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Hill KS, Schuler EE, Ellingson SR, Kolesar JM. Artesunate acts through cytochrome c to inhibit growth of pediatric AML cells. Sci Rep 2023; 13:22383. [PMID: 38104159 PMCID: PMC10725448 DOI: 10.1038/s41598-023-49928-y] [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: 11/16/2022] [Accepted: 12/13/2023] [Indexed: 12/19/2023] Open
Abstract
Artesunate is a derivative of artemisinin, an active compound isolated from Artemisia annua which has been used in Traditional Chinese Medicine and to treat malaria worldwide. Artemisinin derivatives have exhibited anti-cancer activity against both solid tumors and leukemia. The direct target(s) of artesunate are controversial; although, heme-bound proteins in the mitochondria have been implicated. We utilized computational modeling to calculate the predicted binding score of artesunate with heme-bound mitochondrial proteins and identified cytochrome c as potential artesunate target. UV-visible spectroscopy showed changes in the absorbance spectrum, and thus protein structure, when cytochrome c was incubated with artesunate. Artesunate induces apoptosis, disrupts mitochondrial membrane potential, and is antagonized by methazolamide in pediatric AML cells indicating a probable mechanism of action involving cytochrome c. We utilized a multi-disciplinary approach to show that artesunate can interact with and is dependent on cytochrome c release to induce cell death in pediatric AML cell lines.
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Affiliation(s)
- Kristen S Hill
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Erin E Schuler
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA
| | - Sally R Ellingson
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
- Division of Biomedical Informatics, UK College of Medicine, Cancer Research Informatics, University of Kentucky, Lexington, KY, USA
| | - Jill M Kolesar
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
- Department of Pharmacy Practice and Research, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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3
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Cancer extracellular vesicles, tumoroid models, and tumor microenvironment. Semin Cancer Biol 2022; 86:112-126. [PMID: 35032650 DOI: 10.1016/j.semcancer.2022.01.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/21/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022]
Abstract
Cancer extracellular vesicles (EVs), or exosomes, promote tumor progression through enhancing tumor growth, initiating epithelial-to-mesenchymal transition, remodeling the tumor microenvironment, and preparing metastatic niches. Three-dimensionally (3D) cultured tumoroids / spheroids aim to reproduce some aspects of tumor behavior in vitro and show increased cancer stem cell properties. These properties are transferred to their EVs that promote tumor growth. Moreover, recent tumoroid models can be furnished with aspects of the tumor microenvironment, such as vasculature, hypoxia, and extracellular matrix. This review summarizes tumor tissue culture and engineering platforms compatible with EV research. For example, the combination experiments of 3D-tumoroids and EVs have revealed multifunctional proteins loaded in EVs, such as metalloproteinases and heat shock proteins. EVs or exosomes are able to transfer their cargo molecules to recipient cells, whose fates are often largely altered. In addition, the review summarizes approaches to EV labeling technology using fluorescence and luciferase, useful for studies on EV-mediated intercellular communication, biodistribution, and metastatic niche formation.
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Farmanpour-Kalalagh K, Beyraghdar Kashkooli A, Babaei A, Rezaei A, van der Krol AR. Artemisinins in Combating Viral Infections Like SARS-CoV-2, Inflammation and Cancers and Options to Meet Increased Global Demand. FRONTIERS IN PLANT SCIENCE 2022; 13:780257. [PMID: 35197994 PMCID: PMC8859114 DOI: 10.3389/fpls.2022.780257] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 01/03/2022] [Indexed: 05/05/2023]
Abstract
Artemisinin is a natural bioactive sesquiterpene lactone containing an unusual endoperoxide 1, 2, 4-trioxane ring. It is derived from the herbal medicinal plant Artemisia annua and is best known for its use in treatment of malaria. However, recent studies also indicate the potential for artemisinin and related compounds, commonly referred to as artemisinins, in combating viral infections, inflammation and certain cancers. Moreover, the different potential modes of action of artemisinins make these compounds also potentially relevant to the challenges the world faces in the COVID-19 pandemic. Initial studies indicate positive effects of artemisinin or Artemisia spp. extracts to combat SARS-CoV-2 infection or COVID-19 related symptoms and WHO-supervised clinical studies on the potential of artemisinins to combat COVID-19 are now in progress. However, implementing multiple potential new uses of artemisinins will require effective solutions to boost production, either by enhancing synthesis in A. annua itself or through biotechnological engineering in alternative biosynthesis platforms. Because of this renewed interest in artemisinin and its derivatives, here we review its modes of action, its potential application in different diseases including COVID-19, its biosynthesis and future options to boost production.
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Affiliation(s)
- Karim Farmanpour-Kalalagh
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Arman Beyraghdar Kashkooli
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
- *Correspondence: Arman Beyraghdar Kashkooli,
| | - Alireza Babaei
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Ali Rezaei
- Department of Horticultural Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
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Shen S, Luo J, Ye J. Artesunate alleviates schistosomiasis-induced liver fibrosis by downregulation of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in hepatic stellate cells. Acta Trop 2021; 214:105781. [PMID: 33264632 DOI: 10.1016/j.actatropica.2020.105781] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/08/2020] [Accepted: 11/21/2020] [Indexed: 01/03/2023]
Abstract
Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. Inhibition of the HSCs activity is an ideal strategy in the treatment of fibrosis, but there is no drug yet for this strategy. Artesunate (ART) has been shown to protect liver from fibrosis through inhibition of HSCs activity. However, the mechanism of ART activity remains to be fully uncovered. In this study, we tested ART in a mouse model of hepatic fibrosis established in the schistosomiasis-infected mice. The mechanism of ART action was investigated in the HSC cell line LX-2. ART significantly inhibited hepatic fibrosis. In LX-2 cells, ART efficiently inhibited the cell activity in proliferation and mRNA expression of fibrosis marker genes including Col1a1 and Col3a1. An impact of ART on mitochondria was observed for suppression of enzymes in the citric acid cycle (TCA), such as citrate synthase (CS), isocitrate dehydrogenase (IDH2), and alpha ketoglutarate dehydrogenase (OGDH) in a dose-dependent manner. ART decreased the mitochondrial oxygen consumption rate (OCR) and the protein levels of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in HSCs. All of these alterations were observed with an increase in HSC apoptosis. This study suggests that ART may alleviate liver fibrosis by downregulation of HSC activity through suppression of NDUFB8 and UQCRC2 in mitochondria. This study provides a new insight into the mechanism of the ART activity in the inhibition of schistosomiasis-induced liver fibrosis.
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Affiliation(s)
- Shuang Shen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Central laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, China.
| | - Juntao Luo
- Central laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, China; National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China
| | - Jianping Ye
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Central laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, China
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Xu C, Zhang H, Mu L, Yang X. Artemisinins as Anticancer Drugs: Novel Therapeutic Approaches, Molecular Mechanisms, and Clinical Trials. Front Pharmacol 2020; 11:529881. [PMID: 33117153 PMCID: PMC7573816 DOI: 10.3389/fphar.2020.529881] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 09/16/2020] [Indexed: 12/26/2022] Open
Abstract
Artemisinin and its derivatives have shown broad-spectrum antitumor activities in vitro and in vivo. Furthermore, outcomes from a limited number of clinical trials provide encouraging evidence for their excellent antitumor activities. However, some problems such as poor solubility, toxicity and controversial mechanisms of action hamper their use as effective antitumor agents in the clinic. In order to accelerate the use of ARTs in the clinic, researchers have recently developed novel therapeutic approaches including developing novel derivatives, manufacturing novel nano-formulations, and combining ARTs with other drugs for cancer therapy. The related mechanisms of action were explored. This review describes ARTs used to induce non-apoptotic cell death containing oncosis, autophagy, and ferroptosis. Moreover, it highlights the ARTs-caused effects on cancer metabolism, immunosuppression and cancer stem cells and discusses clinical trials of ARTs used to treat cancer. The review provides additional insight into the molecular mechanism of action of ARTs and their considerable clinical potential.
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Affiliation(s)
- Cangcang Xu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Huihui Zhang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Lingli Mu
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, China
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Elgendy SM, Alyammahi SK, Alhamad DW, Abdin SM, Omar HA. Ferroptosis: An emerging approach for targeting cancer stem cells and drug resistance. Crit Rev Oncol Hematol 2020; 155:103095. [PMID: 32927333 DOI: 10.1016/j.critrevonc.2020.103095] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/24/2020] [Accepted: 08/26/2020] [Indexed: 02/08/2023] Open
Abstract
Resistance to chemotherapeutic agents remains a major challenge in the fierce battle against cancer. Cancer stem cells (CSCs) are a small population of cells in tumors that possesses the ability to self-renew, initiate tumors, and cause resistance to conventional anticancer agents. Targeting this population of cells was proven as a promising approach to eliminate cancer recurrence and improve the clinical outcome. CSCs are less susceptible to death by classical anticancer agents inducing apoptosis. CSCs can be eradicated by ferroptosis, which is a non-apoptotic-regulated mechanism of cell death. The induction of ferroptosis is an attractive strategy to eliminate tumors due to its ability to selectively target aggressive CSCs. The current review critically explored the crosstalk and regulatory pathways controlling ferroptosis, which can selectively induce CSCs death. In addition, successful chemotherapeutic agents that achieve better therapeutic outcomes through the induction of ferroptosis in CSCs were discussed to highlight their promising clinical impact.
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Affiliation(s)
- Sara M Elgendy
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Shatha K Alyammahi
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Dima W Alhamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Shifaa M Abdin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Hany A Omar
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
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Yang Y, Li X, Wang T, Guo Q, Xi T, Zheng L. Emerging agents that target signaling pathways in cancer stem cells. J Hematol Oncol 2020; 13:60. [PMID: 32456660 PMCID: PMC7249421 DOI: 10.1186/s13045-020-00901-6] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) contribute to the initiation, recurrence, and metastasis of cancer; however, there are still no drugs targeting CSCs in clinical application. There are several signaling pathways playing critical roles in CSC progression, such as the Wnt, Hedgehog, Notch, Hippo, and autophagy signaling pathways. Additionally, targeting the ferroptosis signaling pathway was recently shown to specifically kill CSCs. Therefore, targeting these pathways may suppress CSC progression. The structure of small-molecule drugs shows a good spatial dispersion, and its chemical properties determine its good druggability and pharmacokinetic properties. These characteristics make small-molecule drugs show a great advantage in drug development, which is increasingly popular in the market. Thus, in this review, we will summarize the current researches on the small-molecule compounds suppressing CSC progression, including inhibitors of Wnt, Notch, Hedgehog, and autophagy pathways, and activators of Hippo and ferroptosis pathways. These small-molecule compounds emphasize CSC importance in tumor progression and propose a new strategy to treat cancer in clinic via targeting CSCs.
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Affiliation(s)
- Yue Yang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Ting Wang
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450003, People's Republic of China
| | - Tao Xi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People's Republic of China.
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Ma L, Fei H. Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism. J Bioenerg Biomembr 2020; 52:123-130. [PMID: 32036542 DOI: 10.1007/s10863-020-09824-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 02/02/2020] [Indexed: 12/29/2022]
Abstract
Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid malignancies and resistant to chemotherapy. Novel therapeutic strategy is required for better management of ATC. In this work, we show that artesunate, an antimalarial drug, is active against chemoresistant ATC cells. Artesunate dose-dependently inhibits growth and induces apoptosis in chemo-sensitive (8505C and KAT-4) and -resistant (8505C-r and KAT-4-r) ATC cells, and acts synergistically with doxorubicin. Using multiple xenograft mouse models, artesunate is active against chemo-sensitive and -resistant ATC cells in vivo at doses that do not cause toxicity in mice. Our mechanism analysis reveals that artesunate acts on ATC cells through suppressing mitochondrial functions without affecting glycolysis, leading to oxidative stress and damage, regardless of whether they are sensitive or resistant to chemotherapy. Interestingly, KAT-4-r cells demonstrate decreased glycolysis, increased mitochondrial membrane potential and mitochondrial respiration compared to KAT-4 cells whereas such phenomenon is not observed between 8505C and 8505C-r cells. This suggests that some but not all ATC cells gain enhanced mitochondrial biogenesis after prolonged exposure to chemotherapy drug, which may explain the different sensitivities of 8505C-r and KAT-4-r to artesunate. Our work demonstrates that artesunate is a potential addition to the treatment armamentarium for ATC, particularly those with chemoresistance. Our findings also highlight the therapeutic value of targeting mitochondria in chemoresistant ATC.
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Affiliation(s)
- Ling Ma
- Department of Endocrinology, First Affiliated Hospital, First Clinical Medical College, Yangtze University, Jingzhou, Hubei, 434000, China
| | - Honghua Fei
- Department of Endocrinology, People's Hospital of Rizhao, No.126, Taian Road, Rizhao, 276826, Shandong, China.
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Artesunate targets oral tongue squamous cell carcinoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition. J Bioenerg Biomembr 2020; 52:113-121. [PMID: 31965456 DOI: 10.1007/s10863-020-09823-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
Although mitochondrial metabolism has recently gained attention as a promising therapeutic strategy in cancer, little is known on the impact of mitochondrial respiration inhibition on oral tongue squamous cell carcinoma (OTSCC). Using in vitro and in vivo OTSCC models, our work demonstrates that inducing mitochondrial dysfunction by anti-malarial drug artesunate is effective in targeting OTSCC stem-cell like and bulk cells. Artesunate inhibits anchorage-independent colony formation, proliferation and survival in all tested OTSCC cell lines although with varying efficacy. Artesunate displays preferential anti-OTSCC activity by sparing normal cells. Mechanism analysis indicates that artesunate inhibits mitochondrial respiration via suppressing mitochondrial complex I and II but not IV or V, resulting in oxidative stress and damage. Interestingly, OTSCC cells that are more sensitive to artesunate have higher level of basal mitochondrial respiration and reversed respiratory capacity compared to those with less sensitivity to artesunate, suggesting the varying dependence on mitochondrial respiration among OTSCC cell lines. In addition, artesunate induces oxidative stress and damage in cells with low sensitivity to a less extent than in those with high sensitivity. We confirm that mitochondrial respiration inhibition is required for the action of artesunate in OTSCC. Mitochondrial dysfunction by artesunate further activates AMPK and suppresses Akt/mTOR. Importantly, the in vitro observations are reproducible in vivo OTSCC xenograft mouse model. Our findings provide pre-clinical evidence on the efficacy of artesunate and emphasize the therapeutic value of targeting mitochondrial respiration in OTSCC.
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Sogawa C, Eguchi T, Okusha Y, Ono K, Ohyama K, Iizuka M, Kawasaki R, Hamada Y, Takigawa M, Sogawa N, Okamoto K, Kozaki KI. A Reporter System Evaluates Tumorigenesis, Metastasis, β-catenin/MMP Regulation, and Druggability. Tissue Eng Part A 2019; 25:1413-1425. [PMID: 30734664 DOI: 10.1089/ten.tea.2018.0348] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cancer invasion, metastasis, and therapy resistance are the crucial phenomena in cancer malignancy. The high expression of matrix metalloproteinase 9 (MMP9) is a biomarker as well as a causal factor of cancer invasiveness and metastatic activity. However, a regulatory mechanism underlying MMP9 expression in cancer is not clarified yet. In addition, a new strategy for anticancer drug discovery is becoming an important clue. In the present study, we aimed (i) to develop a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability with a combination of three-dimensional tumoroid model and Mmp9 promoter and (ii) to examine pharmacological actions of anticancer medications using this reporter system. High expression and genetic amplification of MMP9 were found in colon cancer cases. We found that proximal promoter sequences of MMP9 in murine and human contained conserved binding sites for transcription factors β-catenin/TCF/LEF, glucocorticoid receptor (GR), and nuclear factor kappa-B (NF-κB). The murine Mmp9 promoter (-569 to +19) was markedly activated in metastatic colon cancer cells and additionally activated by tumoroid formation and by β-catenin signaling stimulator lithium chloride. The Mmp9 promoter-driven fluorescent reporter cells enabled the monitoring of activities of MMP9/gelatinase, tumorigenesis, invasion, and metastasis in syngeneic transplantation experiments. We also demonstrated pharmacological actions as follows: dexamethasone and hydrocortisone, steroidal medications binding to GR, inhibited the Mmp9 promoter but did not inhibit tumorigenesis. On the contrary, antimetabolite 5-fluorouracil, a gold standard for colon cancer chemotherapy, inhibited tumoroid formation but did not inhibit Mmp9 promoter activity. Notably, antimalaria medication artesunate inhibited both tumorigenesis and the Mmp9 promoter in vitro, potentially through inhibition of β-catenin/TCF/LEF signaling. Thus, this novel reporter system enabled monitoring tumorigenesis, invasiveness, metastasis, key regulatory signalings such as β-catenin/MMP9 axis, and druggability. Impact Statement Cancer invasion and metastasis have been shown to be driven by matrix metalloproteinase 9 (MMP9), whose expression mechanism is not clarified yet. In addition, a new strategy for anticancer drug discovery is becoming important. We established a novel reporter system evaluating tumorigenesis, invasiveness, metastasis, and druggability with a combination of three-dimensional (3D) tumoroid model and Mmp9 promoter. Using this reporter system, we demonstrated pharmacological actions of anticancer medications such as antimetabolite 5-fluorouracil (5-FU) and antimalaria medication artesunate (ART), which inhibited both tumorigenesis and β-catenin/MMP regulatory signaling. Our study impacts the translational fields of oncology, drug discovery, and organoid model.
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Affiliation(s)
- Chiharu Sogawa
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takanori Eguchi
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.,Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuka Okusha
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kisho Ono
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kazumi Ohyama
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Motoharu Iizuka
- Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan
| | - Ryu Kawasaki
- Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan
| | - Yusaku Hamada
- Research Program for Undergraduate Students, Okayama University Dental School, Okayama, Japan
| | - Masaharu Takigawa
- Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Norio Sogawa
- Department of Dental Pharmacology, Matsumoto Dental University, Shiojiri, Japan
| | - Kuniaki Okamoto
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ken-Ichi Kozaki
- Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Aasen DM, Vergara MN. New Drug Discovery Paradigms for Retinal Diseases: A Focus on Retinal Organoids. J Ocul Pharmacol Ther 2019; 36:18-24. [PMID: 31059378 PMCID: PMC6985764 DOI: 10.1089/jop.2018.0140] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Retinal disease represents a growing global problem, both in terms of quality of life and economic impact, yet new therapies are not being developed at a sufficient rate to meet this mounting need. In this context, retinal organoids derived from human induced pluripotent stem cells hold significant promise for improving upon the current drug development process, increasing the speed and efficiency of moving potential therapeutic agents from bench to bedside. These organoid systems display the cell–cell and cell–matrix interactions, cellular heterogeneity, and physiological responses reflective of human biology and, thus, have the ability to replicate retinal disease pathology in a way that 2-dimensional cell cultures and animal models have been heretofore unable to achieve. However, organoid technology is not yet mature enough to meet the high-throughput demands of the first stages of drug screening. Hence, the augmentation of the existing drug development pipeline with retinal organoids, rather than the replacement of existing pathway components, may provide a way to harness the benefits of this improved pathological modeling. In this study, we outline the possible benefits of such a symbiosis, discuss other potential uses, and highlight barriers that remain to be overcome.
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Affiliation(s)
- Davis M Aasen
- Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, Colorado
| | - M Natalia Vergara
- Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, Colorado.,CellSight Ocular Stem Cell and Regeneration Program, University of Colorado School of Medicine, Aurora, Colorado.,Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, Colorado
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Subedi A, Muroi M, Futamura Y, Kawamura T, Aono H, Nishi M, Ryo A, Watanabe N, Osada H. A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition. FEBS Lett 2019; 593:763-776. [PMID: 30874300 DOI: 10.1002/1873-3468.13361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/11/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023]
Abstract
Differences in the metabolism of cancer cells or cancer stem cells (CSCs) as compared to normal cells have provided avenues to safely target cancers. To discover metabolic inhibitors of CSCs, we performed alkaline phosphatase- and tumoursphere-based drug screening using induced cancer stem cell-like cells. From the screening of a RIKEN NPDepo chemical library, we discovered NPD2381 as a novel and selective cancer-stemness inhibitor that targets mitochondrial metabolism. Using our ChemProteoBase profiling, we found that NPD2381 increases the expression of enzymes within the serine biosynthesis pathway. We also found a role for serine in protecting cancer cells from mitochondrial inhibitors. Our results suggest the existence of a compensatory mechanism to increase the level of intracellular serine in response to mitochondrial inhibitors.
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Affiliation(s)
- Amit Subedi
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Makoto Muroi
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Yushi Futamura
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Tatsuro Kawamura
- RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Harumi Aono
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Mayuko Nishi
- Department of Microbiology, Yokohama City University School of Medicine, Japan
| | - Akihide Ryo
- Department of Microbiology, Yokohama City University School of Medicine, Japan
| | - Nobumoto Watanabe
- RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Wako, Japan.,Bio-Active Compounds Discovery Research Unit, RIKEN Center for Sustainable Resource Science, Wako, Japan
| | - Hiroyuki Osada
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan.,RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science, Wako, Japan
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14
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Vanneste M, Huang Q, Li M, Moose D, Zhao L, Stamnes MA, Schultz M, Wu M, Henry MD. High content screening identifies monensin as an EMT-selective cytotoxic compound. Sci Rep 2019; 9:1200. [PMID: 30718715 PMCID: PMC6361972 DOI: 10.1038/s41598-018-38019-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 10/11/2018] [Indexed: 01/03/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis and drug resistance. Specifically targeting cancer cells in an EMT-like state may have therapeutic value. In this study, we developed a cell imaging-based high-content screening protocol to identify EMT-selective cytotoxic compounds. Among the 2,640 compounds tested, salinomycin and monensin, both monovalent cation ionophores, displayed a potent and selective cytotoxic effect against EMT-like cells. The mechanism of action of monensin was further evaluated. Monensin (10 nM) induced apoptosis, cell cycle arrest, and an increase in reactive oxygen species (ROS) production in TEM 4-18 cells. In addition, monensin rapidly induced swelling of Golgi apparatus and perturbed mitochondrial function. These are previously known effects of monensin, albeit occurring at much higher concentrations in the micromolar range. The cytotoxic effect of monensin was not blocked by inhibitors of ferroptosis. To explore the generality of our findings, we evaluated the toxicity of monensin in 24 human cancer cell lines and classified them as resistant or sensitive based on IC50 cutoff of 100 nM. Gene Set Enrichment Analysis identified EMT as the top enriched gene set in the sensitive group. Importantly, increased monensin sensitivity in EMT-like cells is associated with elevated uptake of 3H-monensin compared to resistant cells.
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Affiliation(s)
- Marion Vanneste
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Qin Huang
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Mengshi Li
- Human Toxicology, University of Iowa, Iowa City, IA, 52242, USA
| | - Devon Moose
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Lei Zhao
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Mark A Stamnes
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA.,Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA
| | - Michael Schultz
- Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA.,Human Toxicology, University of Iowa, Iowa City, IA, 52242, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA
| | - Meng Wu
- Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA.,University of Iowa High Throughput Screening Facility (UIHTS), University of Iowa, Iowa City, IA, 52242, USA.,Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA
| | - Michael D Henry
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA. .,Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA. .,Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA. .,Department of Urology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA. .,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA.
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15
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Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2019; 1867:28-37. [DOI: 10.1016/j.bbapap.2018.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 12/14/2022]
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16
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Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis. Semin Cancer Biol 2018; 53:90-109. [PMID: 29966677 DOI: 10.1016/j.semcancer.2018.06.006] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/20/2018] [Accepted: 06/28/2018] [Indexed: 12/18/2022]
Abstract
Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.
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17
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Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. Biochem J 2018; 475:1611-1634. [PMID: 29743249 PMCID: PMC5941316 DOI: 10.1042/bcj20170164] [Citation(s) in RCA: 188] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/12/2018] [Accepted: 04/12/2018] [Indexed: 02/08/2023]
Abstract
Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full repertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, oncogenic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly, the action of metabolic pathways in CSC maintenance might not be merely a consequence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the biochemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to 'force' CSCs within certain metabolic dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer.
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18
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Alguacil-Núñez C, Ferrer-Ortiz I, García-Verdú E, López-Pirez P, Llorente-Cortijo IM, Sainz B. Current perspectives on the crosstalk between lung cancer stem cells and cancer-associated fibroblasts. Crit Rev Oncol Hematol 2018; 125:102-110. [PMID: 29650269 DOI: 10.1016/j.critrevonc.2018.02.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 02/17/2018] [Accepted: 02/26/2018] [Indexed: 12/16/2022] Open
Abstract
Lung cancer, in particular non-small cell lung carcinoma (NSCLC), is the second most common cancer in both men and women and the leading cause of cancer-related deaths worldwide. Its prognosis and diagnosis are determined by several driver mutations and diverse risk factors (e.g. smoking). While immunotherapy has proven effective in some patients, treatment of NSCLC using conventional chemotherapy is largely ineffective. The latter is believed to be due to the existence of a subpopulation of stem-like, highly tumorigenic and chemoresistant cells within the tumor population known as cancer stem cells (CSC). To complicate the situation, CSCs interact with the tumor microenvironment, which include cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, growth factors, cytokines and connective tissue components, which via a dynamic crosstalk, composed of proteins and exosomes, activates the CSC compartment. In this review, we analyze the crosstalk between CSCs and CAFs, the primary component of the NSCLC microenvironment, at the molecular and extracellular level and contemplate therapies to disrupt this communication.
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Affiliation(s)
- Cristina Alguacil-Núñez
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Inés Ferrer-Ortiz
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Elena García-Verdú
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Pilar López-Pirez
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Irene Maria Llorente-Cortijo
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Bruno Sainz
- Department of Biochemistry, Cancer Stem Cell and Tumor Microenvironment Group, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM), CSIC-UAM, Madrid, Spain; Chronic Diseases and Cancer Area 3 - Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
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19
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Dominguez-Gomez G, Chavez-Blanco A, Medina-Franco JL, Saldivar-Gonzalez F, Flores-Torrontegui Y, Juarez M, Díaz-Chávez J, Gonzalez-Fierro A, Dueñas-González A. Ivermectin as an inhibitor of cancer stem‑like cells. Mol Med Rep 2018; 17:3397-3403. [PMID: 29257278 DOI: 10.3892/mmr.2017.8231] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 08/07/2017] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to demonstrate that ivermectin preferentially inhibited cancer stem‑like cells (CSC) in breast cancer cells and downregulated the expression of 'stemness' genes. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of two‑dimensional similarity searching; the chemical structure of salinomycin was used as a query. Growth inhibition of the breast cancer cell lin e MDA‑MB‑231 by ivermectin was investigated in the total cell population, in cell spheroids and in sorted cells that expressed cluster of differentiation (CD)44+/CD24‑. The effects of ivermectin treatment on the expression of pluripotency and self‑renewal transcription factors, such as homeobox protein nanog (nanog), octamer‑binding protein 4 (oct‑4) and SRY‑box 2 (sox‑2), were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blotting. Ivermectin exhibited a similarity value of 0.78 in reference to salinomycin. Ivermectin demonstrated an inhibitory effect upon the growth of MDA‑MB‑231 cells in the range of 0.2‑8 µM. Ivermectin preferentially inhibits the viability of CSC‑enriched populations (CD44+/CD24‑ and cells growing in spheroids) compared with the total cell population. The opposite pattern was observed with paclitaxel treatment. Ivermectin exposure reduced the expression of nanog, oct‑4 and sox‑2 at the mRNA and protein levels. Ivermectin preferentially inhibited the CSC subpopulation in the MDA‑MB‑231 cells and downregulated the expression of genes involved in the maintenance of pluripotency and self‑renewal.
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Affiliation(s)
| | - Alma Chavez-Blanco
- Division of Basic Research, National Cancer Institute Mexico, Mexico City 14080, Mexico
| | - Jose Luis Medina-Franco
- Faculty of Chemistry, Pharmacy Department, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Fernanda Saldivar-Gonzalez
- Faculty of Chemistry, Pharmacy Department, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | | | - Mandy Juarez
- Division of Basic Research, National Cancer Institute Mexico, Mexico City 14080, Mexico
| | - José Díaz-Chávez
- Division of Basic Research, National Cancer Institute Mexico, Mexico City 14080, Mexico
| | | | - Alfonso Dueñas-González
- Unit of Biomedical Research in Cancer, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico
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20
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From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017; 46:65-83. [DOI: 10.1016/j.semcancer.2017.02.009] [Citation(s) in RCA: 385] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/15/2017] [Accepted: 02/24/2017] [Indexed: 12/24/2022]
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21
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Pützer BM, Solanki M, Herchenröder O. Advances in cancer stem cell targeting: How to strike the evil at its root. Adv Drug Deliv Rev 2017; 120:89-107. [PMID: 28736304 DOI: 10.1016/j.addr.2017.07.013] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/10/2017] [Accepted: 07/16/2017] [Indexed: 12/18/2022]
Abstract
Cancer progression to metastatic stages is still unmanageable and the promise of effective anti-metastatic therapy remains largely unmet, emphasizing the need to develop novel therapeutics. The special focus here is on cancer stem cells (CSC) as the seed of tumor initiation, epithelial-mesenchymal transition, chemoresistance and, as a consequence, drivers of metastatic dissemination. We report on targeted therapies gearing towards the CSC's internal and membrane-anchored markers using agents such as antibody derivatives, nucleic therapeutics, small molecules and genetic payloads. Another emphasis lies on novel proceedings envisaged to deliver current and prospective therapies to the target sites using newest viral and non-viral vector technologies. In this review, we summarize recent progress and remaining challenges in therapeutic strategies to combat CSC.
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Affiliation(s)
- Brigitte M Pützer
- Institute of Experimental Gene Therapy and Cancer Research, Biomedical Research Center (BMFZ), Rostock University Medical School, Germany.
| | - Manish Solanki
- Institute of Experimental Gene Therapy and Cancer Research, Biomedical Research Center (BMFZ), Rostock University Medical School, Germany
| | - Ottmar Herchenröder
- Institute of Experimental Gene Therapy and Cancer Research, Biomedical Research Center (BMFZ), Rostock University Medical School, Germany
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22
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Targeting epithelial-mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring. Biochem J 2017; 474:3269-3306. [PMID: 28931648 DOI: 10.1042/bcj20160782] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/01/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023]
Abstract
The concept of epithelial-mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial-mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. The focus of this review is to consolidate the existing knowledge on the strategies currently in development to combat cancer progression via inhibition of specific facets of EMP. The prevalence of relapse due to therapy resistance and metastatic propensity that EMP endows should be considered when designing therapy regimes, and such therapies should synergise with existing chemotherapeutics to benefit efficacy. To further improve upon EMP-targeted therapies, it is imperative to devise monitoring strategies to assess the impact of such treatments on EMP-related phenomenon such as CTC burden, chemosensitivity/-resistance and micrometastasis in patients.
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23
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Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WSF, Shen HM, Wang J. Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Med Res Rev 2017. [PMID: 28643446 DOI: 10.1002/med.21446] [Citation(s) in RCA: 168] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents.
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Affiliation(s)
- Yin Kwan Wong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chengchao Xu
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Karunakaran A Kalesh
- Department of Chemical Engineering, Imperial College London, London, United Kingdom
| | - Yingke He
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Qingsong Lin
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jigang Wang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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24
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Fitzpatrick PA, Akrap N, Söderberg EMV, Harrison H, Thomson GJ, Landberg G. Robotic Mammosphere Assay for High-Throughput Screening in Triple-Negative Breast Cancer. SLAS DISCOVERY 2017; 22:827-836. [PMID: 28346100 DOI: 10.1177/2472555217692321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In order to identify novel treatment principles specifically affecting cancer stem cells in triple-negative breast cancer, we have developed a high-throughput screening method based on the mammosphere and anoikis resistance assays allowing us to screen compounds using a functional readout. The assay was validated against manual protocols and through the use of positive controls, such as the response to hypoxia and treatment with the known cancer stem cell-targeting compound salinomycin. Manual and robotic procedures were compared and produced similar results in cell handling, cell cultures, and counting techniques, with no statistically significant difference produced from either method. The variance between samples processed manually versus robotically was no greater than 0.012, while Levene's test of significance was 0.2, indicating no significant difference between mammosphere data produced manually or robotically. Through the screening of 989 FDA-approved drugs and a follow-up screen assessing the antineoplastic subgroup, we have identified three therapeutic compounds with the ability to modulate the breast cancer stem cell fraction in the triple-negative breast cancer cell line MDA-MB-231, highlighting their potential usage as stem cell-specific adjuvant treatments.
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Affiliation(s)
- P A Fitzpatrick
- 1 Sahlgrenska Cancer Center, Göteborgs Universitet, Göteborg, Sweden
| | - N Akrap
- 1 Sahlgrenska Cancer Center, Göteborgs Universitet, Göteborg, Sweden
| | - E M V Söderberg
- 1 Sahlgrenska Cancer Center, Göteborgs Universitet, Göteborg, Sweden
| | - H Harrison
- 2 Faculty of Life Sciences, Manchester University, Manchester, UK
| | - G J Thomson
- 3 Drug Discovery Unit, CRUK Manchester Institute, Manchester, UK
| | - G Landberg
- 1 Sahlgrenska Cancer Center, Göteborgs Universitet, Göteborg, Sweden
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25
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Müller S, Cañeque T, Acevedo V, Rodriguez R. Targeting Cancer Stem Cells with Small Molecules. Isr J Chem 2017. [DOI: 10.1002/ijch.201600109] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Sebastian Müller
- Institut Curie Research Center; CNRS UMR 3666; Organic Synthesis and Cell Biology Group; 26 rue d'Ulm 75248 Paris France
| | - Tatiana Cañeque
- Institut Curie Research Center; CNRS UMR 3666; Organic Synthesis and Cell Biology Group; 26 rue d'Ulm 75248 Paris France
| | - Verónica Acevedo
- Institut Curie Research Center; CNRS UMR 3666; Organic Synthesis and Cell Biology Group; 26 rue d'Ulm 75248 Paris France
| | - Raphaël Rodriguez
- Institut Curie Research Center; CNRS UMR 3666; Organic Synthesis and Cell Biology Group; 26 rue d'Ulm 75248 Paris France
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