|
1
|
Manmuan S, Sirirak T, Tubtimsri S, Petchsomrit A, Chuenbarn T. Phytochemical analysis, antioxidant activity, and cytotoxic effects of Caulerpa lentillifera extracts inducing cell apoptosis and sub-G/G0-G1 cell cycle arrest in KON oral cancer cells. BMC Complement Med Ther 2025; 25:101. [PMID: 40069755 PMCID: PMC11899751 DOI: 10.1186/s12906-025-04835-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Marine algae have excellent phytoconstituents with notable biological activity and bioactive therapeutic benefits, but the anti-oral cancer activity of Caulerpa lentillifera (C. lentillifera) has not been widely studied. This study aimed to explore the anti-cancer properties of C. lentillifera to gain insights into possible treatment approaches. METHODS The three C. lentillifera extracts were prepared using the maceration method with methanol (CLM), ethanol (CLE), and acetone (CLA). The chemical composition of extracts of C. lentillifera was investigated. Its metabolite profiles were selectively further investigated using the LC-QTOF MS/MS technique and their antioxidative activity was evaluated. The cytotoxic effect on KON cells and MRC-5 cells was assessed using the MTT test. Morphological changes and apoptosis were examined through Hoechst 33,258 and AO double staining, while DAPI and FDA double labeling were used to observe the nucleus and cytoplasm. Using a flow cytometer, the percentage of cell cycle arrest was calculated and the fraction of cell death was examined. RESULTS The CLA exhibited higher quantities of TPC, TFC, chlorophyll a, and chlorophyll b compared to the CLM and CLE. The LC-QTOF MS/MS analysis revealed ten major phytochemicals in the CLA. The three C. lentillifera extracts exhibited antioxidative activity, with the CLE demonstrating significantly higher antioxidant activity compared to the CLM and CLA. In-vitro, the KON oral cancer cells exhibited sensitivity to CLA, CLE, and CLM in that order. The three extracts induced ROS-mediated cell death as well as disruption of mitochondrial membrane potential, with concentrations at IC40, IC60, and IC80 leading to apoptosis within 24 h. Furthermore, the cell cycle of KON cells was blocked in sub-G and G0-G1 by all three extracts. Notably, the extracts significantly impeded colony growth, migration, and invasion. The increase in cellular uptake was measured using the TEER test. CONCLUSION The findings showed that C. lentillifera has several functional metabolites, antioxidative activity, and strong anti-tumor properties. According to these results, C. lentillifera extracts may be utilized to treat oral cancer.
Collapse
Affiliation(s)
- Suwisit Manmuan
- Division of Pharmacology and Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand.
| | - Thanchanok Sirirak
- Division of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand
| | - Sukannika Tubtimsri
- Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand
| | - Arpa Petchsomrit
- Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand
| | - Tiraniti Chuenbarn
- Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand
| |
Collapse
|
|
2
|
Ko SY, Park S, Choi YH. Protocatechualdehyde Induced Breast Cancer Stem Cell Death via the Akt/Sox2 Signaling Pathway. Int J Mol Sci 2025; 26:1811. [PMID: 40076435 PMCID: PMC11899452 DOI: 10.3390/ijms26051811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Breast cancer (BC) is most frequently recognized in women and characterized by histological and molecular heterogeneity. Among the various subtypes, triple-negative BC remains the most challenging disease owing to the lack of effective molecular targets and the high frequency of breast cancer stem cells (BCSCs), which account for both recurrence and resistance to conventional treatments. Despite the availability of hormonal therapies and targeted treatments, patients still face early and late relapses, necessitating new cytotoxic and selective treatment strategies. Our study focuses on investigating the effects of protocatechualdehyde (PCA), a potent bioactive compound derived from Artemisia princeps, on CSCs in BC cells. PCA inhibited BC growth and mammosphere formation as the concentration increased. This agent decreased the fraction of the CD44+/CD24- population, the aldehyde dehydrogenase 1A-expressing population, and the protein level of Sox2 in breast CSCs by downregulating Akt and pAkt. Moreover, PCA treatment reduced the tumor volume and weight in 4T1-challenged BALB/c mice. Collectively, our findings support the anti-tumor effect of Akt/Sox2-targeting PCA, suggesting a novel utilization of PCA in BC therapy.
Collapse
Affiliation(s)
- Seung-Yeon Ko
- Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea; (S.-Y.K.); (S.P.)
- Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Seonghee Park
- Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea; (S.-Y.K.); (S.P.)
| | - Youn-Hee Choi
- Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea; (S.-Y.K.); (S.P.)
- Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| |
Collapse
|
|
3
|
Lee SO, Joo SH, Park J, Khong QT, Seo SY, Yoon G, Park JW, Na M, Shim JH. Deoxybouvardin Glucoside Induces Apoptosis in Oxaliplatin-Sensitive and -Resistant Colorectal Cancer Cells via Reactive Oxygen Species-Mediated Activation of JNK and p38 MAPK. J Microbiol Biotechnol 2025; 35:e2410008. [PMID: 39947664 DOI: 10.4014/jmb.2410.10008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/22/2024] [Accepted: 12/06/2024] [Indexed: 03/06/2025]
Abstract
The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.
Collapse
Affiliation(s)
- Seung-On Lee
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Sang Hoon Joo
- College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea
| | - Jisu Park
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Quan T Khong
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Si Yeong Seo
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Goo Yoon
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Jin Woo Park
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - MinKyun Na
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jung-Hyun Shim
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
- The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, P.R. China
| |
Collapse
|
|
4
|
Abdelaziz MA, Alalawy AI, Sobhi M, Alatawi OM, Alaysuy O, Alshehri MG, Mohamed ELI, Abdelaziz MM, Algrfan IA, Mohareb RM. Elaboration of chitosan nanoparticles loaded with star anise extract as a therapeutic system for lung cancer: Physicochemical and biological evaluation. Int J Biol Macromol 2024; 279:135099. [PMID: 39197631 DOI: 10.1016/j.ijbiomac.2024.135099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/13/2024] [Accepted: 08/24/2024] [Indexed: 09/01/2024]
Abstract
The research study aimed to maximize the important medical role of star anise extract (SAE) through its loading on a widely available natural polymer (chitosan, Cs). Thus, SAE loaded chitosan nanoparticles (CsNPs) was prepared. The finding illustrated the formation of spherical particles of SAE loaded CsNPs as proved by transmission electron microscope (TEM). In addition, the average particle size of CsNPs and SAE loaded CsNPs are 131.8 ± 24.63 and 318.5 ± 73.94 nm, respectively. Scanning electron microscope (SEM) showed the presence of many spherical particles deposited on the surface of CsNPs owing to the deposition of SAE on the surface and encapsulated into pores of CsNPs. It also showed the presence of elements such as sodium, potassium, copper, magnesium, zinc, calcium, and iron, as well as the elements that accompanied with CsNPs: carbon, oxygen, nitrogen, and phosphorus. The extract was rich in bioactive components, such as anethole, shikimic acid, and different flavonoids, contributing to its medicinal qualities. The bioactive molecules in SAE were assessed by chromatographic analysis. Using the agar well diffusion test, the antibacterial qualities of CsNPs and SAE loaded CsNPs were evaluated against pathogenic bacteria linked to lung illnesses. The most significant inhibition zones showed that the SAE loaded CsNPs had the most antibacterial activity. The anticancer activity using MTT assay was used in the biological assessments to determine the cytotoxicity against the NCl-H460 lung cancer cell line. The results showed that CsNPs loaded with SAE considerably decreased cell viability in a dose-dependent manner, with the most significant anticancer impact by SAE loaded CsNPs. Furthermore, in vivo tests on lung cancer therapy revealed that when compared to other treatment groups, the SAE loaded CsNPs group showed the greatest reduction in tumor biomarkers and inflammation, as seen by decreased levels of Plasma malondialdehyde (MDA), tumor protein 53 (p53), Tumor necrosis factor-alpha (TNF- alpha), and fibronectin. Results concluded that these thorough characterizations, biological assessments, and antibacterial tests have confirmed the effective integration of SAE into CsNPs. Further, SAE loaded CsNPs could be a suitable option for various biomedical applications in tackling lung cancer and the inactivation of bacterial infection.
Collapse
Affiliation(s)
- Mahmoud A Abdelaziz
- Organic Chemistry Research Laboratory, Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia.
| | - Adel I Alalawy
- Department of Biochemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Mohamed Sobhi
- Organic Chemistry Research Laboratory, Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Omar M Alatawi
- Organic Chemistry Research Laboratory, Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Omaymah Alaysuy
- Organic Chemistry Research Laboratory, Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Maryam G Alshehri
- Department of Mathematics, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - ELsiddig Idriss Mohamed
- Department of Statistics, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Maiar M Abdelaziz
- Department of Mathematics, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Ibrahim A Algrfan
- Organic Chemistry Research Laboratory, Department of Chemistry, Faculty of Science, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
| | - Rafat M Mohareb
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| |
Collapse
|
|
5
|
Xu P, Zhou J, Xing X, Hao Y, Gao M, Li Z, Li X, Li M, Xiao Y. Melitoxin Inhibits Proliferation, Metastasis, and Invasion of Glioma U251 Cells by Down-regulating F2RL1. Appl Biochem Biotechnol 2024; 196:6234-6252. [PMID: 38252207 DOI: 10.1007/s12010-023-04841-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2023] [Indexed: 01/23/2024]
Abstract
As the principal active component of bee venom, melittin has an anti-cancer effect in different cancers. This study was aimed to investigate the effect of melittin in glioma and explore whether F2RL1 is closely involved in glioblastoma cells proliferation. TCGA and GES databases were used to evaluate the role of F2RL1 in gliomas. The U251 cells were divided into a control lentivirus + PBS group (NC-PBS), F2RL1 intervention lentivirus + PBS group (KD-PBS), control lentivirus + melittin group (NC-melittin), and F2RL1 intervention lentivirus + melittin group (KD-melittin). Cell proliferation was detected by MTT and EDU staining assays. The apoptosis rate was assessed by flow cytometry. Expressions of genes related to apoptosis, cycle arrest, migration, and invasion were detected by qRT-PCR. Cellular LDH concentrations were detected by ELISA. The subcutaneous tumor volume of nude mice was analyzed by xenograft method. F2RL1 was significantly overexpressed in glioma tissues and were reduced in the melittin-treated group compared to the blank group. F2RL1 knockdown and melittin alone or in combination increased the proportion of cells in the G1-phase, and the combination was more pronounced. The KD-melittin group showed a decrease in the number of viable cells at 24, 48, 72, and 96 h compared to the NC-PBS group. The number of cell migration and invasion was decreased in the KD-melittin group compared to the other groups. Moreover, the genes related to cell cycle arrest and apoptosis were significantly changed in the KD-melittin group. At weeks 4, 5, and 6, the tumor volume in the KD-melittin group was smaller than that in the KD-PBS group and NC-melittin group. Interference with the target gene F2RL1 inhibited the proliferation of glioma U251 cells, and melittin treatment inhibited the proliferation of glioma U251 cells. Melittin inhibited the proliferation of glioma U251 cells by suppressing the expression of target gene F2RL1.
Collapse
Affiliation(s)
- Peng Xu
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Jie Zhou
- Department of Nursing, Liaocheng Vocational and Technical College, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Xiaohui Xing
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Yuan Hao
- Department of Pathology, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Mingxu Gao
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Zhongchen Li
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Xin Li
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China
| | - Mengyou Li
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China.
| | - Yilei Xiao
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong Province, 252000, People's Republic of China.
| |
Collapse
|
|
6
|
de Lima CA, Maquedano LK, Jaalouk LS, dos Santos DC, Longato GB. Biflavonoids: Preliminary Reports on Their Role in Prostate and Breast Cancer Therapy. Pharmaceuticals (Basel) 2024; 17:874. [PMID: 39065725 PMCID: PMC11279920 DOI: 10.3390/ph17070874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/19/2024] [Accepted: 06/22/2024] [Indexed: 07/28/2024] Open
Abstract
Dimeric flavonoids, also called biflavonoids, are bioactive compounds that exhibit various activities described in the literature, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antioxidant, vasorelaxant, and anticancer properties. This work focuses on the anticancer action of naturally occurring dimeric flavonoids against prostate and breast cancer, as well as on the mechanisms of action involved in their activity and presents the most current information on this subject in the literature. In the present review, we summarize the latest findings on the antiproliferative activity of 33 dimeric flavonoid-based compounds selected from recently published studies. The tests conducted were in silico and in vitro and demonstrated the cytotoxic activity potential of biflavonoids against prostate and breast tumor cells. Biflavonoids were capable of interfering with the migration and replication of cancer cells and their mechanism of action is related to cell death pathways, especially apoptosis, necrosis, and ferroptosis. These compounds decreased mitochondrial membrane potential and significantly increased intracellular levels of reactive oxygen species (ROS). Additionally, they significantly upregulated the expression of p21, Bax, and cleaved caspase-3, while downregulating Bcl-2 and caspase-3 levels, indicating their cell death mechanism of action is through the Bcl-2/Bax/cleaved caspase-3 pathway and cell cycle arrest. The biflavonoids here related have shown promising anticancer activity and are considered potential drug candidates for prostate and breast cancer treatment.
Collapse
Affiliation(s)
| | | | | | | | - Giovanna Barbarini Longato
- Laboratory of Molecular Pharmacology and Bioactive Compounds, São Francisco University, 218 São Francisco Avenue, Bragança Paulista 12916-900, SP, Brazil; (C.A.d.L.); (L.K.M.); (L.S.J.); (D.C.d.S.)
| |
Collapse
|
|
7
|
Hur GH, Lee TK, Cho YJ, Kim JH, Park JHY, Yang H, Lee KW. Optimization of cultivar, germination time and extraction for radish sprout extract with high sulforaphene content. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:5010-5020. [PMID: 38314949 DOI: 10.1002/jsfa.13357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 01/10/2024] [Indexed: 02/07/2024]
Abstract
BACKGROUND Cruciferous vegetable sprout has been highlighted as a promising functional material rich in bioactive compounds called isothiocyanates (ITCs) and it can be grown in very short periods in controlled indoor farms. However, because ITCs content depends on multiple factors such as cultivar, germination time and myrosinase activity, those variables need to be controlled during germination or extraction to produce functional materials enriched in ITCs. Sulforaphene (SFEN), an ITC found primarily in radishes (Raphanus sativus L.), exerts beneficial effects on obesity. However, the optimal germination and extraction conditions for radish sprout (RSP) to increase SFEN content remain unascertained, and the extract's anti-obesity effect has yet to be evaluated. RESULTS The present study found that the SFEN content was highest in purple radish sprout (PRSP) among the six cultivars investigated. Optimal SFEN content occurred after 2 days of PRSP germination (2 days PRSP). To maximize the dry matter yield, total ITCs and SFEN contents in RSP extract, we found the optimal conditions for extracting PRSP [27.5 °C, 60 min, 1:75.52 solute/solvent (w/v), no ascorbic acid] using response surface methodology. Consistent with high SFEN content, 2 days PRSP extract significantly outperformed 3 days or 4 days PRSP extract in inhibiting lipid accumulation in 3T3-L1 cells. Moreover, 2 days PRSP extract suppressed adipogenesis and lipogenesis-related protein expression. CONCLUSION Regarding the cultivar, germination time and extraction conditions, optimally produced PRSP extract contains high SFEN content and exerts anti-obesity effects. Thus, we suggest PRSP extract as a potent functional material for obesity prevention. © 2024 Society of Chemical Industry.
Collapse
Affiliation(s)
- Gi Hyun Hur
- Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
| | - Tae Kyung Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
| | - Yeon-Jin Cho
- Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea
| | - Jong Hun Kim
- Department of Food Science and Biotechnology, Sungshin University, Seoul, Republic of Korea
- Basic Science Research Institute, Sungshin University, Seoul, Republic of Korea
| | | | - Hee Yang
- Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea
| | - Ki Won Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea
- Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea
- Advanced Institute of Convergence Technology, Seoul National University, Suwon, Republic of Korea
- Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
- Institutes of Green Bio Science & Technology, Seoul National University, Pyeongchang, Republic of Korea
- Center for Food and Bio convergence, Seoul National University, Seoul, Republic of Korea
| |
Collapse
|
|
8
|
Saeedi F, Salehi M, Kamali MJ, Mir MA, Kazemi S, Shirafkan F, Neyshaburi EZ, Moeeni R, Gorji N, Memariani Z. Evaluation of the cytotoxic activities of the essential oil from Pistacia atlantica Desf. oleoresin on human gastric cancer cell lines. Med Oncol 2024; 41:148. [PMID: 38733486 DOI: 10.1007/s12032-024-02339-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 02/21/2024] [Indexed: 05/13/2024]
Abstract
Numerous herbal products have been the subject of research regarding their potential role in cancer prevention or adjuvant therapy. Pistacia atlantica and its main phytochemicals have garnered significant attention for their potential anti-cancer effects. The study aimed to assess the growth inhibitory effects of P. atlantica essential oil (PAEO) on MKN-45 and AGS cells. This study quantified the volatile compounds in PAEO using Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, MKN-45 and AGS cells were treated with varying concentrations of PAEO (5%, 2.5%, 1.25%, 0.625%, 0.3125%, 0.156%, 0.0781%, 0.0391%, 0.0195%) for 24 h. Cell viability was evaluated through the MTT assay. The impact of PAEO on gene expression was investigated by quantifying the mRNA levels of Bax and Bcl2 in the various experimental groups using quantitative Real-Time PCR (qRT-PCR) analysis. Additionally, flow cytometry was utilized to evaluate apoptosis in the treated cells. The analysis of PAEO revealed that α-pinene was the predominant monoterpene, constituting 87.9% of the oil composition. The cytotoxic effects of PAEO were evaluated, and it was found that the oil significantly reduced the viability of MKN-45 and AGS cells. The IC50 for MKN-45 cells was determined to be 1.94 × 10-3% after 24 h of treatment, while for AGS cells the IC50 was 2.8 × 10-3% after 24 h. Additionally, the research revealed that PAEO triggered a notable rise in apoptotic cells in both AGS and MKN-45 cell lines. Moreover, at the molecular level, the findings indicated an increase in Bax expression and a decrease in Bcl2 mRNA expression, providing further evidence of the induction of apoptosis in both MKN-45 and AGS cell lines following PAEO treatment. The findings of this study offer evidence supporting the cytotoxic effects of PAEO on gastric cancer cell lines by promoting apoptosis. The findings suggest that PAEO may offer potential as a therapeutic candidate in managing and treating gastric cancer.
Collapse
Affiliation(s)
- Fatemeh Saeedi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Salehi
- Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
- Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Javad Kamali
- Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mahsa Aghajani Mir
- Deputy of Research and Technology, Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Fatemeh Shirafkan
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Ebrahim Zabihi Neyshaburi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Reihaneh Moeeni
- Traditional Medicine and History of Medical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Narjes Gorji
- Traditional Medicine and History of Medical Sciences Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Zahra Memariani
- Pharmaceutical Sciences Research Center, Babol University of Medical Sciences, Babol, Iran.
| |
Collapse
|
|
9
|
Manzano JAH, Abellanosa EA, Aguilar JP, Brogi S, Yen CH, Macabeo APG, Austriaco N. Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations. Cells 2024; 13:772. [PMID: 38727308 PMCID: PMC11082999 DOI: 10.3390/cells13090772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant Voacanga globosa, along with their mechanisms of action. Thus, the alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.1, A431, MCF-7, A549, PC-3, and SKOV-3) using MTT and CellTiter-Blue assays. Globospiramine (1) was also screened against a panel of breast cancer cell lines using the sulforhodamine B (SRB) assay and showed moderate cytotoxicity. It also promoted the activation of apoptotic effector caspases 3 and 7 using Caspase-Glo 3/7 and CellEvent-3/7 apoptosis assays. Increased expressions of cleaved caspase 3 and PARP in A549 cells treated with 1 were also observed. Apoptotic activity was also confirmed when globospiramine (1) failed to promote the rapid loss of membrane integrity according to the HeLa cell membrane permeability assay. Network pharmacology analysis, molecular docking, and molecular dynamics simulations identified MAPK14 (p38α), a pharmacological target leading to cancer cell apoptosis, as a putative target. Low toxicity risks and favorable drug-likeness were also predicted for 1. Overall, our study demonstrated the anticancer potentials and apoptotic mechanisms of globospiramine (1), validating the traditional medicinal use of Voacanga globosa.
Collapse
Affiliation(s)
- Joe Anthony H. Manzano
- The Graduate School, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
- UST Laboratories for Vaccine Science, Molecular Biology and Biotechnology, Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
- Laboratory for Organic Reactivity, Discovery, and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
| | - Elian Angelo Abellanosa
- Laboratory for Organic Reactivity, Discovery, and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
| | - Jose Paolo Aguilar
- UST Laboratories for Vaccine Science, Molecular Biology and Biotechnology, Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy;
| | - Chia-Hung Yen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Allan Patrick G. Macabeo
- Laboratory for Organic Reactivity, Discovery, and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
- Department of Chemistry, College of Science, University of Santo Tomas, España Blvd., Manila 1015, Philippines
| | - Nicanor Austriaco
- UST Laboratories for Vaccine Science, Molecular Biology and Biotechnology, Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., Manila 1015, Philippines;
- Department of Biological Sciences, College of Science, University of Santo Tomas, España Blvd., Manila 1015, Philippines
| |
Collapse
|
|
10
|
Mediratta K, El-Sahli S, Marotel M, Awan MZ, Kirkby M, Salkini A, Kurdieh R, Abdisalam S, Shrestha A, Di Censo C, Sulaiman A, McGarry S, Lavoie JR, Liu Z, Lee SH, Li X, Sciumè G, D’Costa VM, Ardolino M, Wang L. Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model. Front Immunol 2024; 15:1366197. [PMID: 38601156 PMCID: PMC11004431 DOI: 10.3389/fimmu.2024.1366197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/18/2024] [Indexed: 04/12/2024] Open
Abstract
Introduction Chemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now. Methods We used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses. Results We identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors. Discussion Conclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC.
Collapse
Affiliation(s)
- Karan Mediratta
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Sara El-Sahli
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Marie Marotel
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Muhammad Z. Awan
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Department of Biotechnology, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
| | - Melanie Kirkby
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Ammar Salkini
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Reem Kurdieh
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Salman Abdisalam
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Amit Shrestha
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Chiara Di Censo
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrew Sulaiman
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Department of Pathology, John Hopkins University School of Medicine, Baltimore, MD, United States
| | - Sarah McGarry
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
| | - Jessie R. Lavoie
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada
| | - Zhen Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
| | - Xuguang Li
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Sir Frederick G. Banting Research Centre, Ottawa, ON, Canada
| | - Giuseppe Sciumè
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Instituto Pasteur Italia – Fondazione Cenci Bolognetti, Roma, Italy
| | - Vanessa M. D’Costa
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
| | - Michele Ardolino
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
| |
Collapse
|
|
11
|
Tsai CH, Huang HC, Lin KJ, Liu JM, Chen GL, Yeh YH, Lu TL, Lin HW, Lu MT, Chu PC. Inhibition of Autophagy Aggravates Arachis hypogaea L. Skin Extracts-Induced Apoptosis in Cancer Cells. Int J Mol Sci 2024; 25:1345. [PMID: 38279345 PMCID: PMC10816816 DOI: 10.3390/ijms25021345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/11/2024] [Accepted: 01/20/2024] [Indexed: 01/28/2024] Open
Abstract
The skin of Arachis hypogaea L. (peanut or groundnut) is a rich source of polyphenols, which have been shown to exhibit a wider spectrum of noteworthy biological activities, including anticancer effects. However, the anticancer activity of peanut skin extracts against melanoma and colorectal cancer (CRC) cells remains elusive. In this study, we systematically investigated the cytotoxic, antiproliferative, pro-apoptotic, and anti-migration effects of peanut skin ethanolic extract and its fractions on melanoma and CRC cells. Cell viability results showed that the ethyl acetate fraction (AHE) of peanut skin ethanolic crude extract and one of the methanolic fractions (AHE-2) from ethyl acetate extraction exhibited the highest cytotoxicity against melanoma and CRC cells but not in nonmalignant human skin fibroblasts. AHE and AHE-2 effectively modulated the cell cycle-related proteins, including the suppression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), phosphorylation of Retinoblastoma (p-Rb), E2F1, Cyclin A, and activation of tumor suppressor p53, which was associated with cell cycle arrest and paralleled their antiproliferative efficacies. AHE and AHE-2 could also induce caspase-dependent apoptosis and inhibit migration activities in melanoma and CRC cells. Moreover, it is noteworthy that autophagy, manifested by microtubule-associated protein light chain 3B (LC3B) conversion and the aggregation of GFP-LC3, was detected after AHE and AHE-2 treatment and provided protective responses in cancer cells. Significantly, inhibition of autophagy enhanced AHE- and AHE-2-induced cytotoxicity and apoptosis. Together, these findings not only elucidate the anticancer potential of peanut skin extracts against melanoma and CRC cells but also provide a new insight into autophagy implicated in peanut skin extracts-induced cancer cell death.
Collapse
Affiliation(s)
- Chia-Hung Tsai
- Department of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427213, Taiwan;
| | - Hui-Chi Huang
- School of Chinese Medicine & Graduate Institute of Chinese Medicine, China Medical University, Taichung 406040, Taiwan;
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 406040, Taiwan;
| | - Kuan-Jung Lin
- Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 33004, Taiwan;
- Department of Urology, College of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Jui-Ming Liu
- Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 33004, Taiwan;
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan
| | - Guan-Lin Chen
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 406040, Taiwan; (G.-L.C.); (M.-T.L.)
| | - Yi-Hsien Yeh
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 406040, Taiwan;
| | - Te-Ling Lu
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung 406040, Taiwan; (T.-L.L.); (H.-W.L.)
- Department of Pharmacy, China Medical University Hospital, Taichung 406040, Taiwan
| | - Hsiang-Wen Lin
- School of Pharmacy, College of Pharmacy, China Medical University, Taichung 406040, Taiwan; (T.-L.L.); (H.-W.L.)
- Department of Pharmacy, China Medical University Hospital, Taichung 406040, Taiwan
| | - Meng-Tien Lu
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 406040, Taiwan; (G.-L.C.); (M.-T.L.)
| | - Po-Chen Chu
- Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 406040, Taiwan; (G.-L.C.); (M.-T.L.)
| |
Collapse
|
|
12
|
Hanuš L, Naor T, Gloriozova T, Dembitsky VM. Natural isothiocyanates of the genus Capparis as potential agonists of apoptosis and antitumor drugs. World J Pharmacol 2023; 12:35-52. [DOI: 10.5497/wjp.v12.i4.35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/12/2023] [Accepted: 11/24/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND Using gas chromatography-mass spectrometry (GC/MS) analysis, we examined the composition of volatile components present in the yellow and green fruits, seeds, and jam of the scrambling shrub Capparis cartilaginea (C. cartilaginea). These plant samples were collected from Kibbutz Yotvata in Israel. In all the tested samples, isothiocyanates were identified. Utilizing the PASS program, we ascertained the biological activity of these isothiocyanates present in the Capparis genus. The study results highlighted that all isothiocyanates could potentially act as apoptosis agonists, making them strong candidates for antitumor drugs. This information holds significant value for the fields of medicinal chemistry, pharmacology, and practical medicine.
AIM To investigate the volatile components present in the yellow and green fruits, seeds, and jam of the C. cartilaginea shrub using GC/MS analysis, to detect isothiocyanates in all the analyzed plant samples, and to assess the biological activity of these isothiocyanates utilizing the PASS program.
METHODS We utilized two primary methods to analyze the volatile compounds present in the yellow and green fruits, seeds, and jams of the C. cartilaginea, native to Israel. We identified biologically active isothiocyanates in these samples. Their anticipated biological activities were determined using the PASS program, with the most dominant activities being apoptosis agonist, anticarcinogenic, and antineoplastic specifically for genitourinary cancer.
RESULTS Fruits, seeds, and jams containing isothiocyanates, which exhibit antineoplastic and anticarcinogenic activities, could be suggested for cancer prevention and management. Specific isothiocyanates, with therapeutic potential in this realm, could be recommended as potent anticancer agents in practical medicine following clinical trials.
CONCLUSION The discovery that isothiocyanates exhibit potent antineoplastic and anticarcinogenic activities was unexpected. Additionally, certain isothiocyanates demonstrated antifungal, antiviral (specifically against arbovirus), and antiparasitic properties.
Collapse
Affiliation(s)
- Lumír Hanuš
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Ein Kerem Campus, Jerusalem 91120, Israel
| | - Tuvia Naor
- Food Chemistry, Kibbutz, Yotvata 8882000, Israel
| | - Tatyana Gloriozova
- Department of Bioinformatics, Institute of Biomedical Chemistry, Moscow 119121, Russia
| | - Valery M Dembitsky
- Centre for Applied Research and Innovation, Lethbridge College, Lethbridge AB T1K 1L6, Canada
| |
Collapse
|
|
13
|
Moiseeva N, Eroshenko D, Laletina L, Rybalkina E, Susova O, Karamysheva A, Tolmacheva I, Nazarov M, Grishko V. The Molecular Mechanisms of Oleanane Aldehyde-β-enone Cytotoxicity against Doxorubicin-Resistant Cancer Cells. BIOLOGY 2023; 12:biology12030415. [PMID: 36979107 PMCID: PMC10045559 DOI: 10.3390/biology12030415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023]
Abstract
Oleanane aldehyde-β-enone (OA), being the semi-synthetic derivative of the triterpenoid betulin, effectively inhibits the proliferation of HBL-100 and K562 cancer cells (IC50 0.47–0.53 µM), as well as the proliferation of their resistant subclones with high P-gp expression HBL-100/Dox, K562/i-S9 and K562/i-S9_Dox (IC50 0.45−1.24 µM). A molecular docking study, rhodamine efflux test, synergistic test with Dox, and ABC transporter gene expression were used to investigate the ability of OA to act as a P-gp substrate or inhibitor against Dox-resistant cells. We noted a trend toward a decrease in ABCB1, ABCC1 and ABCG2 expression in HBL-100 cells treated with OA. The in silico and in vitro methods suggested that OA is neither a direct inhibitor nor a competitive substrate of P-gp in overexpressing P-gp cancer cells. Thus, OA is able to overcome cellular resistance and can accumulate in Dox-resistant cells to realize toxic effects. The set of experiments suggested that OA toxic action can be attributed to activating intrinsic/extrinsic or only intrinsic apoptosis pathways in Dox-sensitive and Dox-resistant cancer cells, respectively. The cytotoxicity of OA in resistant cells is likely mediated by a mitochondrial cell death pathway, as demonstrated by positive staining with Annexin V–FITC, an increasing number of cells in the subG0/G1 phase, reactive oxygen species generation, mitochondrial dysfunction, cytochrome c migration and caspases-9,-6 activation.
Collapse
Affiliation(s)
- Natalia Moiseeva
- The N.N. Blokhin National Medical Research Center of Oncology, Health Ministry of Russia, 115478 Moscow, Russia
| | - Daria Eroshenko
- Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural Branch, Russian Academy of Science, 614013 Perm, Russia
| | - Lidia Laletina
- The N.N. Blokhin National Medical Research Center of Oncology, Health Ministry of Russia, 115478 Moscow, Russia
| | - Ekaterina Rybalkina
- The N.N. Blokhin National Medical Research Center of Oncology, Health Ministry of Russia, 115478 Moscow, Russia
| | - Olga Susova
- The N.N. Blokhin National Medical Research Center of Oncology, Health Ministry of Russia, 115478 Moscow, Russia
| | - Aida Karamysheva
- The N.N. Blokhin National Medical Research Center of Oncology, Health Ministry of Russia, 115478 Moscow, Russia
| | - Irina Tolmacheva
- Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural Branch, Russian Academy of Science, 614013 Perm, Russia
| | - Mikhail Nazarov
- Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural Branch, Russian Academy of Science, 614013 Perm, Russia
| | - Victoria Grishko
- Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural Branch, Russian Academy of Science, 614013 Perm, Russia
- Correspondence:
| |
Collapse
|
|
14
|
Attenuation of Inflammatory Responses in Breast and Ovarian Cancer Cells by a Novel Chalcone Derivative and Its Increased Potency by Curcumin. Mediators Inflamm 2023; 2023:5156320. [PMID: 36687217 PMCID: PMC9851785 DOI: 10.1155/2023/5156320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 11/20/2022] [Accepted: 12/07/2022] [Indexed: 01/15/2023] Open
Abstract
Background Breast and ovarian cancers are two common malignancies in women and a leading cause of death globally. The aim of the present study was to explore the effects of a novel chalcone derivative 1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)-3-(p-tolyl)propane-1-one (MPP) individually or combined with curcumin, a well-known herbal medicine with anticancer properties, as a new combination therapy on inflammatory pathways in breast and ovarian cancer cell lines. Methods LPS-induced NF-κB DNA-binding activity and the levels of proinflammatory cytokines were measured in the MPP- and MPP-curcumin combination-treated MDA-MB-231 and SKOV3 cells by ELISA-based methods. The expression of COX2, INOS, and MMP9 genes and nitrite levels was also evaluated by real-time qRT-PCR and Griess method, respectively. IκB levels were evaluated by Western blotting. Results MPP significantly inhibited the DNA-binding activity of NF-κB in each cell line and subsequently suppressed the expression of downstream genes including COX2, MMP9, and INOS. The levels of proinflammatory cytokines, as well as NO, were also decreased in response to MPP. All the effects of MPP were enhanced by the addition of curcumin. MPP, especially when combined with curcumin, caused a remarkable increase in the concentration of IκB. Conclusion MPP and its coadministration with curcumin effectively reduced the activity of the NF-κB signaling pathway, leading to a reduced inflammatory response in the environment of cancer cells. Thus, MPP, either alone or combined with curcumin, might be considered an effective remedy for the suppression of inflammatory processes in breast and ovarian cancer cells.
Collapse
|
|
15
|
Akter Z, Khan FZ, Khan MA. Gold Nanoparticles in Triple-Negative Breast Cancer Therapeutics. Curr Med Chem 2023; 30:316-334. [PMID: 34477507 DOI: 10.2174/0929867328666210902141257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer with enhanced metastasis and poor survival. Though chemotherapy, radiotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), and gene delivery are used to treat TNBC, various side effects limit these therapeutics against TNBC. In this review article, we have focused on the mechanism of action of gold nanoparticles (AuNPs) to enhance the efficacy of therapeutics with targeted delivery on TNBC cells. METHODS Research data were accumulated from PubMed, Scopus, Web of Science, and Google Scholar using searching criteria "gold nanoparticles and triple-negative breast cancer" and "gold nanoparticles and cancer". Though we reviewed many old papers, the most cited papers were from the last ten years. RESULTS Various studies indicate that AuNPs can enhance bioavailability, site-specific drug delivery, and efficacy of chemotherapy, radiotherapy, PTT, and PDT as well as modulate gene expression. The role of AuNPs in the modulation of TNBC therapeutics through the inhibition of cell proliferation, progression, and metastasis has been proved in vitro and in vivo studies. As these mechanistic actions of AuNPs are most desirable to develop drugs with enhanced therapeutic efficacy against TNBC, it might be a promising approach to apply AuNPs for TNBC therapeutics. CONCLUSION This article reviewed the mechanism of action of AuNPs and their application in the enhancement of therapeutics against TNBC. Much more attention is required for studying the role of AuNPs in developing them either as a single or synergistic anticancer agent against TNBC.
Collapse
Affiliation(s)
- Zakia Akter
- Biological Sciences Department, The University of Texas at Dallas, Richardson, Texas, USA
| | - Fabiha Zaheen Khan
- Biochemistry and Molecular Biology, Department of Biological Sciences, University of North Texas, Denton, Texas, USA
| | - Md Asaduzzaman Khan
- Key laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, P.R. China
| |
Collapse
|
|
16
|
Sachdeva A, Dhawan D, Jain GK, Yerer MB, Collignon TE, Tewari D, Bishayee A. Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer. Cancers (Basel) 2022; 15:cancers15010268. [PMID: 36612264 PMCID: PMC9818473 DOI: 10.3390/cancers15010268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.
Collapse
Affiliation(s)
- Alisha Sachdeva
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Dimple Dhawan
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Gaurav K. Jain
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
- Center for Advanced Formulation Development, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Mükerrem Betül Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey
| | - Taylor E. Collignon
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
- Correspondence: or (D.T.); or (A.B.)
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
- Correspondence: or (D.T.); or (A.B.)
| |
Collapse
|
|
17
|
Ursolic Acid Analogs as Potential Therapeutics for Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248981. [PMID: 36558113 PMCID: PMC9785537 DOI: 10.3390/molecules27248981] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Ursolic acid (UA) is a pentacyclic triterpene isolated from a large variety of vegetables, fruits and many traditional medicinal plants. It is a structural isomer of Oleanolic Acid. The medicinal application of UA has been explored extensively over the last two decades. The diverse pharmacological properties of UA include anti-inflammatory, antimicrobial, antiviral, antioxidant, anti-proliferative, etc. Especially, UA holds a promising position, potentially, as a cancer preventive and therapeutic agent due to its relatively non-toxic properties against normal cells but its antioxidant and antiproliferative activities against cancer cells. Cell culture studies have shown interference of UA with multiple pharmacological and molecular targets that play a critical role in many cells signaling pathways. Although UA is considered a privileged natural product, its clinical applications are limited due to its low absorption through the gastro-intestinal track and rapid elimination. The low bioavailability of UA limits its use as a therapeutic drug. To overcome these drawbacks and utilize the importance of the scaffold, many researchers have been engaged in designing and developing synthetic analogs of UA via structural modifications. This present review summarizes the synthetic UA analogs and their cytotoxic antiproliferative properties reported in the last two decades.
Collapse
|
|
18
|
Dietary Polyphenol Intake and Gastric Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:cancers14235878. [PMID: 36497359 PMCID: PMC9737802 DOI: 10.3390/cancers14235878] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Phenolic compound consumption may have a protective effect against gastric cancer (GC). Most GC studies focus on the flavonoids class, but results are conflicting and knowledge gaps remain for other classes and total polyphenol intake. This study aimed to assess the association between polyphenol intake (total, flavonoids, and other classes) and GC. METHODS In this systematic review and meta-analysis, the PubMed, Embase, Scopus, LILACS, Web of Science, and OpenGrey databases were searched for studies published up to 20 March 2022. Case-control and cohort studies analyzing the association between polyphenol intake and GC were included. For the meta-analysis, pooled summary estimates were calculated using a random-effects model, and the estimates extracted adjusted for most variables. Subgroup analyses were performed for subclass (e.g., flavonoids and other classes), sex, geographical area, study design, anatomical subtype, histological subtype, family history of GC and fruit and/or vegetable intake. The study was registered with PROSPERO (#CRD42022306014). FINDINGS The search identified 2752 records, of which 19 studies published during the period 1999-2021 including a total of 1,197,857 subjects were eligible. Polyphenol consumption reduced GC risk by 29% (RR = 0.71; 95% CI: 0.62-0.81; I2 = 60.5%); while flavonoid intake decreased GC risk by 28% (RR = 0.72; 95% CI: 0.61-0.85; I2 = 64.3%), similar to the reduction fort other classes (RR = 0.65; 95% CI: 0.54-0.79; I2 = 72.0%). Protective effects against GC were observed in both sexes (male, RR = 0.79; 95% CI: 0.67-0.94, I2 = 31.6%; female, RR = 0.65; 95% CI: 0.48-0.87, I2 = 49.7%) and for intestinal subtype (RR = 0.65; 95% CI: 0.52-0.82, I2 = 0.0%). By continent, polyphenol consumption reduced GC risk in both Europe (RR = 0.67; 95% CI: 0.57-0.79, I2 = 44.2%) and Asia (RR = 0.67; 95% CI: 0.51-0.89, I2 = 60.7%). CONCLUSIONS Dietary polyphenol intake decreased GC risk. The reduction was greatest in females. Most previous studies were carried out in Europe and Asia. Further studies investigating polyphenol consumption and GC in Latin American populations are warranted.
Collapse
|
|
19
|
Al Safi MA, Rashid HM, Afifi FU, Talib WH. Gaz Alafi: A Traditional Dessert in the Middle East With Anticancer, Immunomodulatory, and Antimicrobial Activities. Front Nutr 2022; 9:900506. [PMID: 35845806 PMCID: PMC9283951 DOI: 10.3389/fnut.2022.900506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundFrom the earliest times, manna has been widely used as a tasty local sweet or folk medicine. The type of manna being investigated in the present study is called Gaz-alafi, a mixture of insect and Quercus brantii leaves secretions from oak forests in the north of Iraq and west of Iran.MethodsAqueous and ethanol extracts were prepared as decoction. Various phytochemical tests were conducted to analyze manna composition, including total phenolic contents using the Folin-Ciocalteu method and LC-MS. Gallic acid and catechin were detected in both extracts, in addition to tiliroside presence in ethanol extract, which added more value to the phenolic content of ethanol extract. Cytotoxic activities of Gaz alafi were evaluated against breast cancer cell lines and compared to normal cell lines and doxorubicin using the MTT assay. Antimicrobial properties were assessed against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, and Candida albicans using the dilution method of the micro-titer plate. Serum levels of IFN-γ, interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-10 (IL-10) were measured using ELISA. The effect of extracts on splenocyte proliferation was evaluated using the lymphocytes proliferation assay. Macrophage function was evaluated using the nitro blue tetrazolium assay, whereas pinocytosis was evaluated using the neutral red uptake assay. Ten days after tumor inoculation, changes in tumor size, survival rates, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine were measured.ResultsThe growth of cancer cells was inhibited by Gaz alafi ethanol extract. An alteration in IFN- γ, IL-2, and IL-4 levels toward antiproliferation immune response were reported for both extracts. The aqueous extract efficiently stimulated lymphocyte proliferation, phagocytosis, and pinocytosis, followed by the ethanol extracts with moderate activity. After treating the mice with ethanol extracts, a significant reduction in tumor size and several undetected tumors were recorded.ConclusionsGaz alafi extracts (aqueous and ethanol) are promising sources for anticancer and immunostimulatory agents. Further studies are needed to fully identify the chemical composition of Gaz alafi extracts.
Collapse
Affiliation(s)
- Meena A. Al Safi
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan
| | - Hasan M. Rashid
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan
| | - Fatma U. Afifi
- Department of Pharmaceutical Chemistry and Pharmacognosy, Applied Science Private University, Amman, Jordan
| | - Wamidh H. Talib
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman, Jordan
- *Correspondence: Wamidh H. Talib
| |
Collapse
|
|
20
|
Azees PAA, Natarajan S, Amaechi BT, Thajuddin N, Raghavendra VB, Brindhadevi K, Pugazhendhi A. An empirical review on the risk factors, therapeutic strategies and materials at nanoscale for the treatment of oral malignancies. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
21
|
Li Z, Mao L, Yu B, Liu H, Zhang Q, Bian Z, Zhang X, Liao W, Sun S. GB7 acetate, a galbulimima alkaloid from Galbulimima belgraveana, possesses anticancer effects in colorectal cancer cells. J Pharm Anal 2022; 12:339-349. [PMID: 35582406 PMCID: PMC9091789 DOI: 10.1016/j.jpha.2021.06.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 11/23/2022] Open
Abstract
GB7 acetate is a galbulimima alkaloid obtained from Galbulimima belgraveana. However, information regarding its structure, biological activities, and related mechanisms is not entirely available. A series of spectroscopic analyses, structural degradation, interconversion, and crystallography were performed to identify the structure of GB7 acetate. The MTT assay was applied to measure cell proliferation on human colorectal cancer HCT 116 cells. The expressions of the related proteins were measured by Western blotting. Transmission electron microscopy (TEM), acridine orange (AO) and monodansylcadaverine (MDC) staining were used to detect the presence of autophagic vesicles and autolysosomes. A transwell assay was performed to demonstrate metastatic capabilities. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays were performed to determine the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis activity of HCT 116 cells. The data showed that GB7 acetate suppressed the proliferation and colony-forming ability of HCT 116 cells. Pretreatment with GB7 acetate significantly induced the formation of autophagic vesicles and autolysosomes. GB7 acetate upregulated the expressions of LC3 and Thr172 phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase α (p-AMPKα), which are key elements of autophagy. In addition, GB7 acetate suppressed the metastatic capabilities of HCT 116 cells. Additionally, the production of matrix metallo-proteinase-2 (MMP-2) and MMP-9 was reduced, whereas the expression of E-cadherin (E-cad) was upregulated. Furthermore, GB7 acetate significantly reduced mitochondrial OXPHOS and glycolysis. In conclusion, the structure of the novel Galbulimima alkaloid GB7 acetate was identified. GB7 acetate was shown to have anti-proliferative, pro-autophagic, anti-metastatic, and anti-metabolite capabilities in HCT 116 cells. This study might provide new insights into cancer treatment efficacy and cancer chemoprevention.
Collapse
Affiliation(s)
- Ziyin Li
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Lianzhi Mao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Bin Yu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Huahuan Liu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Qiuyu Zhang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Zhongbo Bian
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Xudong Zhang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Wenzhen Liao
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Suxia Sun
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| |
Collapse
|
|
22
|
Antiproliferative Activity of Two Unusual Dimeric Flavonoids, Brachydin E and Brachydin F, Isolated from Fridericia platyphylla (Cham.) L.G.Lohmann: In Vitro and Molecular Docking Evaluation. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3319203. [PMID: 35187163 PMCID: PMC8856817 DOI: 10.1155/2022/3319203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/08/2022] [Indexed: 12/24/2022]
Abstract
Despite the breakthrough in the development of anticancer therapies, plant-derived chemotherapeutics continue to be the basis of treatment for most types of cancers. Fridericia platyphylla is a shrub found in Brazilian cerrado biome which has cytotoxic, anti-inflammatory, and analgesic properties. The aim of this study was to investigate the antiproliferative potential of the crude hydroethanolic extract, subfraction (containing 59.3% of unusual dimeric flavonoids Brachydin E and 40.7% Brachydin F), as well as Brachydin E and Brachydin F isolated from F. platyphylla roots. The cytotoxic activity was evaluated in glioblastoma, lung, prostate, and colorectal human tumor cell lines. The crude hydroethanolic extract did not present cytotoxic activity, but its subfraction presented lower IC50 values for glioblastoma (U-251) and prostate adenocarcinoma (PC-3) cell lines. Brachydins E and F significantly reduced cell viability, proliferation, and clonogenic potential of PC-3, inducing them to the process of regulated cell death. In silico studies have indicated nuclear receptors as targets for Brachydins E and F, and molecular docking has pointed out their binding into glucocorticoid receptor (GR) ligand pocket. Targeting GR pathway has been described as a therapeutic strategy, especially for prostate cancer. These results suggest that Brachydin E and Brachydin F are promising compounds to be further explored for their antitumor effects.
Collapse
|
|
23
|
Balan DJ, Das M, Sathya S, Kiruthiga C, Jeyakumar M, Antoniraj MG, Devi KP. Chitosan based encapsulation increased the apoptotic efficacy of thymol on A549 cells and exhibited non toxic response in swiss albino mice. Int J Biol Macromol 2022; 202:620-631. [PMID: 35066022 DOI: 10.1016/j.ijbiomac.2022.01.093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 01/10/2022] [Accepted: 01/13/2022] [Indexed: 12/30/2022]
Abstract
Thymol is a plant-derived natural phenolic compound abundantly present in Thymus vulgaris species. In the present study, we developed a chitosan-based drug delivery system to deliver thymol to A549 cells. The physicochemical properties of thymol-loaded chitosan nanoparticles (thymol-NP) were characterized using polyphasic techniques viz., FTIR, XRD, DLS, and SEM. Thymol-NP exhibited a size of 282.5 nm and encapsulation efficiency of 74.08 ± 0.73%. The IC50 of thymol-NP against A549 cells was 99.57 μg/ml at 24 h, which was lower than that of the pure form. Clear apoptotic features such as cellular morphology, cell shrinkage, and augmentation of dead cells were observed in both the thymol and thymol-NP treated A549 cells. The percentage of apoptotic cells in the thymol-NP IC50 treated cells was >90% which was considerably higher than the group treated with thymol alone. In vivo toxicity study showed that the swiss albino mice treated up to a concentration of 1000 mg/kg of thymol-NP neither showed signs of toxicity nor death up to 14 days. Also, no significant influence was observed on behavior, body weight, organ weight, and organ histology. Overall, the data concluded that thymol-NP can be considered a safe and potent drug candidate against A549 cells.
Collapse
Affiliation(s)
- Devasahayam Jaya Balan
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Mamali Das
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Sethuraman Sathya
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Chandramohan Kiruthiga
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Mahalingam Jeyakumar
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Mariya Gover Antoniraj
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India
| | - Kasi Pandima Devi
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi 630 003, Tamil Nadu, India.
| |
Collapse
|
|
24
|
Park KH, Joo SH, Seo JH, Kim J, Yoon G, Jeon YJ, Lee MH, Chae JI, Kim WK, Shim JH. Licochalcone H Induces Cell Cycle Arrest and Apoptosis in Human Skin Cancer Cells by Modulating JAK2/STAT3 Signaling. Biomol Ther (Seoul) 2022; 30:72-79. [PMID: 34873073 PMCID: PMC8724845 DOI: 10.4062/biomolther.2021.149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/30/2022] Open
Abstract
Licochalcone H (LCH) is a phenolic compound synthetically derived from licochalcone C (LCC) that exerts anticancer activity. In this study, we investigated the anticancer activity of LCH in human skin cancer A375 and A431 cells. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assay was used to evaluate the antiproliferative activity of LCH. Cell cycle distribution and the induction of apoptosis were analyzed by flow cytometry. Western blotting assays were performed to detect the levels of proteins involved in cell cycle progression, apoptosis, and the JAK2/STAT3 signaling pathway. LCH inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay revealed that LCH induced apoptosis, and the LCH-induced apoptosis was accompanied by cell cycle arrest in the G1 phase. Western blot analysis showed that the phosphorylation of JAK2 and STAT3 was decreased by treatment with LCH. The inhibition of the JAK2/STAT3 signaling pathway by pharmacological inhibitors against JAK2/STAT3 (cryptotanshinone (CTS) and S3I-201) simulated the antiproliferative effect of LCH suggesting that LCH induced apoptosis by modulating JAK2/STAT3 signaling.
Collapse
Affiliation(s)
- Kyung-Ho Park
- Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Sang Hoon Joo
- College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea
| | - Ji-Hye Seo
- Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Jumi Kim
- Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Goo Yoon
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Young-Joo Jeon
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Mee-Hyun Lee
- College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea
| | - Jung-Il Chae
- Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Woo-Keun Kim
- Biosystem Research Group, Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
| | - Jung-Hyun Shim
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea.,The China -US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
| |
Collapse
|
|
25
|
Ke DYJ, El-Sahli S, Wang L. The Potential of Natural Products in the Treatment of Triple-Negative Breast Cancer. Curr Cancer Drug Targets 2021; 22:388-403. [PMID: 34970954 DOI: 10.2174/1568009622666211231140623] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/01/2021] [Accepted: 11/09/2021] [Indexed: 11/22/2022]
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products, specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds were reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/β-catenin, and YAP. Clinicals trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.
Collapse
Affiliation(s)
- Danny Yu Jia Ke
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Ottawa, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- The Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| | - Sara El-Sahli
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Ottawa, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- The Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Ottawa, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- The Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| |
Collapse
|
|
26
|
The Combination of AHCC and ETAS Decreases Migration of Colorectal Cancer Cells, and Reduces the Expression of LGR5 and Notch1 Genes in Cancer Stem Cells: A Novel Potential Approach for Integrative Medicine. Pharmaceuticals (Basel) 2021; 14:ph14121325. [PMID: 34959725 PMCID: PMC8705140 DOI: 10.3390/ph14121325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 12/11/2021] [Indexed: 11/18/2022] Open
Abstract
The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with immunomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.
Collapse
|
|
27
|
Smirnova I, Drăghici G, Kazakova O, Vlaia L, Avram S, Mioc A, Mioc M, Macaşoi I, Dehelean C, Voicu A, Şoica C. Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms. Bioorg Chem 2021; 119:105535. [PMID: 34906859 DOI: 10.1016/j.bioorg.2021.105535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/27/2021] [Accepted: 11/29/2021] [Indexed: 11/26/2022]
Abstract
The use of natural compounds as starting point for semisynthetic derivatives has already been proven as a valuable source of active anticancer agents. Hollongdione (4,4,8,14-tetramethyl-18-norpregnan-3,20-dion), obtained by few steps from dammarane type triterpenoid dipterocarpol, was chemically modified at C2 and C21 carbon atoms by the Claisen-Schmidt aldol condensation to give a series of arylidene derivatives. The anticancer activity of the obtained compounds was assessed on NCI-60 cancer cell panel, revealing strong antiproliferative effects against a large variety of cancer cells. 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 emerged as the most active derivative as indicated by its GI50 values in the micromolar range which, combined with its high selectivity index values, indicated its suitability for deeper biological investigation. The mechanisms involved in compound 9 antiproliferative activity, were investigated through in vitro (DAPI staining) and ex vivo (CAM assay) tests, which exhibited its apoptotic and antiangiogenic activities. In addition, compound 9 showed an overall inhibition of mitochondrial respiration. rtPCR analysis identified the more intimate activity at pro-survival/pro-apoptotic gene level. Collectively, the hollongdione derivative stand as a promising therapeutic option against melanoma and breast cancer provided that future in vivo analysis will certify its clinical efficacy.
Collapse
Affiliation(s)
- Irina Smirnova
- Ufa Institute of Chemistry UFRC RAS, pr. Octyabrya 71, 450054 Ufa, Russian Federation
| | - George Drăghici
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Oxana Kazakova
- Ufa Institute of Chemistry UFRC RAS, pr. Octyabrya 71, 450054 Ufa, Russian Federation.
| | - Lavinia Vlaia
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Stefana Avram
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Alexandra Mioc
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Marius Mioc
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Ioana Macaşoi
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Cristina Dehelean
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Adrian Voicu
- Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| | - Codruța Şoica
- Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania; Res. Ctr. Pharmacotoxicol Evaluat, Facculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Sq., Timisoara 300041, Romania
| |
Collapse
|
|
28
|
Tagde P, Tagde S, Tagde P, Bhattacharya T, Monzur SM, Rahman MH, Otrisal P, Behl T, ul Hassan SS, Abdel-Daim MM, Aleya L, Bungau S. Nutraceuticals and Herbs in Reducing the Risk and Improving the Treatment of COVID-19 by Targeting SARS-CoV-2. Biomedicines 2021; 9:biomedicines9091266. [PMID: 34572452 PMCID: PMC8468567 DOI: 10.3390/biomedicines9091266] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/23/2022] Open
Abstract
The worldwide transmission of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a deadly or devastating disease is known to affect thousands of people every day, many of them dying all over the planet. The main reason for the massive effect of COVID-19 on society is its unpredictable spread, which does not allow for proper planning or management of this disease. Antibiotics, antivirals, and other prescription drugs, necessary and used in therapy, obviously have side effects (minor or significant) on the affected person, there are still not clear enough studies to elucidate their combined effect in this specific treatment, and existing protocols are sometimes unclear and uncertain. In contrast, it has been found that nutraceuticals, supplements, and various herbs can be effective in reducing the chances of SARS-CoV-2 infection, but also in alleviating COVID-19 symptoms. However, not enough specific details are yet available, and precise scientific studies to validate the approved benefits of natural food additives, probiotics, herbs, and nutraceuticals will need to be standardized according to current regulations. These alternative treatments may not have a direct effect on the virus or reduce the risk of infection with it, but these products certainly stimulate the human immune system so that the body is better prepared to fight the disease. This paper aims at a specialized literary foray precisely in the field of these “cures” that can provide real revelations in the therapy of coronavirus infection
Collapse
Affiliation(s)
- Priti Tagde
- Bhabha Pharmacy Research Institute, Bhabha University, Bhopal 462026, India
- PRISAL Foundation, Pharmaceutical Royal International Society, Bhopal 462042, India;
- Correspondence: (P.T.); (M.H.R.); (S.B.)
| | - Sandeep Tagde
- PRISAL Foundation, Pharmaceutical Royal International Society, Bhopal 462042, India;
| | - Pooja Tagde
- Practice of Medicine Department, Government Homeopathic Medical College, Bhopal 462003, India;
| | - Tanima Bhattacharya
- School of Chemistry and Chemical Engineering, Hubei University, Hubei 430062, China;
- Techno India NJR Institute of Technology, Udaipur 313003, India
| | | | - Md. Habibur Rahman
- Department of Pharmacy, Jagannath University, Sadarghat, Dhaka 1100, Bangladesh
- Department of Pharmacy, Southeast University, Banani, Dhaka 1213, Bangladesh
- Correspondence: (P.T.); (M.H.R.); (S.B.)
| | - Pavel Otrisal
- Faculty of Physical Culture, Palacký University Olomouc, 77111 Olomouc, Czech Republic;
| | - Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India;
| | - Syed Shams ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China;
- Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Mohamed M. Abdel-Daim
- Department of Pharmaceutical Sciences, Batterjee Medical College, P.O. Box 6231, Jedah 21442, Saudi Arabia;
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Lotfi Aleya
- Chrono-Environment CNRS 6249, Université de Franche-Comté, 25000 Besançon, France;
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
- Correspondence: (P.T.); (M.H.R.); (S.B.)
| |
Collapse
|
|
29
|
Al-Ghamdi MA, Al-Enazy A, Huwait EA, Albukhari A, Harakeh S, Moselhy SS. Enhancement of Annexin V in response to combination of epigallocatechin gallate and quercetin as a potent arrest the cell cycle of colorectal cancer. BRAZ J BIOL 2021; 83:e248746. [PMID: 34495165 DOI: 10.1590/1519-6984.248746] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/30/2021] [Indexed: 11/22/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.
Collapse
Affiliation(s)
- Maryam A Al-Ghamdi
- King Abdulaziz University, Faculty of Science, Department of Biochemistry, Jeddah, Saudi Arabia.,King Abdulaziz University, Pharmacogenomics Research Group, Jeddah, Saudi Arabia.,King Abdulaziz University, King Fahad Medical Research Center, Experimental Biochemistry Unit, Jeddah, Saudi Arabia
| | - A Al-Enazy
- King Abdulaziz University, Faculty of Science, Department of Biochemistry, Jeddah, Saudi Arabia
| | - E A Huwait
- King Abdulaziz University, Faculty of Science, Department of Biochemistry, Jeddah, Saudi Arabia.,King Abdulaziz University, Pharmacogenomics Research Group, Jeddah, Saudi Arabia.,King Abdulaziz University, King Fahad Medical Research Center, Experimental Biochemistry Unit, Jeddah, Saudi Arabia
| | - A Albukhari
- King Abdulaziz University, Faculty of Science, Department of Biochemistry, Jeddah, Saudi Arabia.,King Abdulaziz University, King Fahad Medical Research Center, Experimental Biochemistry Unit, Jeddah, Saudi Arabia.,King Abdulaziz University, King Fahad Medical Research Center, Cancer and Mutagenesis Unit, Jeddah, Saudi Arabia
| | - S Harakeh
- King Abdulaziz University - KAU, King Fahd Medical Research Center - KFMRC, Special Infectious Agents Unit, Jeddah, Kingdom of Saudi Arabia (KSA)
| | - Said S Moselhy
- Ain Shams University, Faculty of Science, Department of Biochemistry, Cairo, Egypt
| |
Collapse
|
|
30
|
Wang D, Starr R, Chang WC, Aguilar B, Alizadeh D, Wright SL, Yang X, Brito A, Sarkissian A, Ostberg JR, Li L, Shi Y, Gutova M, Aboody K, Badie B, Forman SJ, Barish ME, Brown CE. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med 2021; 12:12/533/eaaw2672. [PMID: 32132216 DOI: 10.1126/scitranslmed.aaw2672] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 11/01/2019] [Accepted: 01/29/2020] [Indexed: 12/16/2022]
Abstract
Although chimeric antigen receptor (CAR) T cells have demonstrated signs of antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To achieve broader and more effective GBM targeting, we developed a peptide-bearing CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). We find that CLTX peptide binds a great proportion of tumors and constituent tumor cells. CAR T cells using CLTX as the targeting domain (CLTX-CAR T cells) mediate potent anti-GBM activity and efficiently target tumors lacking expression of other GBM-associated antigens. Treatment with CLTX-CAR T cells resulted in tumor regression in orthotopic xenograft GBM tumor models. CLTX-CAR T cells do not exhibit observable off-target effector activity against normal cells or after adoptive transfer into mice. Effective targeting by CLTX-CAR T cells requires cell surface expression of matrix metalloproteinase-2. Our results pioneer a peptide toxin in CAR design, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.
Collapse
Affiliation(s)
- Dongrui Wang
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA.,Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Renate Starr
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Wen-Chung Chang
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Brenda Aguilar
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Darya Alizadeh
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Sarah L Wright
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Xin Yang
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Alfonso Brito
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Aniee Sarkissian
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Julie R Ostberg
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Li Li
- Irell and Manella Graduate School of Biological Sciences, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.,Department of Developmental and Stem Cell Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Yanhong Shi
- Department of Developmental and Stem Cell Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Margarita Gutova
- Department of Developmental and Stem Cell Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Karen Aboody
- Department of Developmental and Stem Cell Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Behnam Badie
- Division of Neurosurgery, Department of Surgery, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Stephen J Forman
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Michael E Barish
- Department of Developmental and Stem Cell Biology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Christine E Brown
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA. .,Department of Immuno-Oncology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| |
Collapse
|
|
31
|
Cardona-Mendoza A, Olivares-Niño G, Díaz-Báez D, Lafaurie GI, Perdomo SJ. Chemopreventive and Anti-tumor Potential of Natural Products in Oral Cancer. Nutr Cancer 2021; 74:779-795. [PMID: 34100309 DOI: 10.1080/01635581.2021.1931698] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Oral cancer (OC) is a multifactorial disease caused by isolated or combined risk factors related to tobacco, alcohol consumption, and human papillomavirus infection. It is an aggressive pathology with a low five-year survival rate after surgery, chemotherapy, and/or radiotherapy, frequently associated with severe side effects. Drugs with the highest anti-tumor effect are obtained from natural products with diverse biological and molecular activities and potential chemopreventive and anticancer properties. This review summarizes the natural products reported to have the chemopreventive and anti-tumor potential for OC treatment, showing that several of these compounds are promising candidates as chemopreventive agents, and those with the highest anti-tumor potential induce apoptosis and inhibit proliferation and metastasis-related processes. For this reason, natural products have the potential to be important preventive and therapeutic options for OC in the future.
Collapse
Affiliation(s)
- Andrés Cardona-Mendoza
- Grupo de Inmunología Celular y Molecular Universidad El Bosque-INMUBO, Universidad El Bosque, Bogotá, Colombia.,School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| | | | - David Díaz-Báez
- Unidad de Investigación Básica Oral-UIBO, Universidad El Bosque, Bogotá, Colombia.,School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| | - Gloria Inés Lafaurie
- Unidad de Investigación Básica Oral-UIBO, Universidad El Bosque, Bogotá, Colombia.,School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| | - Sandra J Perdomo
- Grupo de Inmunología Celular y Molecular Universidad El Bosque-INMUBO, Universidad El Bosque, Bogotá, Colombia.,School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| |
Collapse
|
|
32
|
Ma Q, Cai S, Liu X, Shi J, Yi J. Characterization of phytochemical components and identification of main antioxidants in Crateva unilocalaris Buch. shoots by UHPLC-Q-Orbitrap-MS 2 analysis. Food Res Int 2021; 143:110264. [PMID: 33992365 DOI: 10.1016/j.foodres.2021.110264] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 11/26/2022]
Abstract
The chemical constituents and antioxidant activity of the three different extracts (80% methanol, 80% ethanol, and 80% acetone) of Crateva unilocalaris Buch. shoots were investigated. Six phenolic compounds and seven saponins were characterized in all extracts. Chikusetsusaponin IVa had the highest content (17.92 to 29.16 mg/g), and chlorogenic acid was the most abundant phenolic compound (10.48 to 13.99 mg/g). The acetone extract had the highest total phenolic, flavonoid, and saponin contents and the strongest antioxidant activity. Moreover, all extracts exhibited good effects on the inhibition of intracellular ROS generation in HepG2 cells. Phenolic compounds but not saponins contributed significantly to the DPPH or ABTS radical scavenging activity of C. unilocalaris shoots according to the results of DPPH•-UHPLC-HRMS and ABTS•+-UHPLC-HRMS analyses. These results may be helpful for further understandings and utilization of C. unilocalaris shoots as a potential natural source in the food or nutraceuticals industry.
Collapse
Affiliation(s)
- Qian Ma
- Faculty of Agriculture and Food, Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming, Yunnan Province 650500, People's Republic of China.
| | - Shengbao Cai
- Faculty of Agriculture and Food, Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming, Yunnan Province 650500, People's Republic of China.
| | - Xiaojing Liu
- Faculty of Agriculture and Food, Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming, Yunnan Province 650500, People's Republic of China.
| | - Jiyuan Shi
- Faculty of Agriculture and Food, Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming, Yunnan Province 650500, People's Republic of China.
| | - Junjie Yi
- Faculty of Agriculture and Food, Yunnan Institute of Food Safety, Kunming University of Science and Technology, Kunming, Yunnan Province 650500, People's Republic of China.
| |
Collapse
|
|
33
|
Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1. Int J Mol Sci 2021; 22:ijms22041700. [PMID: 33567682 PMCID: PMC7915236 DOI: 10.3390/ijms22041700] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/30/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.
Collapse
|
|
34
|
Concentration-Dependent Pro- and Antitumor Activities of Quercetin in Human Melanoma Spheroids: Comparative Analysis of 2D and 3D Cell Culture Models. Molecules 2021; 26:molecules26030717. [PMID: 33573155 PMCID: PMC7866537 DOI: 10.3390/molecules26030717] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 01/06/2023] Open
Abstract
Quercetin, a dietary flavonoid found in fruits and vegetables, has been described as a substance with many anti-cancer properties in a variety of preclinical investigations. In the present study, we demonstrate that 2D and 3D melanoma models exhibit not only different sensitivities to quercetin, but also opposite, cancer-promoting effects when metastatic melanoma spheroids are treated with quercetin. Higher concentrations of quercetin reduce melanoma growth in three tested cell lines, whereas low concentrations induce the opposite effect in metastatic melanoma spheroids but not in the non-metastatic cell line. High (>12.5 µM) or low (<6.3 µM) quercetin concentrations decrease or enhance cell viability, spheroid size, and cell proliferation, respectively. Additionally, melanoma cells cultivated in 2D already show significant caspase 3 activity at very low concentrations (>0.4 µM), whereas in 3D spheroids apoptotic cells, caspase 3 activity can only be detected in concentrations ≥12.5 µM. Further, we show that the tumor promoting or repressing effect in the 3D metastatic melanoma spheroids are likely to be elicited by a precisely controlled regulation of Nrf2/ARE-mediated cytoprotective genes, as well as ERK and NF-κB phosphorylation. According to the results obtained here, further studies are needed to better characterize the mechanisms of action underlying the pro- and anti-carcinogenic effects of quercetin on human melanomas.
Collapse
|
|
35
|
Ribeiro AB, Ozelin SD, da Silva LHD, Rinaldi-Neto F, Freitas KS, Nicolella HD, de Souza LDR, Furtado RA, Cunha WR, Tavares DC. Influence of Asiatic acid on cell proliferation and DNA damage in vitro and in vivo systems. J Biochem Mol Toxicol 2021; 35:e22712. [PMID: 33484013 DOI: 10.1002/jbt.22712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 12/01/2020] [Accepted: 01/09/2021] [Indexed: 11/10/2022]
Abstract
Asiatic acid (AA) is a triterpene with promising pharmacological activity. In the present study, in vitro and in vivo assays were conducted to understand the effect of AA on cell proliferation and genomic instability. AA was cytotoxic to human tumor cell lines (M059J, HeLa, and MCF-7), with IC50 values ranging from 13.91 to 111.72 µM. In the case of M059J, AA exhibited selective cytotoxicity after 48 h of treatment (IC50 = 24 µM), decreasing the percentage of cells in the G0/G1 phase, increasing the percentage of cells in the S phase, and inducing apoptosis. A significant increase in chromosomal damage was observed in V79 cell cultures treated with AA (40 µM), revealing genotoxic activity. In contrast, low concentrations (5, 10, and 20 µM) of AA significantly reduced the frequencies of micronuclei induced by the mutagens doxorubicin (DXR), methyl methanesulfonate, and hydrogen peroxide. A reduction of DXR-induced intracellular free radicals was found in V79 cells treated with AA (10 µM). The antigenotoxic effect of AA (30 mg/kg) was also observed against DXR-induced chromosomal damage in Swiss mice. Significant reductions in p53 levels were verified in the liver tissue of these animals. Taken together, the data indicate that AA exerted antiproliferative activity in M059J tumor cells, which is probably related to the induction of DNA damage, leading to cell cycle arrest and apoptosis. Additionally, low concentrations of AA exhibited antigenotoxic effects and its antioxidant activity may be responsible, at least in part, for chemoprevention.
Collapse
Affiliation(s)
- Arthur B Ribeiro
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | - Saulo D Ozelin
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | - Lucas H D da Silva
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | | | - Karoline S Freitas
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | - Heloiza D Nicolella
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | | | - Ricardo A Furtado
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| | | | - Denise C Tavares
- Laboratório de Mutagênese, Universidade de Franca, Franca, São Paulo, Brazil
| |
Collapse
|
|
36
|
AbouAitah K, Lojkowski W. Delivery of Natural Agents by Means of Mesoporous Silica Nanospheres as a Promising Anticancer Strategy. Pharmaceutics 2021; 13:143. [PMID: 33499150 PMCID: PMC7912645 DOI: 10.3390/pharmaceutics13020143] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
Natural prodrugs derived from different natural origins (e.g., medicinal plants, microbes, animals) have a long history in traditional medicine. They exhibit a broad range of pharmacological activities, including anticancer effects in vitro and in vivo. They have potential as safe, cost-effective treatments with few side effects, but are lacking in solubility, bioavailability, specific targeting and have short half-lives. These are barriers to clinical application. Nanomedicine has the potential to offer solutions to circumvent these limitations and allow the use of natural pro-drugs in cancer therapy. Mesoporous silica nanoparticles (MSNs) of various morphology have attracted considerable attention in the search for targeted drug delivery systems. MSNs are characterized by chemical stability, easy synthesis and functionalization, large surface area, tunable pore sizes and volumes, good biocompatibility, controlled drug release under different conditions, and high drug-loading capacity, enabling multifunctional purposes. In vivo pre-clinical evaluations, a significant majority of results indicate the safety profile of MSNs if they are synthesized in an optimized way. Here, we present an overview of synthesis methods, possible surface functionalization, cellular uptake, biodistribution, toxicity, loading strategies, delivery designs with controlled release, and cancer targeting and discuss the future of anticancer nanotechnology-based natural prodrug delivery systems.
Collapse
Affiliation(s)
- Khaled AbouAitah
- Laboratory of Nanostructures and Nanomedicine, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland
- Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), 33 El-Behouth St., Dokki 12622, Giza, Egypt
| | - Witold Lojkowski
- Laboratory of Nanostructures and Nanomedicine, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland
| |
Collapse
|
|
37
|
Hackman GL, Collins M, Lu X, Lodi A, DiGiovanni J, Tiziani S. Predicting and Quantifying Antagonistic Effects of Natural Compounds Given with Chemotherapeutic Agents: Applications for High-Throughput Screening. Cancers (Basel) 2020; 12:cancers12123714. [PMID: 33322034 PMCID: PMC7763027 DOI: 10.3390/cancers12123714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 01/12/2023] Open
Abstract
Natural products have been used for centuries to treat various human ailments. In recent decades, multi-drug combinations that utilize natural products to synergistically enhance the therapeutic effects of cancer drugs have been identified and have shown success in improving treatment outcomes. While drug synergy research is a burgeoning field, there are disagreements on the definitions and mathematical parameters that prevent the standardization and proper usage of the terms synergy, antagonism, and additivity. This contributes to the relatively small amount of data on the antagonistic effects of natural products on cancer drugs that can diminish their therapeutic efficacy and prevent cancer regression. The ability of natural products to potentially degrade or reverse the molecular activity of cancer therapeutics represents an important but highly under-emphasized area of research that is often overlooked in both pre-clinical and clinical studies. This review aims to evaluate the body of work surrounding the antagonistic interactions between natural products and cancer therapeutics and highlight applications for high-throughput screening (HTS) and deep learning techniques for the identification of natural products that antagonize cancer drug efficacy.
Collapse
Affiliation(s)
- G. Lavender Hackman
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA; (G.L.H.); (M.C.); (X.L.); (A.L.)
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
| | - Meghan Collins
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA; (G.L.H.); (M.C.); (X.L.); (A.L.)
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
| | - Xiyuan Lu
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA; (G.L.H.); (M.C.); (X.L.); (A.L.)
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
| | - Alessia Lodi
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA; (G.L.H.); (M.C.); (X.L.); (A.L.)
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
| | - John DiGiovanni
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA
| | - Stefano Tiziani
- Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA; (G.L.H.); (M.C.); (X.L.); (A.L.)
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA;
- Department of Oncology, Dell Medical School, LiveSTRONG Cancer Institutes, The University of Texas at Austin, Austin, TX 78723, USA
- Correspondence: ; Tel.: +1-512-495-4706
| |
Collapse
|
|
38
|
Bhaskara VK, Mittal B, Mysorekar VV, Amaresh N, Simal-Gandara J. Resveratrol, cancer and cancer stem cells: A review on past to future. Curr Res Food Sci 2020; 3:284-295. [PMID: 33305295 PMCID: PMC7718213 DOI: 10.1016/j.crfs.2020.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer remains to be an unresolved medical challenge despite of tremendous advancement in basic science research and clinical medicine. One of the major limitations is due to the side effects of chemotherapy which remains to be palliative without offering any permanent cure for cancer. Cancer stem cells (CSCs) are the subpopulation of cells in tumors that remain viable even after surgery, chemo- and radio-therapy that eventually responsible for tumor relapse. Hence, by eliminating non-stem cancer cells and cancer stem cells from the patient, permanent cure is expected. Phytochemicals have been under the intensive study to target these CSCs effectively and permanently as they do not cause any side effects. Resveratrol (RSV) is one such compound attaining lot of interest in recent days to target CSCs either alone or in combination. RSV has been used by several researchers to target cancer cells in a variety of disease models, however its CSC targeting abilities are under intensive study at present. This review is to summarize the effects of RSV under in vitro and in vivo conditions along with advantages and disadvantages of its uses against cancer cells and cancer stem cells. From the first reports on phytochemical applications against cancer and cancer stem cells in 1997 and 2002 respectively followed by later reports, up to date observations and developments are enlisted from PubMed in this comprehensive review. RSV is shown to be a potential compound having impact on altering the signal transduction pathways in cancer cells. However, the effects are variable under in vitro and in vivo conditions, and also with its use alone or in combination with other small molecules. Past research on RSV is emphasizing the importance of in vivo experimental models and clinical trials with different prospective combinations, is a hope for future promising treatment regimen.
Collapse
Affiliation(s)
- Vasanth K Bhaskara
- Department of Biochemistry-PG, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India
| | - Bharti Mittal
- Immuniteit Lab Pvt Ltd., Electronic City, Bengaluru 560024, India
| | - Vijaya V Mysorekar
- Department of Pathology, Ramaiah Medical College & Hospitals (RMCH), Bengaluru 560054, India
| | - Nagarathna Amaresh
- Department of Biotechnology, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E32004 Ourense, Spain
| |
Collapse
|
|
39
|
Wi TI, Won JE, Lee CM, Lee JW, Kang TH, Shin BC, Han HD, Park YM. Efficacy of Combination Therapy with Linalool and Doxorubicin Encapsulated by Liposomes as a Two-in-One Hybrid Carrier System for Epithelial Ovarian Carcinoma. Int J Nanomedicine 2020; 15:8427-8436. [PMID: 33149585 PMCID: PMC7605632 DOI: 10.2147/ijn.s272319] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/07/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Epithelial ovarian cancer (EOC) is a fatal gynecologic malignancy that is usually treated with chemotherapy after surgery. However, patients who receive chemotherapy experience severe side effects because of the inherent toxicity and high dose of chemotherapeutics. To overcome these issues, we suggest a combination therapeutic strategy using liposomes encapsulating linalool nanoemulsions (LN-NEs) and doxorubicin (DOX), a chemotherapeutic drug, to increase their synergistic antitumor efficacy and reduce the incidence of side effects from chemotherapeutics for EOC. METHODS The physical properties of LN-NE-DOX-liposomes were characterized by light scattering with a particle size analyzer. Cell viability was determined by MTT assay. Therapeutic efficacy was evaluated in a mouse HeyA8 EOC tumor model of ovarian carcinoma. Additionally, biochemical toxicity was analyzed for levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) using BALB/c nude mice. RESULTS The size of the liposomes encapsulating LN-NEs and DOX (LN-NE-DOX-liposomes) was 267.0 ± 4.6 nm, with a loading efficiency of 55.1 ± 3.1% and 27.2 ± 0.9% for linalool and DOX, respectively. Cell viability after treatment with LN-NE-DOX-liposomes was significantly decreased compared to that of cells treated with DOX liposomes, and apoptosis was significantly increased. Additionally, LN-NE-DOX-liposomes significantly inhibited HeyA8 EOC tumor growth compared to that of the control (p < 0.01) and DOX-liposome-treated groups (p < 0.05), while decreasing cell proliferation (Ki67) and microvessel density (CD31), and promoting apoptosis (caspase-3) compared to the control (p < 0.05). Moreover, the liposomal formulations induced no significant differences in biochemical toxicity (AST, ALT, and BUN) compared to healthy control mice, indicating that the liposomal formulations showed no overt toxicity in mice. CONCLUSION This study demonstrates that the production of LN-NE-DOX-liposomes is a pivotal approach for EOC treatment, suggesting a novel combination therapeutic strategy.
Collapse
Affiliation(s)
- Tae In Wi
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| | - Ji Eun Won
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| | - Chan Mi Lee
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| | - Jeong-Won Lee
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Tae Heung Kang
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| | - Byung Cheol Shin
- Bio/Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea
| | - Hee Dong Han
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| | - Yeong-Min Park
- Department of Immunology, School of Medicine, Konkuk University, Chungju380-701, South Korea
| |
Collapse
|
|
40
|
Huang H, Hao J, Pang K, Lv Y, Wan D, Wu C, Ma Y, Yang X, Zhang WK. A biflavonoid-rich extract from Selaginella moellendorffii Hieron. induces apoptosis via STAT3 and Akt/NF-κB signalling pathways in laryngeal carcinoma. J Cell Mol Med 2020; 24:11922-11935. [PMID: 32869923 PMCID: PMC7579697 DOI: 10.1111/jcmm.15812] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/27/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022] Open
Abstract
Selaginella moellendorffii Hieron. (SM), a perennial evergreen plant, has been used in the treatment of acute infectious hepatitis, thoracic and hypochondriac lumbar contusions, systemic oedema and thrombocytopaenia. However, the role of a biflavonoid-rich extract from SM (SM-BFRE) in anti-larynx cancer has rarely been reported. In this study, the in vitro and in vivo anti-laryngeal cancer activity and potential mechanisms of SM-BFRE were investigated. An off-line semipreparative liquid chromatography-nuclear magnetic resonance protocol was carried out to determine six biflavonoids from SM-BFRE. In vitro, MTT assay revealed that SM-BFRE inhibited the proliferation of laryngeal carcinoma cells. A wound healing assay indicated that SM-BFRE suppressed the migration of laryngeal cancer cells. Hoechst 33 258 and Annexin V-FITC/PI double staining assays were performed and verified that SM-BFRE induced apoptosis in laryngeal carcinoma cells. The Hep-2 bearing nude mouse model confirmed that SM-BFRE also exhibited anticancer effect in vivo. In addition, Western blot analysis demonstrated that SM-BFRE exerted its anti-laryngeal cancer effect by activating the mitochondrial apoptotic pathway and inhibiting STAT3 and Akt/NF-κB signalling pathways. All results suggested that SM-BFRE could be considered as a potential chemotherapeutic drug for laryngeal cancer.
Collapse
Affiliation(s)
- Huiqi Huang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Ji Hao
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Kejian Pang
- Hotian Uygur Pharmaceutical Co., Ltd, Hotian, China
| | - Yibing Lv
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Dingrong Wan
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Chaoqun Wu
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Yuanren Ma
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Xinzhou Yang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| | - Wei K Zhang
- School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China
| |
Collapse
|
|
41
|
Caffeic Acid Phenethyl Ester (CAPE) Induced Apoptosis in Serous Ovarian Cancer OV7 Cells by Deregulation of BCL2/BAX Genes. Molecules 2020; 25:molecules25153514. [PMID: 32752091 PMCID: PMC7435968 DOI: 10.3390/molecules25153514] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/26/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer has the worst prognosis among all gynecological cancers. Therefore, it seems reasonable to seek new drugs that may improve the effectiveness of treatment or mitigate the adverse effects of chemotherapy. Caffeic acid phenethyl ester (CAPE) has many beneficial biological properties. The aim of the study was to assess the anticancer properties of CAPE against serum ovarian carcinoma cells. The morphology of the cells was evaluated in H-E staining and in transmission electron microscopy. The cytotoxic and proapoptotic activity of CAPE was investigated by using the XTT-NR-SRB assay, qRT-PCR analysis of BAX/BCL2 expression, and by cytometric evaluation. CAPE causes constriction in OV7 cells, numerous granulomas were observed in the cytoplasm, the cell nuclei were pyknotic. Autophagosomal vacuoles could suggest the occurrence of aponecrosis. CAPE significantly decreased the lysosomal activity and the total synthesis of cellular proteins. CAPE exhibited, dose and time dependent, cytotoxic activity against OV7 serum ovarian cancer cells. In OV7 cells CAPE induced apoptosis via dysregulation of BAX/BCL2 balance, while activated proapoptotic BAX gene expression level was 10 times higher than BCL2.
Collapse
|
|
42
|
Cao F, Cheng MH, Hu LQ, Shen HH, Tao JH, Li XM, Pan HF, Gao J. Natural products action on pathogenic cues in autoimmunity: Efficacy in systemic lupus erythematosus and rheumatoid arthritis as compared to classical treatments. Pharmacol Res 2020; 160:105054. [PMID: 32645358 DOI: 10.1016/j.phrs.2020.105054] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 06/22/2020] [Accepted: 06/28/2020] [Indexed: 01/04/2023]
Abstract
Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), which are characterized by self-perpetuating inflammation and tissue/organ damage, resulting from the failure of lymphocyte auto-tolerance, cause morbidity and mortality worldwide. The current drugs or therapies including conventional non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs), as well as several biologic therapies such as B cell-targeted, T cell-targeted, cytokines-targeted and cytokines receptors-targeted therapy, cannot completely cure SLE and RA, and are always accompanied by unexpected side effects. Therefore, more studies have explored new methods for therapy and found that the herbal medicine as well as its natural products (NPs) exhibited promising therapeutic value through exerting effects of immunomodulation, anti-inflammation, anti-oxidation, and anti-apoptosis, etc. via regulating abnormal responses in kidney, innate and adaptive immune systems, intestine, synoviocytes, as well as bone system including chondrocytes, osteoclasts, joints and paw tissues. In the present review, we will elucidate the current mainstream drugs and therapies for SLE and RA, and summarize the efficacy and mechanisms of NPs in the treatment of SLE and RA based on available findings including in vitro and in vivo animal models, as well as clinical studies, and further analyze the existing challenges, in order to provide comprehensive evidence for improvement of SLE and RA therapy by NPs and to promote management of these two autoimmune diseases.
Collapse
Affiliation(s)
- Fan Cao
- Department of Clinical Medicine, The Second School of Clinical Medicine, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Ming-Han Cheng
- The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Li-Qin Hu
- The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Anhui, China
| | - Hui-Hui Shen
- Department of Clinical Medicine, The Second School of Clinical Medicine, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Jin-Hui Tao
- Department of Rheumatology and Immunology, Anhui Provincial Hospital Affiliated to Anhui Medical University, No.17 Lu Jiang Road, Hefei, Anhui, China
| | - Xiao-Mei Li
- Department of Rheumatology and Immunology, Anhui Provincial Hospital Affiliated to Anhui Medical University, No.17 Lu Jiang Road, Hefei, Anhui, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; The Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, China.
| | - Jian Gao
- The Second Affiliated Hospital and School of Pharmacy, Dalian Medical University, Dalian, Liaoning, China.
| |
Collapse
|
|
43
|
Hsp90 inhibitor gedunin causes apoptosis in A549 lung cancer cells by disrupting Hsp90:Beclin-1:Bcl-2 interaction and downregulating autophagy. Life Sci 2020; 256:118000. [PMID: 32585246 DOI: 10.1016/j.lfs.2020.118000] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 12/18/2022]
Abstract
AIMS Hsp90 is regarded as an important therapeutic target in cancer treatment. Client proteins of Hsp90 like Beclin-1, PI3K, and AKT, are associated with tumor development, poor prognosis, and resistance to cancer therapies. This study aims to analyze the role of Gedunin, an Hsp-90 inhibitor, in mediation of crosstalk between apoptosis and autophagy by targeting Beclin-1:Bcl-2 interaction, and ER stress. MAIN METHODS A549 cells were treated with different concentrations of gedunin, and inhibitory rate was evaluated by MTT assay. Effect of gedunin on generation of reactive oxygen species, mitochondrial membrane potential, and chromatin condensation was studied by staining methods like DCFH-DA, MitoTracker, and DAPI. Expression of EGFR, PIK3CA, AKT, marker genes for apoptosis and autophagy were studied using semi-quantitative RT-PCR. Interaction study of Hsp90:Beclin-1:Bcl-2 was done by immunoprecipitation analysis. Protein expression of autophagy and apoptosis markers along with Grp78, Hsp70, and Hsp90 was analyzed by immunoblotting. KEY FINDINGS Gedunin exerts cytotoxic effects, causes increase in ROS generation, downregulates mitochondrial membrane potential and induces loss in DNA integrity. mRNA expression analysis revealed that gedunin sensitized A549 cells towards apoptosis by downregulating EGFR, PIK3CA, AKT, and autophagy. Gedunin also inhibited interaction between Hsp90:Beclin-1:Bcl-2, leading to downregulation of autophagy (Beclin-1, Atg5-12 complex, and LC3) and antiapoptotic protein Bcl-2, which may result in ER stress-induced apoptosis. Moreover, Hsp90 inhibition by gedunin did not cause upregulation of Hsp70 expression. SIGNIFICANCE Gedunin induces apoptosis in lung cancer cells by disrupting Hsp90:Beclin-1:Bcl-2 interaction and autophagy downregulation, thus making gedunin a good drug lead for targeting lung cancer.
Collapse
|
|
44
|
Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones. Int J Mol Sci 2020; 21:ijms21103671. [PMID: 32456148 PMCID: PMC7279380 DOI: 10.3390/ijms21103671] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/17/2022] Open
Abstract
Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6,7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6β-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectranthus spp. and showed promising biological activities, such as cytotoxicity. The inhibitory effects of the different natural abietanes (1-3) were compared in MFC7, SkBr3, and SUM159 cell lines, as well as SUM159 grown in cancer stem cell-inducing conditions. Based on the royleanones’ bioactivity, the derivatives RoyBz (4), RoyBzCl (5), RoyPr2 (6), and DihydroxyRoy (7), previously obtained from 2, were selected for further studies. Protein kinases C (PKCs) are involved in several carcinogenic processes. Thus, PKCs are potential targets for cancer therapy. To date, the portfolio of available PKC modulators remains very limited due to the difficulty of designing isozyme-selective PKC modulators. As such, molecular docking was used to evaluate royleanones 1-6 as predicted isozyme-selective PKC binders. Subtle changes in the binding site of each PKC isoform change the predicted interaction profiles of the ligands. Subtle changes in royleanone substitution patterns, such as a double substitution only with non-substituted phenyls, or hydroxybenzoate at position four that flips the binding mode of ParvD (3), can increase the predicted interactions in certain PKC subtypes.
Collapse
|
|
45
|
Metabolite profiling of Artemisia carvifolia Buch transgenic plants and estimation of their anticancer and antidiabetic potential. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2020. [DOI: 10.1016/j.bcab.2020.101539] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
46
|
Corradetti B, Vaiasicca S, Mantovani M, Virgili E, Bonucci M, Hammarberg Ferri I. Bioactive Immunomodulatory Compounds: A Novel Combinatorial Strategy for Integrated Medicine in Oncology? BAIC Exposure in Cancer Cells. Integr Cancer Ther 2020; 18:1534735419866908. [PMID: 31416372 PMCID: PMC6699000 DOI: 10.1177/1534735419866908] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The Standardized Cultured Extract of Lentinula edodes Mycelia (also known as
Active Hexose Correlated Compound, AHCC) and Wasabia japonica
(Wasabi) are natural nutritional supplements known for their immunomodulatory
and anticancer potential. The aim of this study was to evaluate the
combinatorial effect of the bioactive immunomodulatory compound (BAIC), obtained
by combining Wasabi and AHCC, on human breast (MCF-7) and pancreatic (Panc02)
adenocarcinoma cell lines. Data obtained revealed that BAIC determines a
striking decline in cancer cell growth at minimal concentrations compared with
the use of Wasabi and AHCC as single agents. A significant increase in the
G0/G1 subpopulation together with a marked
augmentation in the percentage of apoptotic cells was demonstrated by flow
cytometry, together with a significant upregulation in the expression of genes
associated to the apoptotic cascade in both cell lines. The inhibitory role BAIC
plays in mammospheres formation from MCF-7-derived cancer stem cells was shown
with a marked reduction in size and number. Interestingly, when BAIC was exposed
to monocytic cells, no cytotoxic effects were observed. A
monocytes-to-macrophages differentiation was rather observed with the
concomitant acquisition of an anti-inflammatory phenotype. Taken together, our
findings suggest that BAIC could be used as a potential integration of standard
chemotherapy treatments because of the improved inhibitory activity on cancer
cell proliferation and reduced potential adverse effects.
Collapse
Affiliation(s)
- Bruna Corradetti
- 1 Università Politecnica delle Marche, Ancona, Italy.,2 Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.,3 Center for Nanohealth, Swansea University Medical School, Swansea, UK
| | | | - Mauro Mantovani
- 4 Associazione Ricerche Terapie Innovative BioIntegrate, Bologna, Italy
| | - Edy Virgili
- 5 Associazione Ricerca Terapie Oncologiche Integrate, Rome, Italy
| | - Massimo Bonucci
- 5 Associazione Ricerca Terapie Oncologiche Integrate, Rome, Italy.,6 "Villa Benedetta" Hospital, Rome, Italy
| | | |
Collapse
|
|
47
|
Awad BM, Abd-Alhaseeb MM, Habib ES, Ibrahim AK, Ahmed SA. Antitumor activity of methoxylated flavonoids separated from Achillea fragrantissima extract in Ehrlich’s ascites carcinoma model in mice. JOURNAL OF HERBMED PHARMACOLOGY 2020; 9:28-34. [DOI: 10.15171/jhp.2020.04] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
Abstract
Introduction: Achillea fragrantissima extract has been used in folk medicine as an anticancer. The present study describes the antitumor activities of the extract and the flavonoid compounds and attempts to explain the mechanisms underlying these activities. Methods: The whole plant of A. fragrantissima was collected and ground to produce a fine powder which subjected to the maceration process. Step gradient elution was used using silica gel vacuum liquid chromatography (VLC). The fractions were compared by thin layer chromatography (TLC) and concentrated. Final purification was performed using Sephadex LH-20 to give three compounds cirsiliol, chrysosplenol D and cirsimaritin from F4 and one compound, eupatilin-7-methyl ether from F6. In this study, Ehrlich’s ascites carcinoma (EAC) model was used as the model of cancer. Results: Achillea fragrantissima extract and its isolated methoxylated flavonoids significantly reduced the weight of tumor discs compared to EAC-control group. In addition, cirsimaritin and eupatilin 7-methyl ether treatments produced a dose-dependent reduction in tumor weight. Serum tumor necrosis factor-alpha (TNF-ɑ) level showed that A. fragrantissima extract and its isolated methoxylated flavonoid compounds significantly reduced its serum level compared to the EAC-control group. Furthermore, A. fragrantissima extract and the flavonoids significantly increased the Total antioxidant capacity (TAC) compared to EAC-control. A. fragrantissima extract and its isolated methoxylated flavonoids produced a better differentiation of tumor cells, with reduced nuclear pleomorphism and better formed tubular structures especially with high dose indicating the induction of apoptotic mechanism. Conclusion: Achillea fragrantissima extract and its isolated methoxylated flavonoids exhibit antitumor activities that may be attributed to the antioxidant properties and the induction of the apoptotic process.
Collapse
Affiliation(s)
- Basma M. Awad
- Department of Pharmacognosy, Faculty of Pharmacy & Pharmaceutical Industries, Sinai University, Arish, Egypt
| | - Mohammad M. Abd-Alhaseeb
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Al-Buhaira, Egypt
| | - Eman S. Habib
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Amany K. Ibrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Safwat A. Ahmed
- Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| |
Collapse
|
|
48
|
Contribution of p38 MAPK Pathway to Norcantharidin-Induced Programmed Cell Death in Human Oral Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:ijms20143487. [PMID: 31315217 PMCID: PMC6678691 DOI: 10.3390/ijms20143487] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/08/2019] [Accepted: 07/13/2019] [Indexed: 01/22/2023] Open
Abstract
Norcantharidin (NCTD), a demethylated analog of cantharidin isolated from blister beetles, has been used as a promising anticancer agent; however, the underlying function of NCTD against human oral squamous cell carcinoma (OSCC) has not been fully understood. Here, this study was aimed to investigate the apoptotic effect and molecular targets of NCTD in human OSCC in vitro and in vivo. The anticancer effects of NCTD and its related molecular mechanisms were evaluated by trypan blue exclusion assay, live/dead assay, western blotting, 4-6-Diamidino-2-Phenylindole (DAPI) staining, flow cytometric analysis, Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay, and immunohistochemistry. NCTD significantly inhibited cell growth and increased the number of dead cells in HSC-3 and HN22 cell lines. It induced the following apoptotic phenomena: (1) the cleavages of poly (ADP-ribose) polymerase and casepase-3; (2) increase in apoptotic morphological changes (nuclear condensation and fragmentation); (3) increase in annexin V-positive cells or sub-G1 population of cells. NCTD significantly activated the p38 mitogen-activated protein kinase (MAPK) pathway but inactivated the signal transducer and activator of transcription (STAT)3 pathway. A p38 MAPK inhibitor (SB203580) partially attenuated NCTD-induced programmed cell death (apoptosis) in both cell lines, whereas ectopic overexpression of STAT3 did not affect it. NCTD strongly suppressed tumor growth in the tumor xenograft bearing HSC-3 cells, and the number of TUNEL-positive cells increased in NCTD-treated tumor tissues. In addition, NCTD did not cause any histopathological changes in the liver nor the kidney. NCTD induced programmed cell death via the activation of p38 MAPK in OSCC. Therefore, these results suggest that NCTD could be a potential anticancer drug candidate for the treatment of OSCC.
Collapse
|
|
49
|
Hong KO, Ahn CH, Yang IH, Han JM, Shin JA, Cho SD, Hong SD. Norcantharidin Suppresses YD-15 Cell Invasion Through Inhibition of FAK/Paxillin and F-Actin Reorganization. Molecules 2019; 24:molecules24101928. [PMID: 31109130 PMCID: PMC6572169 DOI: 10.3390/molecules24101928] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 12/12/2022] Open
Abstract
Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported to exhibit activity against various types of cancers. However, the anti-invasive effects of NCTD and its molecular mechanism in human mucoepidermoid carcinoma (MEC) remain incompletely elucidated. Clonogenic, wound healing, invasion, zymography, western blotting and immunocytochemistry assays were performed in YD-15 cells to investigate the anti-invasive effect of NCTD and its molecular mechanism of action. The inhibitory effects of NCTD on invasiveness were compared with those of a novel focal adhesion kinase (FAK) kinase inhibitor, PF-562271. NCTD markedly suppressed the colony formation, migration, and invasion of YD-15 cells as well as the activities of MMP-2 and MMP-9. It disrupted F-actin reorganization through suppressing the FAK/Paxillin axis. Moreover, NCTD exhibited a powerful anti-invasive effect compared with that of PF-562271 in YD-15 cells. Collectively, these results suggest that NCTD has a potential anti-invasive activity against YD-15 cells. This study may clarify the impact of NCTD on migration and invasion of human MEC cells.
Collapse
Affiliation(s)
- Kyoung-Ok Hong
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - Chi-Hyun Ahn
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - In-Hyoung Yang
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - Jung-Min Han
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - Ji-Ae Shin
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - Sung-Dae Cho
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| | - Seong Doo Hong
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea.
| |
Collapse
|
|
50
|
Salehi B, Lopez-Jornet P, Pons-Fuster López E, Calina D, Sharifi-Rad M, Ramírez-Alarcón K, Forman K, Fernández M, Martorell M, Setzer WN, Martins N, Rodrigues CF, Sharifi-Rad J. Plant-Derived Bioactives in Oral Mucosal Lesions: A Key Emphasis to Curcumin, Lycopene, Chamomile, Aloe vera, Green Tea and Coffee Properties. Biomolecules 2019; 9:biom9030106. [PMID: 30884918 PMCID: PMC6468600 DOI: 10.3390/biom9030106] [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: 01/27/2019] [Revised: 03/06/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Oral mucosal lesions have many etiologies, including viral or bacterial infections, local trauma or irritation, systemic disorders, and even excessive alcohol and tobacco consumption. Folk knowledge on medicinal plants and phytochemicals in the treatment of oral mucosal lesions has gained special attention among the scientific community. Thus, this review aims to provide a brief overview on the traditional knowledge of plants in the treatment of oral mucosal lesions. This review was carried out consulting reports between 2008 and 2018 of PubMed (Medline), Web of Science, Embase, Scopus, Cochrane Database, Science Direct, and Google Scholar. The chosen keywords were plant, phytochemical, oral mucosa, leukoplakia, oral lichen planus and oral health. A special emphasis was given to certain plants (e.g., chamomile, Aloe vera, green tea, and coffea) and plant-derived bioactives (e.g., curcumin, lycopene) with anti-oral mucosal lesion activity. Finally, preclinical (in vitro and in vivo) and clinical studies examining both the safety and efficacy of medicinal plants and their derived phytochemicals were also carefully addressed.
Collapse
Affiliation(s)
- Bahare Salehi
- Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran.
| | - Pia Lopez-Jornet
- Instituto Murciano de InvestigaciónBiosanitaria (IMIB-Arrixaca-UMU), Clínica Odontológica Universitaria Hospital Morales Meseguer Adv. Marques de los velez s/n, 30008 Murcia, Spain.
| | - Eduardo Pons-Fuster López
- University of Murciaand, Clínica Odontológica Universitaria Hospital Morales Meseguer, Adv. Marques de los velez s/n, 30008 Murcia, Spain.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.
| | - Mehdi Sharifi-Rad
- Department of Medical Parasitology, Zabol University of Medical Sciences, Zabol 61663-335, Iran.
| | - Karina Ramírez-Alarcón
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile.
| | - Katherine Forman
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile.
| | - Marcos Fernández
- Department of Pharmacy, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile.
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile.
| | - William N Setzer
- Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
| | - Natália Martins
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal.
| | - Célia F Rodrigues
- LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal.
| | - Javad Sharifi-Rad
- Food Safety Research Center (Salt), Semnan University of Medical Sciences, Semnan 35198-99951, Iran.
| |
Collapse
|