouse model, we showed that curcumin inhibited HGF-stimulated tumor growth and induced an increase in E-cadherin expression and a decrease in vimentin, CD34, and vascular endothelial growth factor (VEGF) expression. Collectively, these findings indicated that curcumin could inhibit HGF-promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways.
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Qiao YY, Liu XQ, Xu CQ, Zhang Z, Xu HW. Interleukin-22 ameliorates acute severe pancreatitis-associated lung injury in mice. World J Gastroenterol 2016; 22:5023-32. [PMID: 27275094 PMCID: PMC4886377 DOI: 10.3748/wjg.v22.i21.5023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 04/11/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential protective effect of exogenous recombinant interleukin-22 (rIL-22) on L-arginine-induced acute severe pancreatitis (SAP)-associated lung injury and the possible signaling pathway involved. METHODS Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase (MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin (HE) staining. Expression of B cell lymphoma/leukemia-2 (Bcl-2), Bcl-xL and IL-22RA1 mRNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot. RESULTS Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group (P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-xL mRNAs in the SAP group was decreased markedly, while the IL-22RA1 mRNA expression was increased significantly relative to the normal control group (P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-xL or IL-22RA1 mRNA (P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the rIL-22 group were significantly lower than those in the SAP group (P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, rIL-22 stimulated the expression of Bcl-2, Bcl-xL and IL-22RA1 mRNAs in the lung (P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the rIL-22 group was significantly higher than that in the PBS group (P < 0.05). CONCLUSION Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.
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Jeong CH, Joo SH. Downregulation of Reactive Oxygen Species in Apoptosis. J Cancer Prev 2016; 21:13-20. [PMID: 27051644 PMCID: PMC4819661 DOI: 10.15430/jcp.2016.21.1.13] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 02/28/2016] [Accepted: 02/29/2016] [Indexed: 12/18/2022] Open
Abstract
Generation of reactive oxygen species (ROS) by diverse anti-cancer drugs or phytochemicals has been closely related with the induction of apoptosis in cancers. Also, the downregulation of ROS by these chemicals has been found to block initiation of carcinogenesis. Therefore, modulation of ROS by phytochemicals emerges as a crucial mechanism to regulate apoptosis in cancer prevention or therapy. This review summarizes the current understanding of the selected chemical compounds and related cellular components that modulate ROS during apoptotic process. Metformin, quercetin, curcumin, vitamin C, and other compounds have been shown to downregulate ROS in the cellular apoptotic process, and some of them even induce apoptosis in cancer cells. The cellular components mediating the downregulation of ROS include nuclear factor erythroid 2-related factor 2 antioxidant signaling pathway, thioredoxin, catalase, glutathione, heme oxygenase-1, and uncoupling proteins. The present review provides information on the relationship between these compounds and the cellular components in modulating ROS in apoptotic cancer cells.
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Affiliation(s)
- Chul-Ho Jeong
- College of Pharmacy, Keimyung University, Daegu, Gyeongsan, Korea
| | - Sang Hoon Joo
- Department of Pharmacy, Catholic University of Daegu, Gyeongsan, Korea
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Curcumin and its promise as an anticancer drug: An analysis of its anticancer and antifungal effects in cancer and associated complications from invasive fungal infections. Eur J Pharmacol 2016; 772:33-42. [DOI: 10.1016/j.ejphar.2015.12.038] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 01/26/2023]
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Hemocompatible curcumin–dextran micelles as pH sensitive pro-drugs for enhanced therapeutic efficacy in cancer cells. Carbohydr Polym 2016; 137:497-507. [DOI: 10.1016/j.carbpol.2015.11.017] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 10/27/2015] [Accepted: 11/06/2015] [Indexed: 11/19/2022]
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Tsai JR, Liu PL, Chen YH, Chou SH, Cheng YJ, Hwang JJ, Chong IW. Curcumin Inhibits Non-Small Cell Lung Cancer Cells Metastasis through the Adiponectin/NF-κb/MMPs Signaling Pathway. PLoS One 2015; 10:e0144462. [PMID: 26656720 PMCID: PMC4675518 DOI: 10.1371/journal.pone.0144462] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 11/18/2015] [Indexed: 01/06/2023] Open
Abstract
Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244-amino acid peptide hormone, is associated with insulin resistance and carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan-Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.
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Affiliation(s)
- Jong-Rung Tsai
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Len Liu
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yung-Hsiang Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Shah-Hwa Chou
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Division of Chest Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Jen Cheng
- Department of Health Management, Division of Thoracic Surgery, Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Jhi-Jhu Hwang
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Inn-Wen Chong
- Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail:
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Hosseinzadehdehkordi M, Adelinik A, Tashakor A. Dual effect of curcumin targets reactive oxygen species, adenosine triphosphate contents and intermediate steps of mitochondria-mediated apoptosis in lung cancer cell lines. Eur J Pharmacol 2015; 769:203-10. [PMID: 26593433 DOI: 10.1016/j.ejphar.2015.11.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/12/2015] [Accepted: 11/13/2015] [Indexed: 01/27/2023]
Abstract
Exposure to arsenic is one of the major causes of lung cancer due to production of Reactive Oxygen Species (ROS). Herbal medicine is a new approach used for prevention or treatment of cancers. Among various herbal compounds, a lot of attention has been paid to curcumin, as antioxidant, anti-proliferative, anti-carcinogenic and anti-tumor and pro-apoptotic properties of curcumin have been well studied. In the present study, we investigated the effects of curcumin on lung cancer cell lines and arsenic-treated lung cancer cell lines, originated from different stages of lung cancer development. Here, we measured ROS generation and caspase 3/7 activity for both curcumin-treated cell lines and those co-treated with arsenic and curcumin. Then, we studied lipid peroxidation, intracellular ATP content, and cytochrome c release to further investigate how ROS generation and curcumin exert synergistic effects and direct cells toward apoptosis. According to our data, curcumin has a dual effect on ROS generation which is dependent on specific concentration as a threshold and seems to induce apoptosis by two different mechanisms. Moreover, for the first time we report that curcumin delays the drop in ATP levels in these cell lines and hence provides required energy for apoptosis process. Furthermore, western blot analysis reveals that release of cytochrome c is highest when ATP begins to drop in the presence of curcumin. To sum it up, it seems that curcumin is strong candidate for prevention or treatment of lung cancer, especially at stage 2.
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Affiliation(s)
| | - Armin Adelinik
- Department of Reproductive Genetics and Biotechnology, Avicenna Research Institute, Tehran, Iran
| | - Amin Tashakor
- Department of Biology, Islamic Azad University, Pishva Branch, Varamin, Iran.
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Yao Q, Lin M, Wang Y, Lai Y, Hu J, Fu T, Wang L, Lin S, Chen L, Guo Y. Curcumin induces the apoptosis of A549 cells via oxidative stress and MAPK signaling pathways. Int J Mol Med 2015; 36:1118-26. [PMID: 26310655 DOI: 10.3892/ijmm.2015.2327] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 08/10/2015] [Indexed: 11/05/2022] Open
Abstract
Curcumin has been found to exhibit anticancer activity and certain studies have shown that curcumin triggers the apoptosis of human A549 lung adenocarcinoma cells. However, the mechanism underlying curcumin‑mediated apoptosis is not completely understood. The present study was designed to investigate the effect of curcumin on the induction of apoptosis and apoptosis‑related factors in human A549 lung adenocarcinoma cells. Treatment of A549 cells with curcumin caused a concentration‑dependent inhibition of cell growth and an increase in apoptosis, as confirmed by THE MTT assay, flow cytometry and morphology analysis. Curcumin‑treatment of A549 cells induced a loss of the mitochondrial membrane potential and increased cytosolic cytochrome c. Furthermore, curcumin‑induced apoptosis was accompanied by changes in intracellular oxidative stress‑related enzymes, including decreased intracellular reactive oxygen species levels, increased superoxide dismutase and decreased malondialdehyde and 4‑hydroxynonenal. In addition, induction of apoptosis was also accompanied by phosphorylation and activation of mitogen‑activated protein kinase signaling pathway factors c‑Jun N‑terminal kinase, p38 and extracellular signal-regulated kinase.
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Affiliation(s)
- Qinghua Yao
- Key Laboratory of Traditional Chinese Medicine Oncology, Zhejiang Cancer Hospital, Banshan Qiao, Hangzhou, Zhejiang 310022, P.R. China
| | - Miao Lin
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Yuqi Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Yuebiao Lai
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Jingjing Hu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ting Fu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Lu Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Shuyuan Lin
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Liangliang Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yong Guo
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
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Jardim KV, Joanitti GA, Azevedo RB, Parize AL. Physico-chemical characterization and cytotoxicity evaluation of curcumin loaded in chitosan/chondroitin sulfate nanoparticles. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2015; 56:294-304. [PMID: 26249593 DOI: 10.1016/j.msec.2015.06.036] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/16/2015] [Accepted: 06/16/2015] [Indexed: 11/18/2022]
Abstract
In this study, chitosan (CTS)/chondroitin sulfate (CS) nanoparticles, both pure and curcumin-loaded, were synthesized by ionic gelation. This method is simple and efficient for obtaining nanoparticles with a low polydispersity index (0.151±0.03 to 0.563±0.07) and hydrodynamic diameter in the range of 175.7±2.5 to 710.2±8.9nm, for this study. Samples have a relatively high zeta potential value, a fact that indicates that the colloidal system has good physical and chemical stabilities. The efficiency of the curcumin encapsulation in nanoparticles, which ranged from 62.4±0.61% to 68.3±0.88%, depends on the pH of the chitosan solution. The release of curcumin from the nanoparticles was enabled by a diffusion mechanism, with fast release in a phosphate buffer solution at pH6.8. The assaying of cell viability by the MTT test showed that the presence of both free curcumin and curcumin in the nanoencapsulated form leads to a statistically significant reduction in the viability of A549 cells, by comparison with the control group. The most significant reductions in cell viability of 41.1% and 60.4% (p<0.0001) were observed after 72h, by using 40μmol∙L(-1) free curcumin and curcumin encapsulated in CTS/CS nanoparticles with the chitosan solution at pH6.0, respectively.
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Affiliation(s)
- Katiúscia Vieira Jardim
- Universidade de Brasília (UnB) - Campus Planaltina (FUP) - Área Universitária n°01, Vila N. Sa. De Fátima, CEP: 73345-010 - Planaltina, Brasília, DF, Brazil
| | - Graziella Anselmo Joanitti
- Universidade de Brasília (UnB) - Campus Ceilândia (FCE) - Centro Metropolitano - Conjunto A - Lote 01, CEP: 72220-900 - Ceilândia, Brasília, DF, Brazil
| | - Ricardo Bentes Azevedo
- Laboratório de Nanobiotecnologia - Instituto de Ciências Biológicas - Universidade de Brasília - UnB - Campus Universitário Darcy Ribeiro - CEP 70910-900 - Asa Norte, Brasília, DF, Brazil
| | - Alexandre Luis Parize
- Universidade de Brasília (UnB) - Campus Planaltina (FUP) - Área Universitária n°01, Vila N. Sa. De Fátima, CEP: 73345-010 - Planaltina, Brasília, DF, Brazil; Departamento de Química - Universidade Federal de Santa Catarina - CEP: 88040-900 - Trindade, Florianópolis, SC, Brazil.
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Zhou GZ, Cao FK, Du SW. The apoptotic pathways in the curcumin analog MHMD-induced lung cancer cell death and the essential role of actin polymerization during apoptosis. Biomed Pharmacother 2015; 71:128-34. [DOI: 10.1016/j.biopha.2015.02.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 02/21/2015] [Indexed: 01/13/2023] Open
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Waghela BN, Sharma A, Dhumale S, Pandey SM, Pathak C. Curcumin conjugated with PLGA potentiates sustainability, anti-proliferative activity and apoptosis in human colon carcinoma cells. PLoS One 2015; 10:e0117526. [PMID: 25692854 PMCID: PMC4334672 DOI: 10.1371/journal.pone.0117526] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 12/29/2014] [Indexed: 11/18/2022] Open
Abstract
Curcumin, an ingredient of turmeric, exhibits a variety of biological activities such as anti-inflammatory, anti-atherosclerotic, anti-proliferative, anti-oxidant, anti-cancer and anti-metastatic. It is a highly pleiotropic molecule that inhibits cell proliferation and induces apoptosis in cancer cells. Despite its imperative biological activities, chemical instability, photo-instability and poor bioavailability limits its utilization as an effective therapeutic agent. Therefore, enhancing the bioavailability of curcumin may improve its therapeutic index for clinical setting. In the present study, we have conjugated curcumin with a biodegradable polymer Poly (D, L-lactic-co-glycolic acid) and evaluated its apoptotic potential in human colon carcinoma cells (HCT 116). The results show that curcumin-PLGA conjugate efficiently inhibits cell proliferation and cell survival in human colon carcinoma cells as compared to native curcumin. Additionally, curcumin conjugated with PLGA shows improved cellular uptake and exhibits controlled release at physiological pH as compared to native curcumin. The curcumin-PLGA conjugate efficiently activates the cascade of caspases and promotes intrinsic apoptotic signaling. Thus, the results suggest that conjugation potentiates the sustainability, anti-proliferative and apoptotic activity of curcumin. This approach could be a promising strategy to improve the therapeutic index of cancer therapy.
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Affiliation(s)
- Bhargav N. Waghela
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | - Anupama Sharma
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | - Suhashini Dhumale
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
| | | | - Chandramani Pathak
- Department of Cell Biology, Indian Institute of Advanced Research, Gandhinagar, Gujarat, India
- * E-mail:
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32
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Chuang CH, Liu CH, Lu TJ, Hu ML. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells. Toxicol Appl Pharmacol 2014; 281:310-6. [DOI: 10.1016/j.taap.2014.10.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 10/21/2014] [Accepted: 10/25/2014] [Indexed: 12/16/2022]
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Lu Y, Wei C, Xi Z. Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway. In Vitro Cell Dev Biol Anim 2014; 50:840-50. [PMID: 24938356 DOI: 10.1007/s11626-014-9779-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 05/15/2014] [Indexed: 12/30/2022]
Abstract
Curcumin, a naturally occurring phenolic compound, has a diversity of antitumor activities. It has been previously demonstrated that curcumin can inhibit the invasion and metastasis of tumors through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). However, the specific roles and mechanisms of curcumin in regulating the malignant behaviors of non-small cell lung cancer (NSCLC) cells still remain unclear. In this study, we found that curcumin could inhibit the proliferation and invasion of NSCLC cells and induce G0/G1 phase arrest. Metastasis-associated protein 1 (MTA1) overexpression has been detected in a wide variety of aggressive tumors and plays an important role on cell invasion and metastasis. Our results showed that curcumin could effectively inhibit the MTA1 expression of NSCLC cells. Further research on the subsequent mechanism showed that curcumin inhibited the proliferation and invasion of NSCLC cells through MTA1-mediated inactivation of Wnt/β-catenin pathway. Wnt/β-catenin signaling was reported to play a critical cooperative role on promoting lung tumorigenesis. Thus, these investigations provided novel insights into the mechanisms of curcumin on inhibition of NSCLC cell growth and invasion and showed potential therapeutic strategies for NSCLC.
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Affiliation(s)
- Yimin Lu
- Department of Emergency, First Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People's Republic of China
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34
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Grabacka MM, Gawin M, Pierzchalska M. Phytochemical modulators of mitochondria: the search for chemopreventive agents and supportive therapeutics. Pharmaceuticals (Basel) 2014; 7:913-42. [PMID: 25192192 PMCID: PMC4190497 DOI: 10.3390/ph7090913] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 07/31/2014] [Accepted: 08/13/2014] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are crucially important for maintaining not only the energy homeostasis, but the proper cellular functions in a general sense. Impairment of mitochondrial functions is observed in a broad variety of pathological states such as neoplastic transformations and cancer, neurodegenerative diseases, metabolic disorders and chronic inflammation. Currently, in parallel to the classical drug design approaches, there is an increasing interest in the screening for natural bioactive substances, mainly phytochemicals, in order to develop new therapeutic solutions for the mentioned pathologies. Dietary phytochemicals such as resveratrol, curcumin and sulforaphane are very well tolerated and can effectively complement classical pharmacological therapeutic regimens. In this paper we disscuss the effect of the chosen phytochemicals (e.g., resveratrol, curcumin, sulforaphane) on various aspects of mitochondrial biology, namely mitochondrial biogenesis, membrane potential and reactive oxygen species production, signaling to and from the nucleus and unfolded protein response.
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Affiliation(s)
- Maja M Grabacka
- Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149 Krakow, Poland.
| | - Malgorzata Gawin
- Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149 Krakow, Poland
| | - Malgorzata Pierzchalska
- Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149 Krakow, Poland
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Howells LM, Mahale J, Sale S, McVeigh L, Steward WP, Thomas A, Brown K. Translating curcumin to the clinic for lung cancer prevention: evaluation of the preclinical evidence for its utility in primary, secondary, and tertiary prevention strategies. J Pharmacol Exp Ther 2014; 350:483-94. [PMID: 24939419 DOI: 10.1124/jpet.114.216333] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
Lung cancer is responsible for over one million deaths worldwide each year. Smoking cessation for lung cancer prevention remains key, but it is increasingly acknowledged that prevention strategies also need to focus on high-risk groups, including ex-smokers, and patients who have undergone resection of a primary tumor. Models for chemoprevention of lung cancer often present conflicting results, making rational design of lung cancer chemoprevention trials challenging. There has been much focus on use of dietary bioactive compounds in lung cancer prevention strategies, primarily due to their favorable toxicity profile and long history of use within the human populace. One such compound is curcumin, derived from the spice turmeric. This review summarizes and stratifies preclinical evidence for chemopreventive efficacy of curcumin in models of lung cancer, and adjudges the weight of evidence for use of curcumin in lung cancer chemoprevention strategies.
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Affiliation(s)
- Lynne M Howells
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - Jagdish Mahale
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - Stewart Sale
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - Laura McVeigh
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - William P Steward
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - Anne Thomas
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
| | - Karen Brown
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom
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Kwon SJ, Lee JH, Moon KD, Jeong IY, Yee ST, Lee MK, Seo KI. Isoegomaketone induces apoptosis in SK-MEL-2 human melanoma cells through mitochondrial apoptotic pathway via activating the PI3K/Akt pathway. Int J Oncol 2014; 45:1969-76. [PMID: 25119993 DOI: 10.3892/ijo.2014.2598] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/24/2014] [Indexed: 11/05/2022] Open
Abstract
Isoegomaketone (IK) is a major biologically active component of Perilla frutescens. In this study, we investigated the contribution of reactive oxygen species (ROS) to IK-induced apoptosis in human melanoma SK-MEL-2 cells. We found that IK inhibited the proliferation of SK-MEL-2 human melanoma cells in a dose-dependent manner. IK also induced sub-G1 DNA accumulation, formation of apoptotic bodies, nuclear condensation, and a DNA ladder in SK-MEL-2 cells. IK also induced activation of caspase-3 and -9, whereas caspase‑8 was unaffected. Further, N-acetyl-L-cysteine (NAC, ROS scavenger) treatment to SK-MEL-2 cells significantly reduced IK-induced cell death. Pretreatment of NAC to SK-MEL-2 cells followed by 100 µM IK reduced the protein levels of Bax and cytochrome c as well as PARP cleavage, whereas the protein level of Bcl-2 increased. Moreover, IK inhibited the phosphorylation of AKT/mTOR protein and cell proliferation induced by LY294002, a PI3K inhibitor. In conclusion, IK-induced ROS generation regulates cell growth inhibition and it induces apoptosis through caspase‑dependent and -independent pathways via modulation of PI3K/AKT signaling in SK-MEL-2 cells.
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Affiliation(s)
- Soon-Jae Kwon
- Department of Food Science and Technology, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Ju-Hye Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon, Jeonnam 540-742, Republic of Korea
| | - Kwang-Deog Moon
- Department of Food Science and Technology, Kyungpook National University, Daegu 702-701, Republic of Korea
| | - Il-Yun Jeong
- Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Jeonbuk 580-185, Republic of Korea
| | - Sung-Tae Yee
- Department of Biology, Sunchon National University, Suncheon, Jeonnam 540-742, Republic of Korea
| | - Mi-Kyung Lee
- Department of Food and Nutrition, Sunchon National University, Suncheon, Jeonnam 540-742, Republic of Korea
| | - Kwon-Il Seo
- Department of Food and Nutrition, Sunchon National University, Suncheon, Jeonnam 540-742, Republic of Korea
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Heger M, van Golen RF, Broekgaarden M, Michel MC. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer. Pharmacol Rev 2013; 66:222-307. [PMID: 24368738 DOI: 10.1124/pr.110.004044] [Citation(s) in RCA: 363] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.
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Affiliation(s)
- Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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38
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Chen QY, Zheng Y, Jiao DM, Chen FY, Hu HZ, Wu YQ, Song J, Yan J, Wu LJ, Lv GY. Curcumin inhibits lung cancer cell migration and invasion through Rac1-dependent signaling pathway. J Nutr Biochem 2013; 25:177-85. [PMID: 24445042 DOI: 10.1016/j.jnutbio.2013.10.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 09/16/2013] [Accepted: 10/04/2013] [Indexed: 12/24/2022]
Abstract
Curcumin, a natural and crystalline compound isolated from the plant Curcuma longa with low toxicity in normal cells, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about antimetastasis effects and mechanism of curcumin in lung cancer. Rac1 is an important small Rho GTPases family protein and has been widely implicated in cytoskeleton rearrangements and cancer cell migration, invasion and metastasis. In this study, we examined the influence of curcumin on in vitro invasiveness of human lung cancer cells and the expressions of Rac1. The results indicate that curcumin at 10 μM slightly reduced the proliferation of 801D lung cancer cells but showed an obvious inhibitory effect on epidermal growth factor or transforming growth factor β1-induced lung cancer cell migration and invasion. Meanwhile, we demonstrated that the suppression of invasiveness correlated with inhibition of Rac1/PAK1 signaling pathways and matrix metalloproteinase (MMP) 2 and 9 protein expression by combining curcumin treatment with the methods of Rac1 gene silence and overexpression in lung cancer cells. Laser confocal microscope also showed that Rac1-regulated actin cytoskeleton rearrangement may be involved in anti-invasion effect of curcumin on lung cancer cell. At last, through xenograft experiments, we confirmed the connection between Rac1 and the growth and metastasis inhibitory effect of curcumin in vivo. In summary, these data demonstrated that low-toxic levels of curcumin could efficiently inhibit migration and invasion of lung cancer cells through inhibition of Rac1/PAK1 signaling pathway and MMP-2 and MMP-9 expression, which provided a novel insight into the molecular mechanism of curcumin against lung cancer.
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Affiliation(s)
- Qing-yong Chen
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China.
| | - Ying Zheng
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China; Department of Pharmacy, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China
| | - De-min Jiao
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Fang-yuan Chen
- The Second Affiliated Hospital of Shaanxi Chinese Medicine University, Xianyang, Shaanxi, 712000, P.R. China
| | - Hui-zhen Hu
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Yu-quan Wu
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Jia Song
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Jie Yan
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Li-jun Wu
- Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang 310013, P.R. China
| | - Gui-yuan Lv
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, P.R. China.
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Jiang J, Jin H, Liu L, Pi J, Yang F, Cai J. Curcumin disturbed cell-cycle distribution of HepG2 cells via cytoskeletal arrangement. SCANNING 2013; 35:253-260. [PMID: 23070725 DOI: 10.1002/sca.21058] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 09/05/2012] [Accepted: 09/05/2012] [Indexed: 06/01/2023]
Abstract
Due to its extensive antitumor activity, curcumin has been focused on by more researchers. But, its antiproliferative mechanisms are still unknown. Here we studied the antiproliferative activity of curcumin in human liver cancer HepG2 cells. In order to analyze the cytotoxic activity and anticancer mechanisms of curcumin, we carried out cytotoxicity tests using 3-[4,5-dimethyl-2-thiazolyl]-2,5 diphenyltetrazolium bromide (MTT) assay. The HepG2 cell cycle distribution and the expression of tubulin were detected by flow cytometry. Alterations in morphological and cytoskeletal properties of HepG2 cells were investigated using atomic force microscopy (AFM). Simultaneously, the effects of curcumin on the growth and proliferation of HepG2 cells were also assayed by MTT method. Cells were incubated with different doses of curcumin (0-80 μmol/l) for 24 h, the cell viability decreased from 91.10 ± 3.2% to 10.84 ± 4.0%, and the 50% inhibiting concentration (IC50 ) was 23.15 ± 0.37 μmol/l. Moreover, flow cytometry quantitatively detected that curcumin treatment resulted in a dose-dependent accumulation of HepG2 cells in G2/M phase with concomitant losses from G0/G1 phase, so curcumin caused cell-cycle arrest at G2/M phase. Furthermore, we discovered that curcumin was able to upregulate the expression of tubulin in HepG2 cells. In addition, AFM analysis including cell-membrane structure and cytoskeleton networks is helpful to explain the relationship between the changes of cells and external pharmacologic stimulation.
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Affiliation(s)
- Jinhuan Jiang
- Department of Chemistry, College of Life Science and Technology, Jinan University, Guangzhou, China
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Aggeli IK, Koustas E, Gaitanaki C, Beis I. Curcumin acts as a pro-oxidant inducing apoptosis via JNKs in the isolated perfused Rana ridibunda heart. ACTA ACUST UNITED AC 2013; 319:328-39. [PMID: 23630153 DOI: 10.1002/jez.1797] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 03/26/2013] [Accepted: 04/01/2013] [Indexed: 02/05/2023]
Abstract
Amphibians are known to better tolerate and endure adverse environmental conditions such as redox imbalances conferred by reactive oxygen species (ROS), compared to mammals. Interestingly, the exact adaptation strategies and signaling mechanisms mediating these effects have not been fully elucidated. Therefore, in the present study, we probed into the molecular response of the isolated perfused Rana ridibunda heart to curcumin, in the context of mitogen-activated protein kinases (MAPKs) phosphorylation patterns and apoptotic markers occurrence. In particular, this polyphenol was found to exert a pro-oxidant effect in our model and to significantly upregulate p38-MAPK and JNKs phosphorylation (thus activation). The early apoptosis observed, substantiated by poly(ADP-ribose) polymerase (PARP) cleavage, was established to be JNKs- and ROS-mediated, while no involvement of p38-MAPK was detected. Subsequently, the pro-oxidative activity of curcumin was confirmed to mimic H(2) O(2). Furthermore, NADPH oxidase as well as Na(+) /K(+) -ATPase were found to mediate JNKs phosphorylation as well as PARP proteolytic cleavage. Curcumin exerts pleiotropic actions, both beneficial and detrimental and is currently the subject of intense scientific research. Being a low-molecular-weight antioxidant, it is intriguing to investigate curcumin's role in redox homeostasis in the amphibian heart, under conditions that apparently favor its pro-oxidative properties. Comparative studies of its multifaceted role in different species may contribute to the clarification of the signaling mechanisms it triggers and the terminal physiological response it confers. Collectively, this is to our knowledge, the first time that the signal transduction pathways stimulated by curcumin have been assessed in a non-mammalian species.
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Affiliation(s)
- Ioanna-Katerina Aggeli
- Department of Animal and Human Physiology, School of Biology, University of Athens, Panepistimioupolis, Athens, Greece
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Das S, Das J, Samadder A, Boujedaini N, Khuda-Bukhsh AR. Apigenin-induced apoptosis in A375 and A549 cells through selective action and dysfunction of mitochondria. Exp Biol Med (Maywood) 2013; 237:1433-48. [PMID: 23354402 DOI: 10.1258/ebm.2012.012148] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
We isolated apigenin (5,7,4'-trihydroxy flavone) from ethanolic extract of Lycopodium clavatum (LC) used as a homeopathic mother tincture for treatment of various diseases. We assessed the anticancer potentials of the compound using human malignant melanoma cell line A375 and a lung carcinoma cell line A549 and focussed on its putative molecular mechanism of action on apoptosis induction. We examined the cytotoxicity of apigenin in both cancer cells and normal peripheral blood mononuclear cells (PBMC). A375 cells were more prone to apigenin-induced apoptosis, as compared with A549 cells after 24 h of treatment, while PBMC showed little or no cytotoxicity to apigenin. We also evaluated the effects of apigenin on interaction with DNA by comparative analysis of circular dichroism spectral data and melting temperature profiles (Tm) of calf thymus DNA (CT-DNA) treated with or without apigenin. Reactive oxygen species (ROS) accumulation in mitochondria, super-oxide dismutase and total thiol group (GSH) activities were also analyzed. The apoptotic process involved mitochondrial pathway associated with apigenin-DNA interaction, DNA fragmentation, ROS accumulation, cytochrome c (cyt c) release and mitochondrial transmembrane potential depolarization, Bax, caspase 3, 9, PARP, up-regulation, Bcl-2 down-regulation and down-regulation of cyt c in the mitochondrial fraction. Results of mitochondrial inner membrane swelling measurements, intracellular ADP/ATP ratio and ATPase activity showed that in A549 cells, apigenin did not appear to directly target the mitochondrial oxidative phosphorylation system but rather acted at an upstream step to activate the mitochondrial apoptotic pathway. However, apigenin could directly target and impair mitochondrial function in A375 cells by breaking down their oxidative phosphorylation system. Collectively, these results suggest that apigenin exhibits anticancer potential in A375 and A549 cells that may be mediated through DNA interaction, damage and mitochondrial dysfunction either by direct or indirect action on mitochondrial oxidative phosphorylation system.
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Affiliation(s)
- Sreemanti Das
- Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, India
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Noratto GD, Jutooru I, Safe S, Angel-Morales G, Mertens-Talcott SU. The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis. Mol Nutr Food Res 2013; 57:1638-48. [PMID: 23471840 DOI: 10.1002/mnfr.201200609] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 01/05/2013] [Accepted: 01/08/2013] [Indexed: 12/14/2022]
Abstract
SCOPE Mechanisms involving the curcuminoids effects in decreasing the prooncogenic specificity protein (Sp) transcription factors, and Sp-regulated genes in SW-480 colon cancer cells and how the multidrug resistance protein (MDR1) inhibition is mediated by Sp suppression. METHODS AND RESULTS HT-29 and SW-480 colon cancer and normal CCD-18Co colon fibroblast cells were treated with curcuminoids previously analyzed by HPLC. Gene and protein expression regulation were assessed by RT-PCR, transfections with expression constructs, and Western blots. Curcuminoids (2.5-10 μg/mL) suppressed preferentially the growth of SW-480 and HT-29 compared to CCD-18Co cells and enhanced the anticancer activity of the chemotherapeutic drug 5-fluorouracil due to the suppression of MDR1. Additionally, Sp1, Sp3, and Sp4 and Sp-regulated genes were downregulated by curcuminoids in SW-480 and this was accompanied by suppression of microRNA-27a (miR-27a) and induction of ZBTB10, an mRNA target of miR-27a and a transcriptional repressor of Sp expression. This mechanism was mediated by the induction of ROS. RNA-interference and transfection with ZBTB10-expression plasmid demonstrated that MDR1 was regulated by Sp1 and Sp3 and the disruption of the miR-27a-ZBTB10-Sp axis. CONCLUSION Colon cancer treatment with curcuminoids will enhance the therapeutic effects of drugs in patients who have developed drug resistance.
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Rak S, Čimbora-Zovko T, Gajski G, Dubravčić K, Domijan AM, Delaš I, Garaj-Vrhovac V, Batinić D, Sorić J, Osmak M. Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation. Toxicol In Vitro 2013; 27:523-32. [DOI: 10.1016/j.tiv.2012.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 10/17/2012] [Accepted: 11/01/2012] [Indexed: 01/26/2023]
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Abstract
Multiple studies from independent groups find evidence for signal transducer and activator of transcription 3 (Stat3) activation in nearly 50% of lung cancers, suggesting a functional role for this target in subsets of lung cancer. On the basis of the existing evidence, we hypothesized that bioavailable curcuminoid complex may modulate lung carcinogenesis, primarily by inhibiting Stat3 activation. With the safety of this being botanically well established, the objective of these studies was to test our hypothesis in vitro and in vivo in an effort to inform the design of a phase II chemoprevention trial in former smokers. We treated non-tumor-derived, normal (but immortalized) human bronchial epithelial cells (AALE) (Lundberg et al., 2002; Pillai et al., 2011) and lung adenocarcinoma-derived cells (H441) with bioactive curcumin C3 complex. Asynchronous cells in each case were treated with curcumin for 24 h, followed by immunoblotting for Stat3 and activated Stat3-P, prior signal of which was used for normalization. We also completed a preclinical trial in which 12 mice were randomly divided into three groups and subjected to 3 days or 9 days of curcumin intraperitoneal injections, followed by analysis of lung tissues for Stat3-P changes and growth suppressive effects of the curcumin. The growth suppressive effects were measured using Cyclin D1 and the replicative helicase subunit, Mcm2, as surrogates for the proliferative capacity of the tissues. In-vitro studies with curcuminoid complex demonstrated that the activity of Stat3 in both normal bronchoepithelial cells and lung cancer-derived cells is sensitive to curcumin exposure. In a dose-dependent manner, curcumin treatment resulted in significant suppression of Stat3 phosphorylation and reduction in the proliferative capacity of both cell types. In the preclinical trial with rodent models, curcumin reduced Stat3-P and the proliferative markers CycD1 and Mcm2 in mice lung tissues in vivo. These culture and preclinical studies indicate that the activity of the Stat3 pathway can be suppressed by curcumin treatment, concomitant with a reduction in cell proliferation, supporting our hypothesis that inhibition of the Stat3 pathway represents at least one important mechanism by which curcumin elicits its effects on the bronchoepithelium. These data provide a rationale for the use of curcumin as a promising chemopreventive agent in high-risk populations such as former smokers.
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Hu YH, Huang XR, Qi MX, Hou BY. Curcumin inhibits proliferation of human lens epithelial cells: a proteomic analysis. J Zhejiang Univ Sci B 2012; 13:402-7. [PMID: 22556179 DOI: 10.1631/jzus.b1100278] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The incidence of after-cataracts [also known as posterior capsular opacification (PCO)] is between 30% and 50% three years following cataract surgery. Suppressing the proliferation of lens epithelial cells (LECs) is a primary goal in preventing PCO. Here, we investigated the proteomic regulation of the inhibitory effects of curcumin (Cur) on the proliferation of human lens epithelial B3 (HLE-B3) cells. METHODS Recombinant human basic fibroblast growth factor (rhbFGF) was used to induce proliferation of HLE-B3 cells, which were incubated with 20 mg/L Cur in a CO(2) incubator for 24 h. RESULTS We found that the absorbance (A) value of rhbFGF group was significantly higher than the A value of the control group. Furthermore, the A value of the Cur group was significantly lower compared to the rhbFGF group, with an inhibition of 53.7%. Five different protein spots were obtained from proliferative HLE-B3 cells induced by rhbFGF. Eight different protein spots were obtained in HLE-B3 cells incubated with Cur. There were the common variational protein spots at mass/charge (m/z) ratios of 8093 and 13767 between rhbFGF group and control group as well as between the Cur group and rhbFGF group. CONCLUSIONS These results show that Cur effectively inhibited HLE-B3 cell proliferation induced by rhbFGF. The protein spots at m/z of 8093 and 13767 may be the targets of Cur-induced inhibition of HLE-B3 cell proliferation. Cur may be a reliable and effective drug for prevention and treatment of polymerase chain reaction (PCR).
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Affiliation(s)
- Yan-hong Hu
- Department of Ophthalmology, the Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China.
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Chen W, Liu L, Luo Y, Odaka Y, Awate S, Zhou H, Shen T, Zheng S, Lu Y, Huang S. Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells. Cancer Prev Res (Phila) 2012; 5:778-87. [PMID: 22490436 DOI: 10.1158/1940-6207.capr-11-0551] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.
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Affiliation(s)
- Wenxing Chen
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, 71130, USA
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Lysosomal membrane permeabilization is involved in curcumin-induced apoptosis of A549 lung carcinoma cells. Mol Cell Biochem 2011; 359:389-98. [PMID: 21874542 DOI: 10.1007/s11010-011-1033-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Accepted: 08/05/2011] [Indexed: 12/21/2022]
Abstract
We previously reported that curcumin inhibited lung cancer A549 cells growth and promoted cell apoptosis in vitro. In this study, we further examined the apoptosis-related parameters, including lysosomal damage and cathepsin activation, in A549 cells exposed to curcumin. We found that curcumin caused lysosomal membrane permeabilization (LMP) and cytosolic relocation of cathepsin B (cath B) and cathepsin D (cath D). However, only Z-FA-fmk (a cath B inhibitor) but not pepstatin A (a cath D inhibitor) inhibited curcumin-induced cell apoptosis, mitochondrial membrane potential loss, and cytochrome c release. The antioxidant N-acetylcysteine and glutathione attenuated LMP, suggesting that lysosomal destabilization was dependent on the elevation of reactive oxygen species and which precedes mitochondrial dysfunction. These findings indicated a novel pathway for curcumin regulation of ROS-lysosomal-mitochondrial pathway and provided the key mechanism of regulation of LMP in cell apoptosis, which may be exploited for cancer treatment.
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Tung YT, Chen HL, Lai CW, Shen CJ, Lai YW, Chen CM. Curcumin reduces pulmonary tumorigenesis in vascular endothelial growth factor (VEGF)-overexpressing transgenic mice. Mol Nutr Food Res 2011; 55:1036-43. [DOI: 10.1002/mnfr.201000654] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 02/13/2011] [Accepted: 02/22/2011] [Indexed: 11/06/2022]
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Xiang J, Xia X, Jiang Y, Leung AW, Wang X, Xu J, Wang P, Yu H, Bai D, Xu C. Apoptosis of ovarian cancer cells induced by methylene blue-mediated sonodynamic action. ULTRASONICS 2011; 51:390-395. [PMID: 21147492 DOI: 10.1016/j.ultras.2010.11.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2010] [Revised: 11/15/2010] [Accepted: 11/17/2010] [Indexed: 05/30/2023]
Abstract
OBJECTIVE The present study aims to investigate apoptosis of ovarian cancer cells induced by methylene blue (MB)-mediated sonodynamic therapy (SDT). METHODS The MB concentration was kept constant at 100μM and ovarian cancer HO-8910 cells were exposed to ultrasound therapy for 5s with an intensity of 0.46W/cm(2). The cytotoxicity was investigated 24h after MB-mediated sonodynamic action. Apoptosis was analyzed using a flow cytometer with Annexin V-FITC and propidium iodine (PI) staining as well as fluorescence microscopy with Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured by flow cytometer with 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. RESULTS The cytotoxicity of MB-mediated SDT on HO-8910 cells after MB-mediated SDT was significantly higher than those of other treatments including ultrasound alone, MB alone and sham treatment. Flow cytometric analysis showed a significant increase in the early and late apoptotic cell populations by MB-mediated SDT of HO-8910 cells. Nuclear condensation and increased ROS levels were also found in HO-8910 cells treated by MB-mediated SDT. CONCLUSIONS Our findings demonstrated that MB-mediated sonodynamic action significantly induced apoptosis of HO-8910 cells and an increase in intracellular ROS level. This indicates that apoptosis is an important mechanism of cell death induced by MB-mediated SDT. Thus, MB-mediated SDT might be a potential therapeutic strategy for combating ovarian cancer.
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Affiliation(s)
- Junyan Xiang
- Department of Photodynamic and Sondynamic Therapy, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Ma J, Phillips L, Wang Y, Dai T, LaPage J, Natarajan R, Adler SG. Curcumin activates the p38MPAK-HSP25 pathway in vitro but fails to attenuate diabetic nephropathy in DBA2J mice despite urinary clearance documented by HPLC. Altern Ther Health Med 2010; 10:67. [PMID: 21073732 PMCID: PMC2999583 DOI: 10.1186/1472-6882-10-67] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2010] [Accepted: 11/12/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND Curcumin has anti-inflammatory, anti-oxidant, and anti-proliferative properties, and depending upon the experimental circumstances, may be pro- or anti-apoptotic. Many of these biological actions could ameliorate diabetic nephropathy. METHODS/DESIGN Mouse podocytes, cultured in basal or high glucose conditions, underwent acute exposure to curcumin. Western blots for p38-MAPK, COX-2 and cleaved caspase-3; isoelectric focusing for HSP25 phosphorylation; and DNase I assays for F- to G- actin cleavage were performed for in vitro analyses. In vivo studies examined the effects of dietary curcumin on the development of diabetic nephropathy in streptozotocin (Stz)-induced diabetes in DBA2J mice. Urinary albumin to creatinine ratios were obtained, high performance liquid chromatography was performed for urinary curcuminoid measurements, and Western blots for p38-MAPK and total HSP25 were performed. RESULTS Curcumin enhanced the phosphorylation of both p38MAPK and downstream HSP25; inhibited COX-2; induced a trend towards attenuation of F- to G-actin cleavage; and dramatically inhibited the activation of caspase-3 in vitro. In curcumin-treated DBA2J mice with Stz-diabetes, HPLC measurements confirmed the presence of urinary curcuminoid. Nevertheless, dietary provision of curcumin either before or after the induction of diabetes failed to attenuate albuminuria. CONCLUSIONS Apart from species, strain, early differences in glycemic control, and/or dosing effects, the failure to modulate albuminuria may have been due to a decrement in renal HSP25 or stimulation of the 12/15 lipoxygenase pathway in DBA2J mice fed curcumin. In addition, these studies suggest that timed urine collections may be useful for monitoring curcumin dosing and renal pharmacodynamic effects.
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