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Siedlecka-Kroplewska K, Kmiec Z, Zmijewski MA. The Interplay Between Autophagy and Apoptosis in the Mechanisms of Action of Stilbenes in Cancer Cells. Antioxidants (Basel) 2025; 14:339. [PMID: 40227400 PMCID: PMC11939748 DOI: 10.3390/antiox14030339] [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: 01/31/2025] [Revised: 03/06/2025] [Accepted: 03/10/2025] [Indexed: 04/15/2025] Open
Abstract
Plant-based stilbenes are low-molecular-weight polyphenolic compounds that exhibit anti-oxidant, anti-microbial, anti-fungal, anti-inflammatory, anti-diabetic, cardioprotective, neuroprotective, and anti-cancer activities. They are phytoalexins produced in diverse plant species in response to stress, such as fungal and bacterial infections or excessive UV irradiation. Plant-derived dietary products containing stilbenes are common components of the human diet. Stilbenes appear to be promising chemopreventive and chemotherapeutic agents. Accumulating evidence indicates that stilbenes are able to trigger both apoptotic and autophagic molecular pathways in many human cancer cell lines. Of note, the molecular crosstalk between autophagy and apoptosis under cellular stress conditions determines the cell fate. The autophagy and apoptosis relationship is complex and depends on the cellular context, e.g., cell type and cellular stress level. Apoptosis is a type of regulated cell death, whereas autophagy may act as a pro-survival or pro-death mechanism depending on the context. The interplay between autophagy and apoptosis may have an important impact on chemotherapy efficiency. This review focuses on the in vitro effects of stilbenes in different human cancer cell lines concerning the interplay between autophagy and apoptosis.
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Affiliation(s)
| | - Zbigniew Kmiec
- Department of Anatomy and Histology, School of Medicine, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland;
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Ibrahim RS, Ibrahim SS, El-Naas A, Koklesová L, Kubatka P, Büsselberg D. Could Metformin and Resveratrol Support Glioblastoma Treatment? A Mechanistic View at the Cellular Level. Cancers (Basel) 2023; 15:3368. [PMID: 37444478 DOI: 10.3390/cancers15133368] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
Glioblastoma, a malignant brain tumor, is a common primary brain tumor in adults, with diabetes mellitus being a crucial risk factor. This review examines how the antidiabetic drug metformin and dietary supplement resveratrol can benefit the treatment of glioblastoma. Metformin and resveratrol have demonstrated action against relevant pathways in cancer cells. Metformin and resveratrol inhibit cell proliferation by downregulating the PI3K/Akt pathway, activating mTOR, and increasing AMPK phosphorylation, resulting in lower proliferation and higher apoptosis levels. Metformin and resveratrol both upregulate and inhibit different cascades in the MAPK pathway. In vivo, the drugs reduced tumor growth and volume. These actions show how metformin and resveratrol can combat cancer with both glucose-dependent and glucose-independent effects. The pre-clinical results, alongside the lack of clinical studies and the rise in novel delivery mechanisms, warrant further clinical investigations into the applications of metformin and resveratrol as both separate and as a combination complement to current glioblastoma therapies.
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Affiliation(s)
| | | | - Ahmed El-Naas
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
| | - Lenka Koklesová
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Dietrich Büsselberg
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar
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3
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Sanati M, Binabaj MM, Ahmadi SS, Aminyavari S, Javid H, Mollazadeh H, Bibak B, Mohtashami E, Jamialahmadi T, Afshari AR, Sahebkar A. Recent advances in glioblastoma multiforme therapy: A focus on autophagy regulation. Biomed Pharmacother 2022; 155:113740. [PMID: 36166963 DOI: 10.1016/j.biopha.2022.113740] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 11/02/2022] Open
Abstract
Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran; Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Maryam Moradi Binabaj
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Seyed Sajad Ahmadi
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Bahram Bibak
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Targeting Drug Chemo-Resistance in Cancer Using Natural Products. Biomedicines 2021; 9:biomedicines9101353. [PMID: 34680470 PMCID: PMC8533186 DOI: 10.3390/biomedicines9101353] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.
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Patra S, Pradhan B, Nayak R, Behera C, Das S, Patra SK, Efferth T, Jena M, Bhutia SK. Dietary polyphenols in chemoprevention and synergistic effect in cancer: Clinical evidences and molecular mechanisms of action. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 90:153554. [PMID: 34371479 DOI: 10.1016/j.phymed.2021.153554] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Epidemiological studies has revealed that a diet rich in fruits and vegetables could lower the risk of certain cancers. In this setting, natural polyphenols are potent anticancer bioactive compounds to overcome the non-target specificity, undesirable cytotoxicity and high cost of treatment cancer chemotherapy. PURPOSE The review focuses on diverse classifications of the chemical diversity of dietary polyphenol and their molecular targets, modes of action, as well as preclinical and clinical applications in cancer prevention. RESULTS The dietary polyphenols exhibit chemo-preventive activity through modulation of apoptosis, autophagy, cell cycle progression, inflammation, invasion and metastasis. Polyphenols possess strong antioxidant activity and control multiple molecular events through activation of tumor suppressor genes and inhibition of oncogenes involved in carcinogenesis. Numerous in vitro and in vivo studies have evidenced that these dietary phytochemicals regulate critical molecular targets and pathways to limit cancer initiation and progression. Moreover, natural polyphenols act synergistically with existing clinically approved drugs. The improved anticancer activity of combinations of polyphenols and anticancer drugs represents a promising perspective for clinical applications against many human cancers. CONCLUSION The anticancer properties exhibited by dietary polyphenols are mainly attributed to their anti-metastatic, anti-proliferative, anti-angiogenic, anti-inflammatory, cell cycle arrest, apoptotic and autophagic effects. Hence, regular consumption of dietary polyphenols as food or food additives or adjuvants can be a promising tactic to preclude adjournment or cancer therapy.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, 769008, Odisha, India
| | - Biswajita Pradhan
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur-760007, Odisha, India
| | - Rabindra Nayak
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur-760007, Odisha, India
| | - Chhandashree Behera
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur-760007, Odisha, India
| | - Surajit Das
- Laboratory of Environmental Microbiology and Ecology, Department of Life Science, National Institute of Technology Rourkela, 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology Rourkela, 769008, Odisha, India
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128 Mainz, Germany
| | - Mrutyunjay Jena
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur-760007, Odisha, India.
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, 769008, Odisha, India.
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Arabzadeh A, Mortezazadeh T, Aryafar T, Gharepapagh E, Majdaeen M, Farhood B. Therapeutic potentials of resveratrol in combination with radiotherapy and chemotherapy during glioblastoma treatment: a mechanistic review. Cancer Cell Int 2021; 21:391. [PMID: 34289841 PMCID: PMC8296583 DOI: 10.1186/s12935-021-02099-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma, WHO grade IV astrocytoma, is the most aggressive type of brain tumors. These cancerous cells have a rapid growth rate, tendency to penetrate vital brain structures, molecular heterogeneity, etc. and this cancer is associated with a poor prognosis and low survival rate. Due to the resistance of glioblastoma cells to conventional therapeutic modalities (such as radiation therapy and chemotherapy) as well as the adverse effects of these modalities, the researchers have attempted to discover an appropriate alternative or adjuvant treatment for glioblastoma. Resveratrol, as an herbal and natural polyphenolic compound, has anti-tumoral property and has shown to be effective in GBM treatment. Resveratrol exerts its anti-tumoral effect through various mechanisms such as regulation of cell cycle progression and cell proliferation, autophagy, oxidant system, apoptosis pathways, and so on. Resveratrol in combination with radiation therapy and chemotherapy has also been used. In the present study, we summarized the current findings on therapeutic potentials of resveratrol in glioblastoma radiotherapy and chemotherapy.
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Affiliation(s)
- AmirAhmad Arabzadeh
- Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Tohid Mortezazadeh
- Department of Medical Physics, School of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Tayebeh Aryafar
- Department of Radiation Sciences, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Esmaeil Gharepapagh
- Medical Radiation Sciences Research Team , Tabriz University of Medical Science, Tabriz, Iran
| | - Mehrsa Majdaeen
- Department of Radiotherapy and Oncology, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Chen JC, Hwang JH. Caffeine Inhibits Growth of Temozolomide-Treated Glioma via Increasing Autophagy and Apoptosis but Not via Modulating Hypoxia, Angiogenesis, or Endoplasmic Reticulum Stress in Rats. Nutr Cancer 2021; 74:1090-1096. [PMID: 34060393 DOI: 10.1080/01635581.2021.1931361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Thirty rats with glioma were divided into control group, temozolomide (TMZ) group (TMZ 30 mg/kg once daily for 5 day), and TMZ plus Caffeine group (TMZ 30 mg/kg once daily for 5 day and caffeine 100 mg/kg once daily for 2 weeks). The relative tumor fold and expression of hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), neuropilin-1 (NRP-1), CCAAT/enhancer-binding protein homologous protein (CHOP), LC-3A/B, apoptosis-inducing factor-1 (AIF-1), and cleaved caspase three were compared. The relative tumor fold of TMZ plus Caffeine group was lower significantly than that of TMZ group at day 14. HIF-1α, VEGF, NRP-1, and CHOP expressions were not significantly different in the three groups. The LC-3A/B expression of TMZ plus Caffeine group was higher significantly than that of the control group and TMZ group. The AIF expressions of TMZ group and TMZ plus Caffeine group were higher significantly than that of the control group. The caspase-3 expression of TMZ plus Caffeine group was higher significantly than that of the control group and TMZ group. In conclusions, the inhibitory effect of caffeine on TMZ-treated glioma might be associated with increasing expressions of autophagy- and apoptosis-related genes.
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Affiliation(s)
- Jin-Cherng Chen
- Department of Neurosurgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Juen-Haur Hwang
- School of Medicine, Tzu Chi University, Hualien, Taiwan.,Department of Otolaryngology-Head and Neck Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
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Patra S, Nayak R, Patro S, Pradhan B, Sahu B, Behera C, Bhutia SK, Jena M. Chemical diversity of dietary phytochemicals and their mode of chemoprevention. BIOTECHNOLOGY REPORTS (AMSTERDAM, NETHERLANDS) 2021; 30:e00633. [PMID: 34094892 PMCID: PMC8167155 DOI: 10.1016/j.btre.2021.e00633] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 05/16/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022]
Abstract
Despite the advancement in prognosis, diagnosis and treatment, cancer has emerged as the second leading cause of disease-associated death across the globe. With the remarkable application of synthetic drugs in cancer therapy and the onset of therapy-associated adverse effects, dietary phytochemicals have been materialized as potent anti-cancer drugs owing to their antioxidant, apoptosis and autophagy modulating activities. With dynamic regulation of apoptosis and autophagy in association with cell cycle regulation, inhibition in cellular proliferation, invasion and migration, dietary phytochemicals have emerged as potent anti-cancer pharmacophores. Dietary phytochemicals or their synthetic analogous as individual drug candidates or in combination with FDA approved chemotherapeutic drugs have exhibited potent anti-cancer efficacy. With the advancement in cancer therapeutics, dietary phytochemicals hold high prevalence for their use as precision and personalized medicine to replace conventional chemotherapeutic drugs. Hence, keeping these perspectives in mind, this review focuses on the diversity of dietary phytochemicals and their molecular mechanism of action in several cancer subtypes and tumor entities. Understanding the possible molecular key players involved, the use of dietary phytochemicals will thrive a new horizon in cancer therapy.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India
| | - Rabindra Nayak
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Suryamani Patro
- Department of Home Science, S.B.R. Govt. Women’s College, Berhampur, 760001, India
| | - Biswajita Pradhan
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | | | - Chhandashree Behera
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India
| | - Mrutyunjay Jena
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
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Musial C, Siedlecka-Kroplewska K, Kmiec Z, Gorska-Ponikowska M. Modulation of Autophagy in Cancer Cells by Dietary Polyphenols. Antioxidants (Basel) 2021; 10:123. [PMID: 33467015 PMCID: PMC7830598 DOI: 10.3390/antiox10010123] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
The role of autophagy is to degrade damaged or unnecessary cellular structures. Both in vivo and in vitro studies suggest a dual role of autophagy in cancer-it may promote the development of neoplasms, but it may also play a tumor protective function. The mechanism of autophagy depends on the genetic context, tumor stage and type, tumor microenvironment, or clinical therapy used. Autophagy also plays an important role in cell death as well as in the induction of chemoresistance of cancer cells. The following review describes the extensive autophagic cell death in relation to dietary polyphenols and cancer disease. The review documents increasing use of polyphenolic compounds in cancer prevention, or as agents supporting oncological treatment. Polyphenols are organic chemicals that exhibit antioxidant, anti-inflammatory, anti-angiogenic, and immunomodulating properties, and can also initiate the process of apoptosis. In addition, polyphenols reduce oxidative stress and protect against reactive oxygen species. This review presents in vitro and in vivo studies in animal models with the use of polyphenolic compounds such as epigallocatechin-3-gallate (EGCG), oleuropein, punicalgin, apigenin, resveratrol, pterostilbene, or curcumin and their importance in the modulation of autophagy-induced death of cancer cells.
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Affiliation(s)
- Claudia Musial
- Department of Medical Chemistry, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | | | - Zbigniew Kmiec
- Department of Histology, Medical University of Gdansk, 80-211 Gdansk, Poland; (K.S.-K.); (Z.K.)
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10
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Patra S, Pradhan B, Nayak R, Behera C, Rout L, Jena M, Efferth T, Bhutia SK. Chemotherapeutic efficacy of curcumin and resveratrol against cancer: Chemoprevention, chemoprotection, drug synergism and clinical pharmacokinetics. Semin Cancer Biol 2020; 73:310-320. [PMID: 33152486 DOI: 10.1016/j.semcancer.2020.10.010] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/20/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022]
Abstract
The frequent inefficiency of conventional cancer therapies due to drug resistance, non-targeted drug delivery, chemotherapy-associated toxic side effects turned the focus to bioactive phytochemicals. In this context, curcumin and resveratrol have emerged as potent chemopreventive and chemoprotective compounds modulating apoptotic and autophagic cell death pathways in cancer in vitro and in vivo. As synergistic agents in combination with clinically established anticancer drugs, the enhanced anticancer activity at reduced chemotherapy-associated toxicity towards normal organs can be explained by improved pharmacokinetics, pharmacodynamics, bioavailability and metabolism. With promising preclinical and clinical applications, the design of drug-loaded nanoparticles, nanocarriers, liposomes and micelles have gained much attention to improve target specificity and drug efficacy. The present review focuses on the molecular modes of chemoprevention, chemoprotection and drug synergism with special emphasis to preclinical and clinical applications, pharmacokinetics, pharmacodynamics and advanced drug delivery methods for the development of next-generation personalized cancer therapeutics.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India
| | - Biswajita Pradhan
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Rabindra Nayak
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Chhandashree Behera
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Laxmidhar Rout
- Post Graduate Department of Chemistry, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Mrutyunjay Jena
- Post Graduate Department of Botany, Berhampur University, Bhanja Bihar, Berhampur, 760007, India
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, India.
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11
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Zhao Q, Peng C, Zheng C, He XH, Huang W, Han B. Recent Advances in Characterizing Natural Products that Regulate Autophagy. Anticancer Agents Med Chem 2020; 19:2177-2196. [PMID: 31749434 DOI: 10.2174/1871520619666191015104458] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/16/2018] [Accepted: 08/26/2019] [Indexed: 02/07/2023]
Abstract
Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.
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Affiliation(s)
- Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Chuan Zheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Xiang-Hong He
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu 611137, China.,The RNA Institute, University at Albany, State University of New York, Albany, NY 12222, United States
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12
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Benvenuto M, Albonici L, Focaccetti C, Ciuffa S, Fazi S, Cifaldi L, Miele MT, De Maio F, Tresoldi I, Manzari V, Modesti A, Masuelli L, Bei R. Polyphenol-Mediated Autophagy in Cancer: Evidence of In Vitro and In Vivo Studies. Int J Mol Sci 2020; 21:E6635. [PMID: 32927836 PMCID: PMC7555128 DOI: 10.3390/ijms21186635] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/07/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
One of the hallmarks of cellular transformation is the altered mechanism of cell death. There are three main types of cell death, characterized by different morphological and biochemical features, namely apoptosis (type I), autophagic cell death (type II) and necrosis (type III). Autophagy, or self-eating, is a tightly regulated process involved in stress responses, and it is a lysosomal degradation process. The role of autophagy in cancer is controversial and has been associated with both the induction and the inhibition of tumor growth. Autophagy can exert tumor suppression through the degradation of oncogenic proteins, suppression of inflammation, chronic tissue damage and ultimately by preventing mutations and genetic instability. On the other hand, tumor cells activate autophagy for survival in cellular stress conditions. Thus, autophagy modulation could represent a promising therapeutic strategy for cancer. Several studies have shown that polyphenols, natural compounds found in foods and beverages of plant origin, can efficiently modulate autophagy in several types of cancer. In this review, we summarize the current knowledge on the effects of polyphenols on autophagy, highlighting the conceptual benefits or drawbacks and subtle cell-specific effects of polyphenols for envisioning future therapies employing polyphenols as chemoadjuvants.
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Affiliation(s)
- Monica Benvenuto
- Saint Camillus International University of Health and Medical Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy;
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Loredana Albonici
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
- Department of Human Science and Promotion of the Quality of Life, San Raffaele University Rome, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Sara Ciuffa
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Sara Fazi
- Department of Experimental Medicine, University of Rome “Sapienza”, Viale Regina Elena 324, 00161 Rome, Italy; (S.F.); (L.M.)
| | - Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
- Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy
| | - Martino Tony Miele
- Department of Experimental Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy;
| | - Fernando De Maio
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Ilaria Tresoldi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Vittorio Manzari
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Andrea Modesti
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome “Sapienza”, Viale Regina Elena 324, 00161 Rome, Italy; (S.F.); (L.M.)
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy; (L.A.); (C.F.); (S.C.); (L.C.); (F.D.M.); (I.T.); (V.M.); (A.M.)
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13
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Li M, Wu X, An P, Dang H, Liu Y, Liu R. Effects of resveratrol on autophagy and the expression of inflammasomes in a placental trophoblast oxidative stress model. Life Sci 2020; 256:117890. [PMID: 32497634 DOI: 10.1016/j.lfs.2020.117890] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/21/2020] [Accepted: 05/29/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVE We aim to investigate whether there is activation of NLRP1 and autophagy in trophoblast oxidative stress model. Resveratrol was taken to clarify its role in oxidative damage of placental trophoblasts. METHODS H2O2 was added to HTR-8/SVneo cell for 3 h, then the ROS level and apoptosis panel was performed. The levels of IL-1β, caspase-1, NLRP1, LC3 and Beclin-1 were detected. Resveratrol was added after 8 h, the ROS level and apoptosis rate were detected, the expression of IL-1β, caspase-1, NLRP1, LC3 and Beclin-1 were detected. RESULTS 300 μmol/L H2O2 for 3 h is the optimum combination in establishing the oxidative stress injury model (P < 0.01). LDH, ROS and MDA level was increased, the activity of SOD, CAT were declined (P < 0.01). Apoptosis rate increased (P < 0.01). The expression of IL-1β, caspase-1, NLRP1, LC3 and Beclin-1 protein was higher (P < .01). Resveratrol (50 μmol/L) treatment for 8 h could improve the changes caused by H2O2, increase the survival rate of cells (P < 0.01), reduce the release of LDH, decrease the level of MDA, increase the level of SOD and CAT (P < 0.01). The expression of IL-1β, caspase-1, NLRP1, LC3 and Beclin-1 protein decreased (P < 0.01). CONCLUSION Trophoblast oxidative damage model can be established under 300 μmol/L H2O2 for 3 h, the expression of NLRP1and autophagy after H2O2 treatment were detected. Resveratrol reduces apoptotic cells, thus ensuring the normal biological functions of trophoblasts. CAPSULE H2O2-induced oxidative stress damage model in HTR-8/SVneo cells can be successfully established under 300 μmol/L H2O2 for 3 h, resveratrol alleviates of H2O2-induced damage by its antioxidant and autophagy regulation function.
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Affiliation(s)
- Meihe Li
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiaoling Wu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, China
| | - Peng An
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Huimin Dang
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| | - Yanqiao Liu
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Runxia Liu
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
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14
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Dionigi L, Ragonese F, Monarca L, Covino S, de Luca A, Iannitti RG, Bastioli F, Moulas AN, Allegretti M, Fioretti B. Focus on the Use of Resveratrol as an Adjuvant in Glioblastoma Therapy. Curr Pharm Des 2020; 26:2102-2108. [PMID: 32233996 DOI: 10.2174/1381612826666200401085634] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Abstract
Glioblastoma (GB) represents the most common and malignant form of glioma cancer. The Gold Standard in Glioblastoma is neurosurgical tumor removal and radiotherapy treatment in concomitant with temozolomide (TMZ). Unfortunately, because of tumor chemo and radio-resistance during this therapy, the patient's outcome remains very poor, with a median overall survival of about 14.6 months. Resveratrol is a natural polyphenol with a stilbene structure with chemopreventive and anticancer properties. In the present review, we evaluated data from preclinical studies conducted with resveratrol as a possible adjuvant during the standard protocol of GB. Resveratrol can reach the brain parenchyma at sub-micromolar concentrations when administrated through conventional routes. In this way, resveratrol reduces cell invasion and increases the efficacy of radiotherapy (radiosensitizer effects) and temozolomide. The molecular mechanism of the adjuvant action of resveratrol may depend upon the reduction of PI3K/AKT/NF-κB axis and downstream targets O-6-methylguanine-DNA methyltransferase (MGMT) and metalloproteinase-2 (MMP-2). It has been reported that redox signaling plays an important role in the regulation of autophagy. Resveratrol administration by External Carotid Artery (ECA) injection or by Lumbar Puncture (LP) can reach micromolar concentrations in tumor mass where it would inhibit tumor growth by STAT-3 dependent mechanisms. Preclinical evidences indicate a positive effect on the use of resveratrol as an adjuvant in anti-GB therapy. Ameliorated formulations of resveratrol with a favorable plasmatic profile for a better brain distribution and timing sequences during radio and chemotherapy could represent a critical aspect for resveratrol use as an adjuvant for a clinical evaluation.
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Affiliation(s)
| | - Francesco Ragonese
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy.,Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06132 Perugia, Italy
| | - Lorenzo Monarca
- Department of Experimental Medicine, Perugia Medical School, University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy.,Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06132 Perugia, Italy
| | - Stefano Covino
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06132 Perugia, Italy
| | - Antonella de Luca
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06132 Perugia, Italy
| | - Rossana G Iannitti
- S&R Farmaceutici S.p.A Bastia Umbra, Via dei Pioppi n2, 08063 Perugia, Italy
| | - Federica Bastioli
- S&R Farmaceutici S.p.A Bastia Umbra, Via dei Pioppi n2, 08063 Perugia, Italy
| | | | | | - Bernard Fioretti
- Department of Chemistry, Biology and Biotechnologies, University of Perugia, Via Elce di Sotto 8, 06132 Perugia, Italy
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15
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Allam RM, El-Halawany AM, Al-Abd AM. Chemo-sensitizing agents from natural origin for colorectal cancer: Pharmacodynamic and cellular pharmacokinetics approaches. DRUG RESISTANCE IN COLORECTAL CANCER: MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES 2020:93-116. [DOI: 10.1016/b978-0-12-819937-4.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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16
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Cuomo F, Altucci L, Cobellis G. Autophagy Function and Dysfunction: Potential Drugs as Anti-Cancer Therapy. Cancers (Basel) 2019; 11:cancers11101465. [PMID: 31569540 PMCID: PMC6826381 DOI: 10.3390/cancers11101465] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/25/2019] [Accepted: 09/26/2019] [Indexed: 12/24/2022] Open
Abstract
Autophagy is a highly conserved catabolic and energy-generating process that facilitates the degradation of damaged organelles or intracellular components, providing cells with components for the synthesis of new ones. Autophagy acts as a quality control system, and has a pro-survival role. The imbalance of this process is associated with apoptosis, which is a “positive” and desired biological choice in some circumstances. Autophagy dysfunction is associated with several diseases, including neurodegenerative disorders, cardiomyopathy, diabetes, liver disease, autoimmune diseases, and cancer. Here, we provide an overview of the regulatory mechanisms underlying autophagy, with a particular focus on cancer and the autophagy-targeting drugs currently approved for use in the treatment of solid and non-solid malignancies.
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Affiliation(s)
- Francesca Cuomo
- Department of Precision Medicine, University of Campania "L. Vanvitelli", via L. De Crecchio, 7, 80138 Naples, Italy.
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania "L. Vanvitelli", via L. De Crecchio, 7, 80138 Naples, Italy.
| | - Gilda Cobellis
- Department of Precision Medicine, University of Campania "L. Vanvitelli", via L. De Crecchio, 7, 80138 Naples, Italy.
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17
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Chaurasia M, Gupta S, Das A, Dwarakanath B, Simonsen A, Sharma K. Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy. Autophagy 2019; 15:1391-1406. [PMID: 30773986 PMCID: PMC6613886 DOI: 10.1080/15548627.2019.1582973] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 01/22/2019] [Accepted: 01/29/2019] [Indexed: 12/19/2022] Open
Abstract
Cellular effects of ionizing radiation include oxidative damage to macromolecules, unfolded protein response (UPR) and metabolic imbalances. Oxidative stress and UPR have been shown to induce macroautophagy/autophagy in a context-dependent manner and are crucial factors in determining the fate of irradiated cells. However, an in-depth analysis of the relationship between radiation-induced damage and autophagy has not been explored. In the present study, we investigated the relationship between radiation-induced oxidative stress, UPR and autophagy in murine macrophage cells. A close association was observed between radiation-induced oxidative burst, UPR and induction of autophagy, with the possible involvement of EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) and ERN1/IRE1 (endoplasmic reticulum [ER] to nucleus signaling 1). Inhibitors of either UPR or autophagy reduced the cell survival indicating the importance of these processes after radiation exposure. Moreover, modulation of autophagy affected lethality in the whole body irradiated C57BL/6 mouse. These findings indicate that radiation-induced autophagy is a pro-survival response initiated by oxidative stress and mediated by EIF2AK3 and ERN1. Abbreviations: ACTB: actin, beta; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; CQ: chloroquine; DBSA: 3,5-dibromosalicylaldehyde; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1: endoplasmic reticulum (ER) to nucleus signaling 1; IR: ionizing radiation; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; 3-MA: 3-methyladenine; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; PARP1: poly (ADP-ribose) polymerase family, member 1; 4-PBA: 4-phenylbutyrate; Rap: rapamycin; ROS: reactive oxygen species; UPR: unfolded protein response; XBP1: x-box binding protein 1.
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Affiliation(s)
- Madhuri Chaurasia
- Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Swapnil Gupta
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Asmita Das
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | | | - Anne Simonsen
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kulbhushan Sharma
- Division of Metabolic Cell Signaling Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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18
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Li Y, Yang X, Yao P, Shen W, Wu Y, Ye Z, Zhao K, Chen H, Cao J, Xing C. B7-H3 increases the radioresistance of gastric cancer cells through regulating baseline levels of cell autophagy. Am J Transl Res 2019; 11:4438-4449. [PMID: 31396347 PMCID: PMC6684931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 07/01/2019] [Indexed: 06/10/2023]
Abstract
Gastric cancer remains the second leading cause of cancer-related deaths worldwide. Adjuvant therapy has been shown to improve survival and is delivered either postoperatively (chemoradiotherapy) or perioperatively (chemotherapy) in Western countries. Debate continues regarding which of these approaches is an optimal strategy. Radioresistance in gastric cancer cells remains a serious concern. B7 homologue 3 (B7-H3, CD276), a newly found member of B7 immunoregulatory family, was found to be expressed in aberrant gastric cancer cells, and played a direct role in gastric cancer progression systems in a previous study. With upregulation or downregulation of B7-H3, it was observed that B7-H3 could increase radiotherapy resistance of gastric cancer cells by modulating apoptosis, cell cycle progression, and DNA double-strand breaks. Furthermore, it was found that B7-H3 could regulate baseline levels of cell autophagy. B7-H3 expression was negatively correlated with LC3-B expression in gastric cancer tissues. It was found that increasing baseline levels of cell autophagy with rapamycin in B7-H3-overexpressing cells could improve their sensitivity to radiation. This protein also exerted its function by modulating apoptosis and DNA double-strand breaks. Overall, it is demonstrated that B7-H3 increases the radiotherapy resistance of gastric cancer cells through regulating baseline levels of cell autophagy.
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Affiliation(s)
- Yecheng Li
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Xiaodong Yang
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Pingan Yao
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Wenqi Shen
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Yong Wu
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Zhenyu Ye
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Kui Zhao
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
| | - Hanqing Chen
- Department of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, China
| | - Jianping Cao
- School of Radiation Medicine and Protection, Medical College of Soochow UniversitySuzhou 215123, China
- State Key Laboratory of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow UniversitySuzhou 215123, China
| | - Chungen Xing
- Department of General Surgery, Second Affiliated Hospital of Soochow UniversitySuzhou 215004, China
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19
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Deng S, Shanmugam MK, Kumar AP, Yap CT, Sethi G, Bishayee A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer 2019; 125:1228-1246. [DOI: 10.1002/cncr.31978] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 11/24/2018] [Accepted: 12/10/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Shuo Deng
- Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore Singapore
| | - Muthu K. Shanmugam
- Department of Pharmacology Yong Loo Lin School of Medicine, National University of Singapore Singapore
| | - Alan Prem Kumar
- Department of Pharmacology Yong Loo Lin School of Medicine, National University of Singapore Singapore
- Cancer Science Institute of Singapore National University of Singapore Singapore
- Cancer Program, Medical Science Cluster Yong Loo Lin School of Medicine, National University of Singapore Singapore
- National University Cancer Institute National University Health System Singapore
- Curtin Medical School, Faculty of Health Sciences Curtin University Perth West Australia Australia
| | - Celestial T. Yap
- Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore Singapore
- National University Cancer Institute National University Health System Singapore
| | - Gautam Sethi
- Department of Pharmacology Yong Loo Lin School of Medicine, National University of Singapore Singapore
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20
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Park SH, Kang MK, Choi YJ, Kim YH, Antika LD, Kim DY, Lee EJ, Lim SS, Kang YH. α-Asarone blocks 7β-hydroxycholesterol-exposed macrophage injury through blocking elF2α phosphorylation and prompting beclin-1-dependent autophagy. Oncotarget 2018; 8:7370-7383. [PMID: 28088783 PMCID: PMC5352328 DOI: 10.18632/oncotarget.14566] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/02/2017] [Indexed: 12/27/2022] Open
Abstract
Macrophage apoptosis is salient in advanced atherosclerotic lesions and is induced by several stimuli including endoplasmic reticulum (ER) stress. This study examined that a-asarone present in purple perilla abrogated macrophage injury caused by oxysterols via ER stress- and autophagy-mediated mechanisms. Nontoxic a-asarone at 1-20 M attenuated 7β-hydroxycholesterol-induced activation of eukaryotic initiation factor 2a in macrophages leading to C/EBP homologous protein (CHOP) expression and apoptosis due to sustained ER stress. The a-asarone treatment increased the formation of autophagolysosomes localizing in perinuclear regions of 7β-hydroxycholesterol-exposed macrophages. Consistently, this compound promoted the induction of the key autophagic proteins of beclin-1, vacuolar protein sorting 34 and p150 responsible for vesicle nucleation, and prompted the conversion of microtubule-associated protein 1A/1B-light chain 3 and the induction of p62, neighbor of BRCA1 and autophagy-related (Atg) 12-Atg5-Atg16L conjugate involved in phagophore expansion and autophagosome formation. Additionally, a-asarone increased ER phosphorylation of bcl-2 facilitating beclin-1 entry to autophagic process. Furthermore, the deletion of Atg5 or beclin-1 gene enhanced apoptotic CHOP induction. Collectively, a-asarone-stimulated autophagy may be potential multi-targeted therapeutic avenues in treating ER stress-associated macrophage apoptosis.
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Affiliation(s)
- Sin-Hye Park
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Min-Kyung Kang
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Yean-Jung Choi
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Yun-Ho Kim
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Lucia Dwi Antika
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Dong Yeon Kim
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Eun-Jung Lee
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Soon Sung Lim
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
| | - Young-Hee Kang
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Korea
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21
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Moosavi MA, Haghi A, Rahmati M, Taniguchi H, Mocan A, Echeverría J, Gupta VK, Tzvetkov NT, Atanasov AG. Phytochemicals as potent modulators of autophagy for cancer therapy. Cancer Lett 2018; 424:46-69. [PMID: 29474859 DOI: 10.1016/j.canlet.2018.02.030] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 02/18/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023]
Abstract
The dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, and accordingly universal research efforts have focused on exploring novel compounds with autophagy-modulating properties. While a number of synthetic autophagy modulators have been identified as promising cancer therapy candidates, autophagy-modulating phytochemicals have also attracted attention as potential treatments with minimal side effects. In this review, we firstly highlight the importance of autophagy and its relevance in the pathogenesis and treatment of cancer. Subsequently, we present the data on common phytochemicals and their mechanism of action as autophagy modulators. Finally, we discuss the challenges associated with harnessing the autophagic potential of phytochemicals for cancer therapy.
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Affiliation(s)
- Mohammad Amin Moosavi
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, P.O Box:14965/161, Tehran, Iran.
| | - Atousa Haghi
- Young Researchers & Elite Club, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hiroaki Taniguchi
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland
| | - Andrei Mocan
- Department of Pharmaceutical Botany, "Iuliu Haţieganu" University of Medicine and Pharmacy, Gheorghe Marinescu 23 Street, 400337 Cluj-Napoca, Romania
| | - Javier Echeverría
- Facultad de Química y Biología, Universidad de Santiago de Chile, Casilla 40, Correo 33, Santiago 9170022, Chile
| | - Vijai K Gupta
- Department of Chemistry and Biotechnology, ERA Chair of Green Chemistry, Tallinn University of Technology, 12618 Tallinn, Estonia
| | - Nikolay T Tzvetkov
- Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany; NTZ Lab Ltd., Krasno Selo 198, Sofia 1618, Bulgaria
| | - Atanas G Atanasov
- Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
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22
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Massaro RR, Brohem CA, Almeida RLD, Rivelli DP, Miyake JA, Colquhoun A, Barros SBDM, Maria-Engler SS. 4-Nerolidylcatechol induces autophagy in human glioblastoma cells. BRAZ J PHARM SCI 2018. [DOI: 10.1590/s2175-97902017000300169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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23
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Jawhari S, Bessette B, Hombourger S, Durand K, Lacroix A, Labrousse F, Jauberteau MO, Ratinaud MH, Verdier M. Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis 2017; 38:592-603. [PMID: 28402394 DOI: 10.1093/carcin/bgx029] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 03/21/2017] [Indexed: 01/21/2023] Open
Abstract
Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.
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Affiliation(s)
- Soha Jawhari
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Barbara Bessette
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Sophie Hombourger
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Karine Durand
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - Aurélie Lacroix
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | - François Labrousse
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
| | | | | | - Mireille Verdier
- EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France
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24
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Fu Z, Luo W, Wang J, Peng T, Sun G, Shi J, Li Z, Zhang B. Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma. Biochem Biophys Res Commun 2017; 492:480-486. [PMID: 28834690 DOI: 10.1016/j.bbrc.2017.08.070] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 08/18/2017] [Indexed: 10/19/2022]
Abstract
The long noncoding RNA Malat1 has been reported to be an oncogene that promotes tumor progress and correlates with prognosis in glioma. Growing evidence shows that autophagy plays a very important role in tumorigenesis and tumor cell survival, but whether Malat1 regulates autophagy in glioma is still unclear. In this study, we found that Malat1 expression and autophagy activity were significantly increased in glioma tissues compared with adjacent normal tissues. Additionally, Malat1 level was positively correlated with the expression of LC3-II (autophagy marker) mRNA in vivo. In vitro assays revealed that Malat1 significantly promoted autophagy activation and cell proliferation in glioma cells. More importantly, inhibition of autophagy by 3-MA relieved Malat1-induced cell proliferation. These data demonstrated that Malat1 activates autophagy and increases cell proliferation in glioma. We further investigated the molecular mechanisms whereby Malat1 functioned on glioma cell autophagy and proliferation. We found that Malat1 served as an endogenous sponge to reduce miR-101 expression by directly binding to miR-101. Moreover, Malat1 abolished the suppression effects of miR-101 on glioma cell autophagy and proliferation, which involved in upregulating the expression of miR-101 targets STMN1, RAB5A and ATG4D. Overall, our study elucidated a novel Malat1-miR-101-STMN1/RAB5A/ATG4D regulatory network that Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma cells.
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Affiliation(s)
- Zhenqiang Fu
- Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
| | - Wenzheng Luo
- Department of Neurosurgery, First Affiliated Hospital of Zhengzhou University, China
| | - Jingtao Wang
- Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
| | - Tao Peng
- Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
| | - Guifang Sun
- Department of Neurology, First Affiliated Hospital of Zhengzhou University, China
| | - Jingyu Shi
- Department of Neurology, Luoyang Central Hospital, China
| | - Zhihong Li
- Department of Neurology, Zhengzhou Central Hospital, China
| | - Boai Zhang
- Department of Neurology, First Affiliated Hospital of Zhengzhou University, China.
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25
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Abstract
Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol is a diet-derived cancer chemopreventive agent with high therapeutic potential, as demonstrated by different authors. The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention, molecular signaling (especially regarding the involvement of p53 protein), and therapeutic perspectives with an emphasis on clinical trial results to date.
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26
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Zou H, Wu G, Lv J, Xu G. Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1264-1272. [PMID: 28390948 DOI: 10.1016/j.bbadis.2017.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/21/2017] [Accepted: 04/04/2017] [Indexed: 12/20/2022]
Abstract
PURPOSE To determine whether ACE2 I/D and BDKRB23 +9/-9 polymorphism causatively affect diabetic nephropathy progression RESULTS: STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R4+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp diabetic mice but not ACE II-B2R-9bp, indicating the genetic susceptibility of ACE DD or B2R+9bp to diabetic nephropathy. Furthermore, ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp rather than ACE II-B2R-9bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-β1 (TGF-β1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp, versus ACE II-B2R-9bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp but not ACE II-B2R-9bp. CONCLUSIONS We provide first evidence indicating the causation between ACE DD or B2R+9bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease.
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Affiliation(s)
- Honghong Zou
- Medical Center of the Graduate School, Nanchang University, Nanchang, China
| | - Guoqing Wu
- Department of Nephrology, the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jinlei Lv
- Department of Nephrology, the First Affiliated Hospital of Nanchang University, No.17, Yongwai Street, Donghu District, Nanchang, China
| | - Gaosi Xu
- Department of Nephrology, the Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, China.
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27
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Abstract
Deadly diseases, such as cardiovascular diseases and cancer, remain the major health problems worldwide. Research in cardiovascular diseases and genome-wide association studies were successful in indentifying the gene loci associated with these threatening diseases. Yet, a substantial number of casual factors remain unexplained. Over the last decade, a better understanding of molecular and biochemical mechanisms of cardiac diseases led to developing a rationale for combining various protective agents, such as polyphenols, to target multiple signaling pathways. The present review article summarizes recent advances of the use of polyphenols against diseases, such as cardiac diseases.
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28
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Fukuda T, Oda K, Wada-Hiraike O, Sone K, Inaba K, Ikeda Y, Makii C, Miyasaka A, Kashiyama T, Tanikawa M, Arimoto T, Yano T, Kawana K, Osuga Y, Fujii T. Autophagy inhibition augments resveratrol-induced apoptosis in Ishikawa endometrial cancer cells. Oncol Lett 2016; 12:2560-2566. [PMID: 27698828 PMCID: PMC5038194 DOI: 10.3892/ol.2016.4978] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 06/16/2016] [Indexed: 12/17/2022] Open
Abstract
Resveratrol (RSV), a polyphenolic compound derived from red wine, inhibits the proliferation of various types of cancer. RSV induces apoptosis in cancer cells, while enhancing autophagy. Autophagy promotes cancer cell growth by driving cellular metabolism, which may counteract the effect of RSV. The present study aimed to elucidate the correlation between RSV and autophagy and to examine whether autophagy inhibition may enhance the antitumor effect of RSV in endometrial cancer cells. Cell proliferation, cell cycle progression and apoptosis were examined, following RSV exposure, by performing MTT assays, flow cytometry and annexin V staining, respectively, in an Ishikawa endometrial cancer cell line. Autophagy was evaluated by measuring the expression levels of light chain 3, II (LC3-II; an autophagy marker) by western blotting and immunofluorescence. Chloroquine (CQ) and small interfering RNAs targeting autophagy related (ATG) gene 5 (ATG5) or 7 (ATG7) were used to inhibit autophagy, and the effects in combination with RSV were assessed using MTT assays. RSV treatment suppressed cell proliferation in a dose-dependent manner in Ishikawa cells. In addition, RSV exposure increased the abundance of the sub-G1 population and induced apoptosis. LC3-II accumulation was observed following RSV treatment, indicating that RSV induced autophagy. Combination treatment with CQ and RSV more robustly suppressed growth inhibition and apoptosis, compared with RSV treatment alone. Knocking down ATG5 or ATG7 expression significantly augmented RSV-induced apoptosis. The results of the present study indicated that RSV-induced autophagy may counteract the antitumor effect of RSV in Ishikawa cells. Combination treatment with RSV and an autophagy inhibitor, such as CQ, may be an attractive therapeutic option for treating certain endometrial cancer cells.
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Affiliation(s)
- Tomohiko Fukuda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Katsutoshi Oda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Osamu Wada-Hiraike
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kenbun Sone
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kanako Inaba
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yuji Ikeda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Chinami Makii
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Aki Miyasaka
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tomoko Kashiyama
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Michihiro Tanikawa
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takahide Arimoto
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tetsu Yano
- Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo 162-0052, Japan
| | - Kei Kawana
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yutaka Osuga
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tomoyuki Fujii
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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29
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Liu YP, Dong FX, Chai X, Zhu S, Zhang BL, Gao DS. Role of Autophagy in Capsaicin-Induced Apoptosis in U251 Glioma Cells. Cell Mol Neurobiol 2016; 36:737-43. [PMID: 26351174 PMCID: PMC11482369 DOI: 10.1007/s10571-015-0254-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 08/19/2015] [Indexed: 12/19/2022]
Abstract
In recent years, the role of capsaicin in cancer prevention and treatment has gained people's attention. However, the mechanism of anti-glioma cells by capsaicin has not been elucidated. Here, we discuss the mechanism of capsaicin in U251 cells. Cell viability was detected by MTT and extracellular LDH measurements, while immunofluorescence was performed to measure changes of LC3 in U251 cells. The expressions of LC3II, Puma-α, Beclin1, P62, Procaspase-3, and P53 were observed by immunoblotting. The cell viability decreased and the punctate patterns of LC3 in U251 cells were observed after Capsaicin treatment. Meanwhile, the expressions of Beclin1, P62, and Puma-α increased. After using 3-MA, the expressions of Beclin1 and Procaspase-3 were reduced while those of P53 and Puma-α increased. The expression of LC3II was increased after Pifithrin-α treatment. Therefore, we believed that capsaicin could induce apoptosis in U251 cells, and the inhibition of autophagy could contribute to apoptosis.
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Affiliation(s)
- Ya-Ping Liu
- Experimental Teaching Center of Morphology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China.
| | - Fu-Xing Dong
- Research Center for Neurobiology, Department of Biology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China
| | - Xiang Chai
- Research Center for Neurobiology, Department of Biology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China
| | - Shuang Zhu
- Research Center for Neurobiology, Department of Biology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China
| | - Bao-Le Zhang
- Research Center for Neurobiology, Department of Biology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China
| | - Dian-Shuai Gao
- Research Center for Neurobiology, Department of Biology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China.
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30
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Law BYK, Mok SWF, Wu AG, Lam CWK, Yu MXY, Wong VKW. New Potential Pharmacological Functions of Chinese Herbal Medicines via Regulation of Autophagy. Molecules 2016; 21:359. [PMID: 26999089 PMCID: PMC6274228 DOI: 10.3390/molecules21030359] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 02/29/2016] [Accepted: 03/09/2016] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a universal catabolic cellular process for quality control of cytoplasm and maintenance of cellular homeostasis upon nutrient deprivation and environmental stimulus. It involves the lysosomal degradation of cellular components such as misfolded proteins or damaged organelles. Defects in autophagy are implicated in the pathogenesis of diseases including cancers, myopathy, neurodegenerations, infections and cardiovascular diseases. In the recent decade, traditional drugs with new clinical applications are not only commonly found in Western medicines, but also highlighted in Chinese herbal medicines (CHM). For instance, pharmacological studies have revealed that active components or fractions from Chaihu (Radix bupleuri), Hu Zhang (Rhizoma polygoni cuspidati), Donglingcao (Rabdosia rubesens), Hou po (Cortex magnoliae officinalis) and Chuan xiong (Rhizoma chuanxiong) modulate cancers, neurodegeneration and cardiovascular disease via autophagy. These findings shed light on the potential new applications and formulation of CHM decoctions via regulation of autophagy. This article reviews the roles of autophagy in the pharmacological actions of CHM and discusses their new potential clinical applications in various human diseases.
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Affiliation(s)
- Betty Yuen Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Simon Wing Fai Mok
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - An Guo Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Christopher Wai Kei Lam
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Margaret Xin Yi Yu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - Vincent Kam Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
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31
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Mu H, Liu Q, Niu H, Wang D, Tang J, Duan J. Autophagy promotes DNA-protein crosslink clearance. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2016; 797:21-5. [PMID: 26921017 DOI: 10.1016/j.mrgentox.2015.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 11/25/2015] [Accepted: 12/09/2015] [Indexed: 11/16/2022]
Abstract
Toxic DNA-protein crosslinks (DPCs) can result from exposure to radiation or chemotherapeutic agents. DPCs can also accumulate during aging or stress. However, the cellular mechanisms underlying clearance of DPCs remain largely unknown. Here, we have identified an important role of autophagy in the processing of DPCs induced by three representative agents: formaldehyde, a chemical used widely in industry; UV light; and camptothecin, a cytotoxic anticancer drug. Autophagy inhibitors, 3-methyladenine (3-MA) or chloroquine (CQ), promoted the accumulation of DPCs in damaged cells and injured organs. siRNA-mediated silencing of Atg5 or Atg7, two essential components for the formation of the autophagosome, gave similar results. In contrast, the autophagy inducer rapamycin (RAP) attenuated DPCs in vitro and in vivo. Our findings reveal the importance of autophagy in controlling the level of DPCs, and may open up a new avenue for understanding the formation and clearance of this detrimental DNA adduct.
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Affiliation(s)
- Haibo Mu
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Qianjin Liu
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Hong Niu
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Dongdong Wang
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China
| | - Jiangjiang Tang
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China.
| | - Jinyou Duan
- College of Science, Northwest A&F University, Yangling 712100, Shaanxi, China.
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32
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Resveratrol and STAT inhibitor enhance autophagy in ovarian cancer cells. Cell Death Discov 2016; 2:15071. [PMID: 27551495 PMCID: PMC4979504 DOI: 10.1038/cddiscovery.2015.71] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 11/25/2015] [Accepted: 12/04/2015] [Indexed: 01/02/2023] Open
Abstract
Autophagic activity reflects cellular response to drug treatment and can be regulated by STAT3 signaling. Resveratrol inhibits STAT3 activation and causes remarkable growth arrest and cell death of ovarian cancer (OC) cells. However, the autophagic status and its relevance with resveratrol’s anti-OC effects remain unclear. We analyzed the states of autophagic activities, the nature of autophagosomes and the levels of autophagy-related proteins (LC-3, Beclin 1 and STAT3) in resveratrol-treated CAOV-3 and OVCAR-3 OC cells using multiple approaches. We elucidated the correlation of STAT3 inhibition with autophagic activity by treating OC cells with an upstream inhibitor of STAT proteins, AG490. Resveratrol efficiently suppressed growth, induced apoptosis and inactivated STAT3 signaling of the two OC cell lines. We found enhanced autophagic activity accompanied with Beclin-1 upregulation and LC3 enzymatic cleavage in resveratrol-treated OC cells. Immunofluorescent (IF) microscopic and IF-based confocal examinations demonstrated the accumulation of cytoplasmic granules co-labeled with LC3 and cytochrome C in resveratrol- or AG490-treated OC cells. Using electron microscopy, we confirmed an increase in autophagosomes and mitochondrial spheroids in either resveratrol- or AG490-treated OC cells. This study demonstrates the abilities of resveratrol to enhance apoptotic and autophagic activities in OC cells, presumably via inactivating STAT3 signaling. Resveratrol or the selective JAK2 inhibitor also leads to mitochondrial turnover, which would be unfavorable for OC cell survival and sensitize OC cells to resveratrol.
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33
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Chaurasia M, Bhatt AN, Das A, Dwarakanath BS, Sharma K. Radiation-induced autophagy: mechanisms and consequences. Free Radic Res 2016; 50:273-90. [DOI: 10.3109/10715762.2015.1129534] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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34
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Resveratrol, a potential radiation sensitizer for glioma stem cells both in vitro and in vivo. J Pharmacol Sci 2015; 129:216-25. [DOI: 10.1016/j.jphs.2015.11.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/27/2015] [Accepted: 10/29/2015] [Indexed: 11/19/2022] Open
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35
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BAO WENHUA, GU YIQI, TA LA, WANG KEREN, XU ZHELI. Induction of autophagy by the MG-132 proteasome inhibitor is associated with endoplasmic reticulum stress in MCF-7 cells. Mol Med Rep 2015; 13:796-804. [DOI: 10.3892/mmr.2015.4599] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 10/05/2015] [Indexed: 11/06/2022] Open
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36
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Chang CY, Li JR, Wu CC, Ou YC, Chen WY, Kuan YH, Wang WY, Chen CJ. Valproic acid sensitizes human glioma cells to gefitinib-induced autophagy. IUBMB Life 2015; 67:869-879. [PMID: 26488897 DOI: 10.1002/iub.1445] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 10/04/2015] [Indexed: 12/29/2022]
Abstract
Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), and degradation of p62. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 but not broad-spectrum caspase inhibitor attenuated gefitinib/valproic acid-induced growth inhibition. Gefitinib/valproic acid-induced autophagy was accompanied by the activation of liver kinase-B1 (LKB1)/AMP-activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid-induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N-acetyl cysteine attenuated gefitinib/valproic acid-caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma.
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Affiliation(s)
- Cheng-Yi Chang
- Department of Surgery, Feng Yuan Hospital, Taichung, Taiwan
- Graduate Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Jian-Ri Li
- Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chih-Cheng Wu
- Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan
| | - Yen-Chuan Ou
- Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Hsiang Kuan
- Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wen-Yi Wang
- Department of Nursing, HungKuang University, Taichung, Taiwan
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Nursing, HungKuang University, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
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37
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Junco JJ, Mancha-Ramirez A, Malik G, Wei SJ, Kim DJ, Liang H, Slaga TJ. Ursolic acid and resveratrol synergize with chloroquine to reduce melanoma cell viability. Melanoma Res 2015; 25:103-12. [PMID: 25647735 DOI: 10.1097/cmr.0000000000000137] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Malignant melanoma is associated with a 5-year survival rate of less than 20% once metastasized. Malignant melanoma cells exhibit increased levels of autophagy, a process of intracellular digestion that allows cells to survive various stresses including chemotherapies, resulting in reduced patient survival. Autophagy can be inhibited by chemicals like chloroquine (CQ), which prevents fusion of autophagosomes to lysosomes, resulting in autophagosome accumulation in most systems. Here, we describe how tested CQ to see whether it could sensitize B16F10 metastatic mouse melanoma cells to the anticancer activities of the natural compounds ursolic acid (UA) and resveratrol (RES). CQ with UA or RES strongly and synergistically reduced the viability of B16F10 mouse melanoma and A375 human melanoma cells. Surprisingly, flow cytometry of acridine orange-stained cells showed that UA or RES in combination with CQ significantly reduced autophagosome levels. Western blotting analysis revealed that CQ plus UA or RES paradoxically increased LC3II, indicative of autophagosome accumulation. In addition, CQ plus RES synergistically decreased the levels of both autophagy initiator beclin-1 and autophagy supporter p62. These results indicate that CQ with UA or RES strongly and synergistically reduces the viability of B16F10 and A375 melanoma cells. However, studies on B16F10 cells have shown that the synergistic effect was not mediated by inhibition of autophagy induced by UA or RES. These compounds are well-tolerated in humans, and CQ has shown promise as an adjuvant therapy. These combinations may be valuable treatment strategies for melanoma.
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Affiliation(s)
- Jacob J Junco
- aDepartment of Pharmacology bEdinburg Regional Academic Health Center, Medical Research Division, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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38
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Sayd S, Thirant C, El-Habr EA, Lipecka J, Dubois LG, Bogeas A, Tahiri-Jouti N, Chneiweiss H, Junier MP. Sirtuin-2 activity is required for glioma stem cell proliferation arrest but not necrosis induced by resveratrol. Stem Cell Rev Rep 2015; 10:103-13. [PMID: 23955573 DOI: 10.1007/s12015-013-9465-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Glioblastomas, the most common form of primary brain tumors, are the fourth cause of death by cancer in adults. Increasing evidences suggest that glioblastoma resistance to existing radio- and chemotherapies rely on glioblastoma stem cells (GSCs). GSCs are endowed with a unique combination of stem-like properties alike to normal neural stem cells (NSCs), and of tumor initiating properties. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Here, we used resveratrol to explore the molecular mechanisms differing between GSCs and NSCs. We observed a dual action of resveratrol on GSCs: resveratrol blocked GSC proliferation up to 150 μM and induced their necrosis at higher doses. On the opposite, resveratrol had no effect on NSC behavior. To determine the mechanisms underlying resveratrol effects, we focused our attention on the family of NAD-dependent deacetylases sirtuins (SIRT). A member of this family, SIRT1, has been repetitively shown to constitute a preferential resveratrol target, at least in normal cells. Western blot analysis showed that SIRT1 and SIRT3 were expressed by both GSCs and NSCs whereas SIRT2 expression was restricted to GSCs. Pharmacological blockade of SIRT2 activity or down-regulation of SIRT2 expression with siRNAs counteracted the inhibitory effect of resveratrol on cell proliferation. On the contrary, inhibition of SIRT2 activity or expression did not counteract GSC necrosis observed in presence of high doses of resveratrol. Our results highlight SIRT2 as a novel target for altering GSC properties.
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Affiliation(s)
- Salwa Sayd
- Team Glial Plasticity, U894 Inserm, Université Paris Descartes, Paris, France
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39
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Yuan X, Du J, Hua S, Zhang H, Gu C, Wang J, Yang L, Huang J, Yu J, Liu F. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells. Exp Cell Res 2015; 330:267-276. [DOI: 10.1016/j.yexcr.2014.09.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/29/2014] [Accepted: 09/03/2014] [Indexed: 12/21/2022]
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40
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Hasima N, Ozpolat B. Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer. Cell Death Dis 2014; 5:e1509. [PMID: 25375374 PMCID: PMC4260725 DOI: 10.1038/cddis.2014.467] [Citation(s) in RCA: 211] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/01/2014] [Accepted: 09/02/2014] [Indexed: 12/26/2022]
Abstract
Autophagy, a lysosomal degradation pathway for cellular constituents and organelles, is an adaptive and essential process required for cellular homeostasis. Although autophagy functions as a survival mechanism in response to cellular stressors such as nutrient or growth factor deprivation, it can also lead to a non-apoptotic form of programmed cell death (PCD) called autophagy-induced cell death or autophagy-associated cell death (type II PCD). Current evidence suggests that cell death through autophagy can be induced as an alternative to apoptosis (type I PCD), with therapeutic purpose in cancer cells that are resistant to apoptosis. Thus, modulating autophagy is of great interest in cancer research and therapy. Natural polyphenolic compounds that are present in our diet, such as rottlerin, genistein, quercetin, curcumin, and resveratrol, can trigger type II PCD via various mechanisms through the canonical (Beclin-1 dependent) and non-canonical (Beclin-1 independent) routes of autophagy. The capacity of these compounds to provide a means of cancer cell death that enhances the effects of standard therapies should be taken into consideration for designing novel therapeutic strategies. This review focuses on the autophagy- and cell death-inducing effects of these polyphenolic compounds in cancer.
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Affiliation(s)
- N Hasima
- 1] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA [2] Institute Science Biology, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia [3] Center for Research in Biotechnology for Agriculture, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - B Ozpolat
- 1] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030, USA [2] Center for RNA Interference and Non-Coding RNAs - Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, USA
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41
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Sheng Y, Sun B, Guo WT, Liu X, Wang YC, Xie X, Xiao XL, Li N, Dong DL. (4-[6-(4-isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl] quinoline) is a novel inhibitor of autophagy. Br J Pharmacol 2014; 171:4970-80. [PMID: 24943256 PMCID: PMC4294118 DOI: 10.1111/bph.12821] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 06/06/2014] [Accepted: 06/09/2014] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND AND PURPOSE Autophagy is an important intracellular degradation system, which is related to various diseases. In preliminary experiments we found that D4-[6-(4-isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl] quinoline (DMH1) inhibited autophagy responses. However DMH1 also inhibits the signalling pathway activated by bone morphogenetic protein-4 (BMP4). The aim of the present study was to elucidate the inhibitory effects of DMH1 on autophagy and the underlying mechanisms. EXPERIMENTAL APPROACH The effects of DMH1 on autophagy responses were evaluated in cultures of different cell types and with different stimuli to induce autophagy, using Western blots, transmission electron microscopy and fluorescent microscopy. KEY RESULTS DMH1 inhibited starvation-induced autophagy in cardiomyocytes, HeLa and MCF-7 cells, without involving the signalling pathway of BMP4. DMH1 inhibited aminoimidazole carboxamide ribonucleotide (AICAR)- and rapamycin-induced autophagy in HeLa and MCF-7 cells. DMH1 reversed starvation- and AICAR-induced inhibition of Akt, mammalian target of rapamycin (mTOR) and p70S6 kinase (S6K), and reversed rapamycin-induced inhibition of mTOR and S6K. DMH1 reversed starvation-induced decrease of the phosphorylated form of glycogen synthase kinase-3 in MCF-7 and HT29 cells. Activation of Akt and inhibition of autophagy induced by DMH1 were antagonized by an Akt specific inhibitor or by small interfering RNA for Akt in HeLa cells. CONCLUSION AND IMPLICATIONS DMH1 inhibited cellular autophagy responses in a range of cell types and the underlying mechanisms include activation of the Akt pathway.
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Affiliation(s)
- Yue Sheng
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Bo Sun
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Wen-Ting Guo
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Xiao Liu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Yu-Chun Wang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Xin Xie
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Xiao-Lin Xiao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - Na Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
| | - De-Li Dong
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical UniversityHarbin, Heilongjiang, China
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From nature to bedside: Pro-survival and cell death mechanisms as therapeutic targets in cancer treatment. Biotechnol Adv 2014; 32:1111-22. [DOI: 10.1016/j.biotechadv.2014.03.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 03/04/2014] [Accepted: 03/04/2014] [Indexed: 12/11/2022]
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43
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Resveratrol is active against Leishmania amazonensis: in vitro effect of its association with Amphotericin B. Antimicrob Agents Chemother 2014; 58:6197-208. [PMID: 25114129 DOI: 10.1128/aac.00093-14] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Resveratrol is a polyphenol found in black grapes and red wine and has many biological activities. In this study, we evaluated the effect of resveratrol alone and in association with amphotericin B (AMB) against Leishmania amazonensis. Our results demonstrate that resveratrol possesses both antipromastigote and antiamastigote effects, with 50% inhibitory concentrations (IC50s) of 27 and 42 μM, respectively. The association of resveratrol with AMB showed synergy for L. amazonensis amastigotes, as demonstrated by the mean sums of fractional inhibitory index concentration (mean ΣFIC) of 0.483, although for promastigotes, this association was indifferent. Treatment with resveratrol increased the percentage of promastigotes in the sub-G0/G1 phase of the cell cycle, reduced the mitochondrial potential, and showed an elevated choline peak and CH2-to-CH3 ratio in the nuclear magnetic resonance (NMR) spectroscopy analysis; all these features indicate parasite death. Resveratrol also decreased the activity of the enzyme arginase in uninfected and infected macrophages with and without stimulation with interleukin-4 (IL-4), also implicating arginase inhibition in parasite death. The anti-Leishmania effect of resveratrol and its potential synergistic association with AMB indicate that these compounds should be subjected to further studies of drug association therapy in vivo.
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44
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Chatterjee A, Chattopadhyay D, Chakrabarti G. miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. PLoS One 2014; 9:e95716. [PMID: 24755562 PMCID: PMC3995800 DOI: 10.1371/journal.pone.0095716] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 03/29/2014] [Indexed: 11/19/2022] Open
Abstract
Non- small- cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3′-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression.
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Affiliation(s)
- Abhisek Chatterjee
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, WB, India
| | - Dhrubajyoti Chattopadhyay
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, WB, India
| | - Gopal Chakrabarti
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, WB, India
- * E-mail:
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Wang M, Yu T, Zhu C, Sun H, Qiu Y, Zhu X, Li J. Resveratrol triggers protective autophagy through the ceramide/Akt/mTOR pathway in melanoma B16 cells. Nutr Cancer 2014; 66:435-40. [PMID: 24579778 DOI: 10.1080/01635581.2013.878738] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Resveratrol (3,5,4'-trihydroxy-trans-stilbene, RSV), a natural polyphenolic compound, is known as a promising anti-cancer agent. In this study, we showed that RSV could inhibit the growth of B16 cells via induction of apoptosis. Moreover, our results showed for the first time that RSV induced autophagy in B16 cells, which might occur through ceramide accumulation and Akt/mTOR pathway inhibition. Inhibition of autophagy by an autophagic inhibitor 3-methyladenine (3-MA) or si-Beclin 1 enhanced RSV-induced cytotoxicity and apoptosis. Thus, autophagy inhibition represents a promising approach to improve the efficacy of RSV in the treatment of patients with melanoma.
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Affiliation(s)
- Meng Wang
- a Department of Oncology , Shandong Jining No.1 People's Hospital , Jining , China
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On the molecular pharmacology of resveratrol on oxidative burst inhibition in professional phagocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:706269. [PMID: 24672638 PMCID: PMC3942095 DOI: 10.1155/2014/706269] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 12/12/2013] [Accepted: 12/17/2013] [Indexed: 01/15/2023]
Abstract
Resveratrol—3,5,4′-trihydroxystilbene—possesses antioxidant activities in vitro. It dose-dependently inhibited the generation of peroxyl, hydroxyl, peroxides, and lipid peroxidation products in cell free systems. Oxidative burst of whole human blood stimulated with PMA, fMLP, OpZ, and A23187 was inhibited in a concentration-dependent way, indicating suppression of both receptor and nonreceptor activated chemiluminescence by resveratrol. Results from isolated human neutrophils revealed that resveratrol was active extracellularly as well as intracellularly in inhibiting the generation of reactive oxygen species. Liberation of ATP and analysis of apoptosis showed that in the concentration of 100 μM, resveratrol did not change the viability and integrity of isolated neutrophils. Western blot analysis documented that resveratrol in concentrations of 10 and 100 μM significantly decreased PMA-induced phosphorylation of PKC α/βII. Dose-dependent inhibition of nitrite production and iNOS protein expression in RAW 264.7 cells indicated possible interference of resveratrol with reactive nitrogen radical generation in professional phagocytes. The results suggest that resveratrol represents an effective naturally occurring substance with potent pharmacological effect on oxidative burst of human neutrophils and nitric oxide production by macrophages. It should be further investigated for its pharmacological activity against oxidative stress in ischaemia reperfusion, inflammation, and other pathological conditions, particularly neoplasia.
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Human T-cell leukemia virus type 1 Tax-deregulated autophagy pathway and c-FLIP expression contribute to resistance against death receptor-mediated apoptosis. J Virol 2013; 88:2786-98. [PMID: 24352466 DOI: 10.1128/jvi.03025-13] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
UNLABELLED The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax-expressing cells show resistance to apoptosis induced by Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The regulation of Tax on the autophagy pathway in HeLa cells and peripheral T cells was recently reported, but the function and underlying molecular mechanism of the Tax-regulated autophagy are not yet well defined. Here, we report that HTLV-1 Tax deregulates the autophagy pathway, which plays a protective role during the death receptor (DR)-mediated apoptosis of human U251 astroglioma cells. The cellular FLICE-inhibitory protein (c-FLIP), which is upregulated by Tax, also contributes to the resistance against DR-mediated apoptosis. Both Tax-induced autophagy and Tax-induced c-FLIP expression require Tax-induced activation of IκB kinases (IKK). Furthermore, Tax-induced c-FLIP expression is regulated through the Tax-IKK-NF-κB signaling pathway, whereas Tax-triggered autophagy depends on the activation of IKK but not the activation of NF-κB. In addition, DR-mediated apoptosis is correlated with the degradation of Tax, which can be facilitated by the inhibitors of autophagy. IMPORTANCE Our study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases.
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Das D, Preet R, Mohapatra P, Satapathy SR, Kundu CN. 1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells. World J Gastroenterol 2013; 19:7374-7388. [PMID: 24259968 PMCID: PMC3831219 DOI: 10.3748/wjg.v19.i42.7374] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 03/22/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the mechanism of 5-fluorouracil (5-FU) resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.
METHODS: We established and characterized a 5-FU resistance (5-FU-R) cell line derived from continuous exposure (25 μmol/L) to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells. The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting, respectively, after treatment with Resveratrol (Res) and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis, respectively. The extent of DNA damage was measured by the Comet assay. We measured the visible changes in the DNA damage/repair cascade by Western blotting.
RESULTS: The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner. Combined application of BCNU and Res caused more apoptosis in 5-FU sensitive cells in comparison to individual treatment. In addition, the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells. We established a 5-FU resistance cell line (5-FU-R) from 5-FU-sensitive HCT-116 (mismatch repair deficient) cells that was not resistant to other chemotherapeutic agents (e.g., BCNU, Res) except 5-FU. The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay. There was no significant cell death noted in 5-FU-R cells in comparison to 5-FU sensitive cells after 5-FU treatment. This resistant cell line overexpressed anti-apoptotic [e.g., AKT, nuclear factor κB, FLICE-like inhibitory protein), DNA repair (e.g., DNA polymerase beta (POL-β), DNA polymerase eta (POLH), protein Flap endonuclease 1 (FEN1), DNA damage-binding protein 2 (DDB2)] and 5-FU-resistance proteins (thymidylate synthase) but under expressed pro-apoptotic proteins (e.g., DAB2, CK1) in comparison to the parental cells. Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells. BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells. Fifty percent cell death were noted in parental cells when 18 μmol/L of Res was associated with fixed concentration (20 μmol/L) of BCNU, but a much lower concentration of Res (8 μmol/L) was needed to achieve the same effect in 5-FU resistant cells. Interestingly, increased levels of adenomatous polyposis coli and decreased levels POL-β, POLH, FEN1 and DDB2 were noted after the same combined treatment in resistant cells.
CONCLUSION: BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.
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Bhattacharya S, Kumar NM, Ganguli A, Tantak MP, Kumar D, Chakrabarti G. NMK-TD-100, a novel microtubule modulating agent, blocks mitosis and induces apoptosis in HeLa cells by binding to tubulin. PLoS One 2013; 8:e76286. [PMID: 24116100 PMCID: PMC3792137 DOI: 10.1371/journal.pone.0076286] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 08/22/2013] [Indexed: 11/19/2022] Open
Abstract
Thiadiazoles are one of the most widely utilized agents in medicinal chemistry, having a wide range of pharmacologic activity. Microtubules (MTs) have always remained a sought-after target in rapidly proliferating cancer cells. We screened for the growth inhibitory effect of synthetic 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles on cancer cells and identified NMK-TD-100, as the most potent agent. Cell viability experiments using human cervical carcinoma cell line (HeLa cells) indicated that the IC50 value was 1.42±0.11 µM for NMK-TD-100 for 48 h treatment. In further study, we examined the mode of interaction of NMK-TD-100 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. NMK-TD-100 induced arrest in mitotic phase of cell cycle, caused decline in mitochondrial membrane potential and induced apoptosis in HeLa cells. Immunofluorescence studies using an anti-α-tubulin antibody showed a significant depolymerization of the interphase microtubule network and spindle microtubule in HeLa cells in a concentration-dependent manner. However, the cytotoxicity of NMK-TD-100 towards human peripheral blood mononuclear cells (PBMC) was lower compared to that in cancer cells. Polymerization of tissue purified tubulin into microtubules was inhibited by NMK-TD-100 with an IC50 value of 17.5±0.35 µM. The binding of NMK-TD-100 with tubulin was studied using NMK-TD-100 fluorescence enhancement and intrinsic tryptophan fluorescence of tubulin. The stoichiometry of NMK-TD-100 binding to tubulin is 1:1 (molar ratio) with a dissociation constant of ~1 µM. Fluorescence spectroscopic and molecular modeling data showed that NMK-TD-100 binds to tubulin at a site which is very near to the colchicine binding site. The binding of NMK-TD-100 to tubulin was estimated to be ~10 times faster than that of colchicine. The results indicated that NMK-TD-100 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided insights into its potential of being a chemotherapeutic agent.
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MESH Headings
- Amino Acids/chemistry
- Amino Acids/metabolism
- Apoptosis/drug effects
- Blotting, Western
- Caspase 3/metabolism
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Cells, Cultured
- Dose-Response Relationship, Drug
- HeLa Cells
- Humans
- Indoles/chemistry
- Indoles/metabolism
- Indoles/pharmacology
- Leukocytes, Mononuclear/cytology
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/metabolism
- M Phase Cell Cycle Checkpoints/drug effects
- Membrane Potential, Mitochondrial/drug effects
- Microscopy, Electron
- Microtubules/drug effects
- Microtubules/metabolism
- Mitosis/drug effects
- Models, Molecular
- Molecular Structure
- Protein Binding
- Protein Structure, Tertiary
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Thiadiazoles/chemistry
- Thiadiazoles/metabolism
- Thiadiazoles/pharmacology
- Tubulin/chemistry
- Tubulin/metabolism
- Tubulin/ultrastructure
- Tubulin Modulators/chemistry
- Tubulin Modulators/metabolism
- Tubulin Modulators/pharmacology
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- Surela Bhattacharya
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, India
| | - N. Maruthi Kumar
- Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Arnab Ganguli
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, India
| | - Mukund P. Tantak
- Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India
| | - Dalip Kumar
- Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan, India
- * E-mail: (GC); (DK)
| | - Gopal Chakrabarti
- Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, India
- * E-mail: (GC); (DK)
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Tang Q, Li G, Wei X, Zhang J, Chiu JF, Hasenmayer D, Zhang D, Zhang H. Resveratrol-induced apoptosis is enhanced by inhibition of autophagy in esophageal squamous cell carcinoma. Cancer Lett 2013; 336:325-37. [PMID: 23541682 DOI: 10.1016/j.canlet.2013.03.023] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 03/12/2013] [Accepted: 03/19/2013] [Indexed: 02/05/2023]
Abstract
The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.
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Affiliation(s)
- Qishan Tang
- Department of Integrative Oncology, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China
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