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Luo Y, Ou X, Liu D, Shi H, Liao J, Yu R, Song L, Zhu J. A novel exosome-like nanovesicles from Cordyceps militaris potentiate immunomodulatory and anti-tumor effect by reprogramming macrophages. Life Sci 2024; 358:123163. [PMID: 39442867 DOI: 10.1016/j.lfs.2024.123163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/21/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
AIMS Fungi-derived exosome-like nanovesicles (ENs) are emerging as a highly promising class of nanoparticles, particularly noted for their cost-effective production. However, their impact on immune regulation and their potential as anti-tumor agents need further exploration. Our study specifically focused on the investigation of the immunomodulatory and anti-tumor properties of ENs derived from Cordyceps militaris, an edible fungus that had achieved large-scale commercial production, referred to as CMDENs. MAIN METHODS The ENs of C. militaris were collected through ultra-high-speed centrifugation, followed by characterization of their physicochemical properties and contents. Subsequently, the biological distribution of these vesicles was investigated using in vivo fluorescence imaging experiments. Finally, the immune activation and polarization of macrophages were examined through both in vitro and in vivo experiments. KEY FINDINGS Herein, we presented the discovery of CMDENs that were rich in proteins, lipids, flavonoids and alkaloids. Immunomodulatory experiments conducted in vivo demonstrated that CMDENs exhibited protective effects against cyclophosphamide-induced immunosuppression in mice by significantly enhancing macrophage phagocytosis and peripheral blood immune cell counts. Moreover, CMDENs effectively induced the polarization of M0- and M2-like macrophages toward M1-like phenotype by activating MAPKs signaling pathway. Notably, CMDENs exhibited remarkable capabilities in inhibiting tumor growth by reprogramming tumor-associated macrophages and activating tumor-infiltrating T lymphocytes, without any observed toxicity in mice bearing tumors. SIGNIFICANCE Our research suggested that CMDENs possessed the potential to be explored as a nano-immunomodulatory agent for cancer.
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Affiliation(s)
- Yuanyuan Luo
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 511443, China; Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 511443, China
| | - Xiaozheng Ou
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 511443, China
| | - De Liu
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 511443, China
| | - Hui Shi
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 511443, China
| | - Jiapei Liao
- Department of Natural Product Chemistry, Jinan University, Guangzhou 511443, China
| | - Rongmin Yu
- Department of Natural Product Chemistry, Jinan University, Guangzhou 511443, China.
| | - Liyan Song
- Department of Pharmacology, College of Pharmacy, Jinan University, Guangzhou 511443, China.
| | - Jianhua Zhu
- Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 511443, China.
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Wahnou H, Youlyouz-Marfak I, Liagre B, Sol V, Oudghiri M, Duval RE, Limami Y. Shining a Light on Prostate Cancer: Photodynamic Therapy and Combination Approaches. Pharmaceutics 2023; 15:1767. [PMID: 37376215 DOI: 10.3390/pharmaceutics15061767] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. There are two main types of PSs: synthetic and natural. Synthetic PSs are classified into four generations based on their structural and photophysical properties, while natural PSs are derived from plant and bacterial sources. Combining PDT with other therapies, such as photothermal therapy (PTT), photoimmunotherapy (PIT), and chemotherapy (CT), is also being explored as a way to improve its efficacy. This review provides an overview of conventional treatments for prostate cancer, the underlying principles of PDT, and the different types of PSs used in PDT as well as ongoing clinical studies. It also discusses the various forms of combination therapy being explored in the context of PDT for prostate cancer, as well as the challenges and opportunities associated with this approach. Overall, PDT has the potential to provide a more effective and less invasive treatment option for prostate cancer, and ongoing research is aimed at improving its selectivity and efficacy in clinical settings.
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Affiliation(s)
- Hicham Wahnou
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P. 2693, Maarif, Casablanca 20100, Morocco
| | - Ibtissam Youlyouz-Marfak
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco
| | | | - Vincent Sol
- Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France
| | - Mounia Oudghiri
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P. 2693, Maarif, Casablanca 20100, Morocco
| | | | - Youness Limami
- Laboratory of Immunology and Biodiversity, Faculty of Sciences Ain Chock, Hassan II University, B.P. 2693, Maarif, Casablanca 20100, Morocco
- Laboratory of Health Sciences and Technologies, Higher Institute of Health Sciences, Hassan First University of Settat, Settat 26000, Morocco
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3
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An Overview of Potential Natural Photosensitizers in Cancer Photodynamic Therapy. Biomedicines 2023; 11:biomedicines11010224. [PMID: 36672732 PMCID: PMC9855789 DOI: 10.3390/biomedicines11010224] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Cancer is one of the main causes of death worldwide. There are several different types of cancer recognized thus far, which can be treated by different approaches including surgery, radiotherapy, chemotherapy or a combination thereof. However, these approaches have certain drawbacks and limitations. Photodynamic therapy (PDT) is regarded as an alternative noninvasive approach for cancer treatment based on the generation of toxic oxygen (known as reactive oxygen species (ROS)) at the treatment site. PDT requires photoactivation by a photosensitizer (PS) at a specific wavelength (λ) of light in the vicinity of molecular oxygen (singlet oxygen). The cell death mechanisms adopted in PDT upon PS photoactivation are necrosis, apoptosis and stimulation of the immune system. Over the past few decades, the use of natural compounds as a photoactive agent for the selective eradication of neoplastic lesions has attracted researchers' attention. Many reviews have focused on the PS cell death mode of action and photonanomedicine approaches for PDT, while limited attention has been paid to the photoactivation of phytocompounds. Photoactivation is ever-present in nature and also found in natural plant compounds. The availability of various laser light setups can play a vital role in the discovery of photoactive phytocompounds that can be used as a natural PS. Exploring phytocompounds for their photoactive properties could reveal novel natural compounds that can be used as a PS in future pharmaceutical research. In this review, we highlight the current research regarding several photoactive phytocompound classes (furanocoumarins, alkaloids, poly-acetylenes and thiophenes, curcumins, flavonoids, anthraquinones, and natural extracts) and their photoactive potential to encourage researchers to focus on studies of natural agents and their use as a potent PS to enhance the efficiency of PDT.
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Novel psoralen derivatives as anti-breast cancer agents and their light-activated cytotoxicity against HER2 positive breast cancer cells. Sci Rep 2022; 12:13487. [PMID: 35931753 PMCID: PMC9356065 DOI: 10.1038/s41598-022-17625-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/28/2022] [Indexed: 11/25/2022] Open
Abstract
Psoralen derivatives are well known for their unique phototoxicity and also exhibits promising anti-breast cancer activity both in the presence and the absence of UVA irradiation. However, the structure–activity relationship on this scaffold remains lacking. Herein, a series of psoralen derivatives with various C-5 substituents were synthesized and evaluated for their in vitro dark and light-activated cytotoxicity against three breast cancer cell lines: MDA-MB-231, T47-D, and SK-BR-3. The type of substituents dramatically impacted the activity, with the 4-bromobenzyl amide derivative (3c) exhibiting the highest dark cytotoxicity against T47-D (IC50 = 10.14 µM), with the activity comparable to those of the reference drugs (doxorubicin, 1.46 µM; tamoxifen citrate, 20.86 µM; lapatinib 9.78 µM). On the other hand, the furanylamide 3g exhibits the highest phototoxicity against SK-BR-3 cells with the IC50 of 2.71 µM, which is almost tenfold increase compared to the parent compound, methoxsalen. Moreover, these derivatives showed exceptional selectivity towards HER2+ (SK-BR-3) over the HER2− (MDA-MB-231) breast cancer cell lines, which correlates well with the results from the molecular docking study, revealing that 3g formed favorable interactions within the active site of the HER2. Additionally, the cell morphology of SK-BR-3 cells suggested that the significant phototoxicity was related to induction of cell apoptosis. Most of the synthesized psoralen derivatives possess acceptable physicochemical properties and are suitable for being further developed as a novel anti-breast cancer agent in the future.
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Yang Y, Han J, Lilly RG, Yang Q, Guo Y. Bergapten mediated inflammatory and apoptosis through AMPK/eNOS/AKT signaling pathway of isoproterenol-induced myocardial infarction in Wistar rats. J Biochem Mol Toxicol 2022; 36:e23143. [PMID: 35815753 DOI: 10.1002/jbt.23143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 12/31/2021] [Accepted: 05/31/2022] [Indexed: 11/05/2022]
Abstract
Bergapten (BeG) is explored for its anti-inflammatory and antioxidant properties. Myocardial infarction (MI) is reported to be one of the leading cardiovascular diseases characterized by mitochondrial dysfunction and apoptosis. The main purpose of this study is to assess the cardiopreventive effects of BeG (50 mg/kg) in isoproterenol (ISO)-induced MI in Wistar rats. The increased infarct size after ISO induction was reduced simultaneously on treatment with BeG. Similarly, augmented levels of cardiac biomarkers, namely cardiac troponin T, creatine kinase (CK), cardiac troponin I, and CK-MB were also suppressed by BeG. The increased rate of lipid hydroperoxides and thiobarbituric acid reactive substances owing to the oxidative stress caused by free radical generation in ISO-induced rats were also inhibited by BeG. Antioxidants reduce oxidative stress by scavenging free radicals. ISO induction reduces these antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase, and glutathione, and levels causing oxidative cardiac damage to the heart tissue. BeG supplementation improved these enzymes synthesis preventing potential damage to the myocardium. Inflammation caused by ISO pretreatment increased the secretion of proinflammatory cytokines in ISO-induced rats. Pretreatment with BeG suppressed these inflammatory cytokines to a normal level in ISO + BeG-treated rats. The histopathological examination of the morphological characteristics showed that the intensity of cardiac damage caused by ISO induction was less in BeG pretreated rats with less inflammatory cells and no necrosis. BeG also showed promising results in the molecular alteration of AMP-activated protein kinase/endothelial nitric oxide synthase/protein kinase B signaling molecules. These observations emphasize the cardioprotective effects of BeG and its potential use as a drug in the near future.
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Affiliation(s)
- Yanni Yang
- Department of Cardiology Digital Subtraction Angiography (DSA), Xi'an International Medical Center Hospital, Xi'an, China
| | - Juanping Han
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Renju G Lilly
- Department of Biochemistry, University of Kerala, Palayam, Thiruvananthapuram, Kerala, India
| | - Qin Yang
- Department of Cardiology Digital Subtraction Angiography (DSA), Xi'an International Medical Center Hospital, Xi'an, China
| | - Yanjie Guo
- Department of Cardiology, Xi'an International Medical Center Hospital, Xi'an, China
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Quetglas-Llabrés MM, Quispe C, Herrera-Bravo J, Catarino MD, Pereira OR, Cardoso SM, Dua K, Chellappan DK, Pabreja K, Satija S, Mehta M, Sureda A, Martorell M, Satmbekova D, Yeskaliyeva B, Sharifi-Rad J, Rasool N, Butnariu M, Bagiu IC, Bagiu RV, Calina D, Cho WC. Pharmacological Properties of Bergapten: Mechanistic and Therapeutic Aspects. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8615242. [PMID: 35509838 PMCID: PMC9060977 DOI: 10.1155/2022/8615242] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/01/2021] [Accepted: 03/31/2022] [Indexed: 01/03/2023]
Abstract
Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.
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Affiliation(s)
- Maria Magdalena Quetglas-Llabrés
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands and Health Research Institute of Balearic Islands (IdISBa), 07122 Palma de Mallorca, Spain
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
| | - Jesús Herrera-Bravo
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomas, Chile
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile
| | - Marcelo D. Catarino
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Olívia R. Pereira
- Centro de Investigação de Montanha (CIMO), Instituto Politécnico de Bragança, Campus de Santa Apolónia, 5300-253 Bragança, Portugal
| | - Susana M. Cardoso
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo NSW 2007, Australia
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
| | - Kavita Pabreja
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar, Delhi G.T. Road (NH-1), Phagwara, 144411 Punjab, India
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar, Delhi G.T. Road (NH-1), Phagwara, 144411 Punjab, India
| | - Meenu Mehta
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar, Delhi G.T. Road (NH-1), Phagwara, 144411 Punjab, India
| | - Antoni Sureda
- Research Group in Community Nutrition and Oxidative Stress, University of the Balearic Islands and Health Research Institute of Balearic Islands (IdISBa), 07122 Palma de Mallorca, Spain
- CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, And Centre for Healthy Living, University of Concepción, 4070386 Concepción, Chile
| | - Dinara Satmbekova
- High School of Medicine, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Balakyz Yeskaliyeva
- Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | | | - Naeem Rasool
- Department Pharmacology and Toxicology, University of Veterinary and Animals Science, Lahore, Pakistan
| | - Monica Butnariu
- Banat's University of Agricultural Sciences and Veterinary Medicine “King Michael I of Romania” from Timisoara, Timisoara, Romania
| | - Iulia Cristina Bagiu
- Victor Babes University of Medicine and Pharmacy of Timisoara Department of Microbiology, Timisoara, Romania
- Multidisciplinary Research Center on Antimicrobial Resistance, Timisoara, Romania
| | - Radu Vasile Bagiu
- Victor Babes University of Medicine and Pharmacy of Timisoara Department of Microbiology, Timisoara, Romania
- Preventive Medicine Study Center, Timisoara, Romania
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041192. [PMID: 35208984 PMCID: PMC8879555 DOI: 10.3390/molecules27041192] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 12/26/2022]
Abstract
Despite significant advances in early diagnosis and treatment, cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a therapy for the treatment of many diseases, including cancer. This therapy uses a combination of a photosensitizer (PS), light irradiation of appropriate length and molecular oxygen. The photodynamic effect kills cancer cells through apoptosis, necrosis, or autophagy of tumor cells. PDT is a promising approach for eliminating various cancers but is not yet as widely applied in therapy as conventional chemotherapy. Currently, natural compounds with photosensitizing properties are being discovered and identified. A reduced toxicity to healthy tissues and a lower incidence of side effects inspires scientists to seek natural PS for PDT. In this review, several groups of compounds with photoactive properties are presented. The use of natural products has been shown to be a fruitful approach in the discovery of novel pharmaceuticals. This review focused on the anticancer activity of furanocoumarins, polyacetylenes, thiophenes, tolyporphins, curcumins, alkaloid and anthraquinones in relation to the light-absorbing properties. Attention will be paid to their phototoxic and anti-cancer effects on various types of cancer.
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Babyshkina N, Dronova T, Erdyneeva D, Gervas P, Cherdyntseva N. Role of TGF-β signaling in the mechanisms of tamoxifen resistance. Cytokine Growth Factor Rev 2021; 62:62-69. [PMID: 34635390 DOI: 10.1016/j.cytogfr.2021.09.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/18/2021] [Accepted: 09/19/2021] [Indexed: 12/24/2022]
Abstract
The transforming growth factor beta (TGF-β) signaling pathway plays complex role in the regulation of cell proliferation, apoptosis and differentiation in breast cancer. TGF-β activation can lead to multiple cellular responses mediating the drug resistance evolution, including the resistance to antiestrogens. Tamoxifen is the most commonly prescribed antiestrogen that functionally involved in regulation of TGF-β activity. In this review, we focus on the role of TGF-β signaling in the mechanisms of tamoxifen resistance, including its interaction with estrogen receptors alfa (ERα) pathway and breast cancer stem cells (BCSCs). We summarize the current reported data regarding TGF-β signaling components as markers of tamoxifen resistance and review current approaches to overcoming tamoxifen resistance based on studies of TGF-β signaling.
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Affiliation(s)
- Nataliya Babyshkina
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation; Siberian State Medical University, Tomsk 634050, Russian Federation.
| | - Tatyana Dronova
- Department of Biology of Tumor Progression, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Daiana Erdyneeva
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Polina Gervas
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
| | - Nadejda Cherdyntseva
- Department of Molecular Oncology and Immunology, Саncеr Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russian Federation
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9
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Liang Y, Xie L, Liu K, Cao Y, Dai X, Wang X, Lu J, Zhang X, Li X. Bergapten: A review of its pharmacology, pharmacokinetics, and toxicity. Phytother Res 2021; 35:6131-6147. [PMID: 34347307 DOI: 10.1002/ptr.7221] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/23/2021] [Accepted: 07/03/2021] [Indexed: 12/15/2022]
Abstract
Bergapten is a natural furocoumarin, also known as 5-methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However，bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood-brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes-induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.
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Affiliation(s)
- Youdan Liang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Long Xie
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kai Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Cao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Dai
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xian Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Lu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xumin Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Grande F, Giordano F, Occhiuzzi MA, Rocca C, Ioele G, De Luca M, Ragno G, Panno ML, Rizzuti B, Garofalo A. Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects. Molecules 2021; 26:molecules26133940. [PMID: 34203324 PMCID: PMC8271725 DOI: 10.3390/molecules26133940] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022] Open
Abstract
The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.
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Affiliation(s)
- Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
- Correspondence: (F.G.); (A.G.); Tel.: +39-0984-493019 (F.G.); +39-0984-493118 (A.G.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Maria Antonietta Occhiuzzi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Carmine Rocca
- Department of Biology, Ecology and Earth Sciences, University of Calabria, Via P. Bucci, 87036 Rende, Italy;
| | - Giuseppina Ioele
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Michele De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Gaetano Ragno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Maria Luisa Panno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
| | - Bruno Rizzuti
- CNR-NANOTEC, SS Rende (CS), Department of Physics, University of Calabria, Via P. Bucci, 87036 Rende, Italy;
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, University of Zaragoza, 50018 Zaragoza, Spain
| | - Antonio Garofalo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende, Italy; (F.G.); (M.A.O.); (G.I.); (M.D.L.); (G.R.); (M.L.P.)
- Correspondence: (F.G.); (A.G.); Tel.: +39-0984-493019 (F.G.); +39-0984-493118 (A.G.)
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11
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Kowalczyk J, Kurach Ł, Boguszewska-Czubara A, Skalicka-Woźniak K, Kruk-Słomka M, Kurzepa J, Wydrzynska-Kuźma M, Biała G, Skiba A, Budzyńska B. Bergapten Improves Scopolamine-Induced Memory Impairment in Mice via Cholinergic and Antioxidative Mechanisms. Front Neurosci 2020; 14:730. [PMID: 32903765 PMCID: PMC7438900 DOI: 10.3389/fnins.2020.00730] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/18/2020] [Indexed: 12/28/2022] Open
Abstract
Bergapten is a furanocoumarin naturally occurring in the Apiaceae family and it is a well-known photosensitizing agent used in photochemotherapy. In this study, we investigated the influence of bergapten on cognitive function and mechanism underlying these effects in scopolamine-induced memory impairment in male Swiss mice. The passive avoidance test was used to evaluate the efficiency of memory acquisition and consolidation. The results demonstrated that both single and repeated administration of bergapten improved not only the acquisition but also consolidation of memory. The behavioral tests showed that bergapten prevented memory impairment induced by administration of scopolamine. Observed effects may result from the inhibition of acetylcholinesterase activity in the hippocampus and prefrontal cortex. Also, bergapten caused significant anti-oxidative effects. These new findings provide pharmacological and biochemical support for the development of the coumarin’s potential in cognitive deficits.
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Affiliation(s)
- Joanna Kowalczyk
- Chair and Department of Applied Pharmacy, Medical University of Lublin, Lublin, Poland.,Independent Laboratory of Behavioral Studies, Medical University of Lublin, Lublin, Poland
| | - Łukasz Kurach
- Independent Laboratory of Behavioral Studies, Medical University of Lublin, Lublin, Poland
| | | | - Krystyna Skalicka-Woźniak
- Chair and Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
| | - Marta Kruk-Słomka
- Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin, Poland
| | - Jacek Kurzepa
- Chair and Department of Medicinal Chemistry, Medical University of Lublin, Lublin, Poland
| | | | - Grażyna Biała
- Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin, Poland
| | - Adrianna Skiba
- Chair and Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland
| | - Barbara Budzyńska
- Independent Laboratory of Behavioral Studies, Medical University of Lublin, Lublin, Poland
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12
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Muniyandi K, George B, Parimelazhagan T, Abrahamse H. Role of Photoactive Phytocompounds in Photodynamic Therapy of Cancer. Molecules 2020; 25:E4102. [PMID: 32911753 PMCID: PMC7570746 DOI: 10.3390/molecules25184102] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/26/2020] [Accepted: 09/04/2020] [Indexed: 01/10/2023] Open
Abstract
Cancer is one of the greatest life-threatening diseases conventionally treated using chemo- and radio-therapy. Photodynamic therapy (PDT) is a promising approach to eradicate different types of cancers. PDT requires the administration of photosensitisers (PSs) and photoactivation using a specific wavelength of light in the presence of molecular oxygen. This photoactivation exerts an anticancer effect via apoptosis, necrosis, and autophagy of cancer cells. Recently, various natural compounds that exhibit photosensitising potentials have been identified. Photoactive substances derived from medicinal plants have been found to be safe in comparison with synthetic compounds. Many articles have focused on PDT mechanisms and types of PSs, but limited attention has been paid to the phototoxic activities of phytocompounds. The reduced toxicity and side effects of natural compounds inspire the researchers to identify and use plant extracts or phytocompounds as a potent natural PS candidate for PDT. This review focusses on the importance of common photoactive groups (furanocoumarins, polyacetylenes, thiophenes, curcumins, alkaloids, and anthraquinones), their phototoxic effects, anticancer activity and use as a potent PS for an effective PDT outcome in the treatment of various cancers.
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Affiliation(s)
- Kasipandi Muniyandi
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
- Bioprospecting Laboratory, Department of Botany, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu 641046, India;
| | - Blassan George
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
| | - Thangaraj Parimelazhagan
- Bioprospecting Laboratory, Department of Botany, School of Life Sciences, Bharathiar University, Coimbatore, Tamil Nadu 641046, India;
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, 17011, Doornfontein 2028, South Africa; (K.M.); (B.G.)
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13
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Ahmed S, Khan H, Aschner M, Mirzae H, Küpeli Akkol E, Capasso R. Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects. Int J Mol Sci 2020; 21:E5622. [PMID: 32781533 PMCID: PMC7460698 DOI: 10.3390/ijms21165622] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins' defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.
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Affiliation(s)
- Salman Ahmed
- Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan;
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan;
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10463, USA;
| | - Hamed Mirzae
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan 8715973474, Iran;
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey;
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, Via Università 100, 80055 Portici, Italy
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14
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Ma J, Li J, Wang Y, Chen W, Zheng P, Chen Y, Sun Z, Liu J, Zhou Y, Wang J, Liu S, Han X. WSZG inhibits BMSC-induced EMT and bone metastasis in breast cancer by regulating TGF-β1/Smads signaling. Biomed Pharmacother 2019; 121:109617. [PMID: 31810139 DOI: 10.1016/j.biopha.2019.109617] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/18/2019] [Accepted: 10/31/2019] [Indexed: 02/06/2023] Open
Abstract
Bone metastasis of breast cancer causes severe skeletal-related events and poor prognosis. Wensheng Zhuanggu Formula (WSZG), a traditional Chinese prescription, is used to adjunctively treat breast cancer bone metastases in clinical practice. This study was undertaken to investigate the antibone-metastatic activities and mechanisms of WSZG extract by evaluating the effect of this formula on the cross-talk between bone marrow-derived mesenchymal stem cells (BMSCs) and breast cancer cells in triggering epithelial-mesenchymal transition (EMT) in vivo and in vitro. The results demonstrated that BMSCs might enhance the invasive and metastatic potentials of breast cancer cells as a consequence of EMT induction through direct cell-to-cell contact. WSZG treatment remarkably suppressed motility, invasion, EMT-related gene, and protein markers in BMSC-conditioned breast cancer cells and ameliorated bone metastases and damages in nude mice following co-injection of BMSCs and MDA-MB-231BO breast cancer cells. Further investigation showed that the transforming growth factor-β1 (TGF-β1)/Smads pathway was an important mechanism enabling BMSCs to induce EMT occurrence of breast cancer cells. WSZG treatment reversed BMSC-induced EMT by downregulating TGF-β1/Smads signaling. Thus, WSZG extracts may be regarded as a potential antibone-metastatic agent for breast cancer therapy.
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Affiliation(s)
- Jiao Ma
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jiajia Li
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Ying Wang
- Shanghai University of Traditional Chinese Medicine, School of Chinese Materia Medica, Shanghai 201203, China
| | - Weiling Chen
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yueqiang Chen
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Zhenping Sun
- Department of Breast Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jin Liu
- Department of Breast Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yin Zhou
- Department of Breast Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jianyi Wang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Sheng Liu
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Xianghui Han
- Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
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15
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Abdallah BM, Ali EM. 5'-hydroxy Auraptene stimulates osteoblast differentiation of bone marrow-derived mesenchymal stem cells via a BMP-dependent mechanism. J Biomed Sci 2019; 26:51. [PMID: 31277646 PMCID: PMC6610929 DOI: 10.1186/s12929-019-0544-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/26/2019] [Indexed: 12/28/2022] Open
Abstract
Background Identifying bone anabolic agents is a superior strategy for the treatment of osteoporosis. Naturally, derived coumarin derivatives have shown osteoanabolic effect in vitro and in vivo. In this study, we investigated the effect of 5′-Hydroxy Auraptene (5′-HA), a coumarin derivative that newly isolated from Lotus lalambensis Schweinf on the differentiation of the mouse bone marrow-derived mesenchymal (skeletal) stem cells (mBMSCs) into osteoblast and adipocyte. Methods The effect of 5′-HA on mBMSCs cell proliferation and osteoblast differentiation was assessed by measuring cell viability, quantitative alkaline phosphatase (ALP) activity assay, Alizarin red staining for matrix mineralization and osteogenic gene array expression. Adipogenesis was measured by Oil Red O staining and quantitative real time PCR (qPCR) analysis of adipogenic markers. Regulation of BMPs signaling pathways by 5′-HA was measured by Western blot analysis and qPCR. Results 5′-HA showed to stimulate the differentiation of mBMSCs into osteogenic cell lineage in a dose-dependent manner, without affecting their differentiation into adipocytic cell lineage. Treatment of mBMSCs with 5′-HA showed to promote significantly the BMP2-induced osteogenesis in mBMSCs via activating Smad1/5/8 phosphorylation and increasing Smad4 expression. Blocking of BMP signaling using BMPR1 selective inhibitor LDN-193189 significantly inhibited the stimulatory effect of 5′-HA on osteogenesis. Conclusions Our data identified 5′-HA, as a novel coumarin derivative that function to stimulate the differentiation of mBMSCs into osteoblasts in BMP-signaling dependent mechanism. Electronic supplementary material The online version of this article (10.1186/s12929-019-0544-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Basem M Abdallah
- Biological Sciences Department, College of Science, King Faisal University, Hofuf-31982, Al-Ahsa, Saudi Arabia. .,Endocrine Research (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
| | - Enas M Ali
- Biological Sciences Department, College of Science, King Faisal University, Hofuf-31982, Al-Ahsa, Saudi Arabia.,Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt
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16
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Bruni R, Barreca D, Protti M, Brighenti V, Righetti L, Anceschi L, Mercolini L, Benvenuti S, Gattuso G, Pellati F. Botanical Sources, Chemistry, Analysis, and Biological Activity of Furanocoumarins of Pharmaceutical Interest. Molecules 2019; 24:E2163. [PMID: 31181737 PMCID: PMC6600687 DOI: 10.3390/molecules24112163] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 06/04/2019] [Accepted: 06/06/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of this work is to provide a critical review of plant furanocoumarins from different points of view, including their chemistry and biosynthetic pathways to their extraction, analysis, and synthesis, to the main biological activities found for these active compounds, in order to highlight their potential within pharmaceutical science. The limits and the possible improvements needed for research involving these molecules are also highlighted and discussed.
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Affiliation(s)
- Renato Bruni
- Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
| | - Davide Barreca
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
| | - Michele Protti
- Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
| | - Virginia Brighenti
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy.
| | - Laura Righetti
- Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
| | - Lisa Anceschi
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy.
| | - Laura Mercolini
- Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
| | - Stefania Benvenuti
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy.
| | - Giuseppe Gattuso
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
| | - Federica Pellati
- Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy.
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17
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Tarfiei GA, Shadboorestan A, Montazeri H, Rahmanian N, Tavosi G, Ghahremani MH. GDF15 induced apoptosis and cytotoxicity in A549 cells depends on TGFBR2 expression. Cell Biochem Funct 2019; 37:320-330. [PMID: 31172564 DOI: 10.1002/cbf.3391] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 12/30/2022]
Abstract
GDF15 plays a paradoxical role during carcinogenesis; it inhibits tumour growth in the early stages and promotes tumour cell proliferation in the late stages of cancer. Besides, GDF15 can induce apoptosis in some cancer cells including A549 but not in some others. Moreover, as a potential receptor for GDF15, TGFBR2 is inactivated during carcinogenesis in many types of cancers, and it is not present in cells with no GDF15 induced apoptosis. Thus, we tested whether GDF15 overexpression and/or TGFBR2 silencing can affect the GDF15 induced apoptosis in A549 cells. The full and mature forms of GDF15 were cloned and overexpressed in A549 cells. The TGFBR2 was silenced using specific siRNA and confirmed by real-time PCR. Results indicated that overexpression of full and mature forms of GDF15 as well as TGFBR2 knocked down reduced A549 cell viability in 24 and 48 hours. Flow cytometric analysis of annexin V/PI indicated induction of apoptosis in A549 cells by overexpression of GDF15 or silencing TGFBR2. Interestingly, the silencing of TGFBR2 inhibited the GDF15 induced cytotoxicity and apoptosis in A549 cells. Overexpression of GDF15 activated caspase-9 and caspase-3 and inhibited ERK1/2 and p38 phosphorylation in A549 cells. TGFBR2 knocked down inhibited GDF15 effects on caspases, ERK1/2, and p38MAPK activation. Our results indicated that the effect of GDF15 on apoptosis and activation of MAPK in A549 cells depends on TGFBR2 expression. These findings may point to mechanisms in which GDF15 exerts dual effect during carcinogenesis with regard to TGFBR2 expression. SIGNIFICANCE OF THE STUDY: GDF15 plays a tumour suppressor or promotor roles during carcinogenesis. The expression of GDF15 induced cytotoxicity, apoptosis, and inhibition of MAPK in A549 cells. All these effects were blocked by silencing TGFBR2 expression. These findings may point to mechanisms in which GDF15 exerts dual effect during carcinogenesis with regard to TGFBR2 expression.
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Affiliation(s)
- Ghorban Ali Tarfiei
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Shadboorestan
- Department of Pharmacology -Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Montazeri
- School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Narges Rahmanian
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Tavosi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacology -Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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18
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Bergapten induces G1 arrest of non‑small cell lung cancer cells, associated with the p53‑mediated cascade. Mol Med Rep 2019; 19:1972-1978. [PMID: 30628674 DOI: 10.3892/mmr.2019.9810] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Accepted: 11/28/2018] [Indexed: 11/05/2022] Open
Abstract
The principal subtype of lung cancer, non‑small cell lung cancer (NSCLC) is a life‑threatening malignancy that causes high mortality rates. Bergapten (5‑methoxypsoralen) has been identified to possess anticancer activity against a number of carcinomas. In the present study, the effects of bergapten on NSCLC cells were investigated. The cell viability was determined by MTT assay. Cell cycle distribution was analyzed using flow cytometry. Protein expression and kinase cascade were demonstrated using western blot analysis. The results demonstrated that treatment with bergapten (50 µM for 48 h) inhibited the viability of A549 and NCI‑H460 NSCLC cells to 79.1±2.8% and 74.5±3.1%, respectively, compared with the controls. It was identified that bergapten induced G1 phase accumulation in A549 and NCI‑H460 cells between ~58 and 75% (P<0.01). In addition, bergapten significantly increased the sub‑G1 phase ratio to ~9% (P<0.05) in the two cell types. Further investigation demonstrated that bergapten upregulated the expression of cellular tumor antigen p53 (p53) and its downstream proteins cyclin‑dependent kinase inhibitor 1 and cyclin‑dependent kinase inhibitor 1B, whereas, it downregulated the expression of cyclin D1 and CDK4. Overall, these results suggested that bergapten may inhibit cell viability and trigger G1 arrest and apoptosis in A549 and NCI‑H460 cells, which may be attributed to the activation of p53‑mediated cascades. Therefore, bergapten may be beneficial for NSCLC treatment.
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19
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Xie Z, Wen T, Zhang Z, Huang K, Wu T, Liu J, Wang X. Immuno Modulatory Effects of Bergapten Attenuates D-galactose-induced Aging Model in Balb/C Mice. INT J PHARMACOL 2018. [DOI: 10.3923/ijp.2018.936.944] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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20
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Bafor EE, McKenna J, Rowan EG, Edrada-Ebel R. Characterisation of the antiproliferative constituents and activity of Ficus exasperata (Vahl) on ovarian cancer cells -a preliminary investigation. Nat Prod Res 2017; 31:2164-2168. [PMID: 28092975 DOI: 10.1080/14786419.2016.1277348] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Ovarian cancer is one of the most common gynaecological cancers today. This study therefore investigates the anticancer effects of Ficus exasperata extracts and fractions on ovarian cancer cells. The antiproliferative activity of the crude extracts (1 mg/mL) was assessed using the MTT assay on A2780 (ovarian cancer) cell line. Bio-activity guided fractionation was performed and preliminary identification was further achieved using high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. All crude extracts tested exhibited antiproliferative activity except for the methanol extract which interestingly showed proliferative effects. Five fatty acids were identified from the active fractions (FB1-10 and FB1-12). FB1-12 exhibited an IC50 value of 15.20 μg/mL. The least potent fraction (FB1-4 + 5) had an IC50 value of 34.51 μg/mL. H1-HEX and H1-MET exhibited 97.2 and 97.9%, respectively, compared to control. This study therefore provides proof-of-principle that fatty acids of Ficus exasperata exhibit significant antiproliferative effects on ovarian cancer cells.
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Affiliation(s)
- Enitome E Bafor
- a Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow , United Kingdom
| | - Jennifer McKenna
- a Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow , United Kingdom
| | - Edward G Rowan
- a Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow , United Kingdom
| | - RuAngelie Edrada-Ebel
- a Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow , United Kingdom
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21
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Chemistry and health effects of furanocoumarins in grapefruit. J Food Drug Anal 2017; 25:71-83. [PMID: 28911545 PMCID: PMC9333421 DOI: 10.1016/j.jfda.2016.11.008] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/02/2016] [Accepted: 11/03/2016] [Indexed: 02/07/2023] Open
Abstract
Furanocoumarins are a specific group of secondary metabolites that commonly present in higher plants, such as citrus plants. The major furanocoumarins found in grapefruits (Citrus paradisi) include bergamottin, epoxybergamottin, and 6′,7′-dihydroxybergamottin. During biosynthesis of these furanocoumarins, coumarins undergo biochemical modifications corresponding to a prenylation reaction catalyzed by the cytochrome P450 enzymes with the subsequent formation of furan rings. Because of undesirable interactions with several medications, many studies have developed methods for grapefruit furanocoumarin quantification that include high-performance liquid chromatography coupled with UV detector or mass spectrometry. The distribution of furanocoumarins in grapefruits is affected by several environmental conditions, such as processing techniques, storage temperature, and packing materials. In the past few years, grapefruit furanocoumarins have been demonstrated to exhibit several biological activities including antioxidative, -inflammatory, and -cancer activities as well as bone health promotion both in vitro and in vivo. Notably, furanocoumarins potently exerted antiproliferative activities against cancer cell growth through modulation of several molecular pathways, such as regulation of the signal transducer and activator of transcription 3, nuclear factor-κB, phosphatidylinositol-3-kinase/AKT, and mitogen-activated protein kinase expression. Therefore, based on this review, we suggest furanocoumarins may serve as bioactive components that contribute, at least in part, to the health benefits of grapefruit.
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22
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Nigro A, Mauro L, Giordano F, Panza S, Iannacone R, Liuzzi GM, Aquila S, De Amicis F, Cellini F, Indiveri C, Panno ML. Recombinant Arabidopsis HSP70 Sustains Cell Survival and Metastatic Potential of Breast Cancer Cells. Mol Cancer Ther 2016; 15:1063-73. [PMID: 26939699 DOI: 10.1158/1535-7163.mct-15-0830] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 02/08/2016] [Indexed: 11/16/2022]
Abstract
The chaperone HSP70 protein is widely present in many different tumors and its expression correlates with an increased cell survival, low differentiation, and poor therapeutic outcome in human breast cancer. The intracellular protein has prevalently a cytoprotective function, while the extracellular HSP70 mediates immunologic responses. Evolutionarily, HSPs are well conserved from prokaryotes to eukaryotes, and human HSP70 shows a strong similarity to that of plant origin. In the current article, we have tested the potential effect of recombinant HSP70, from Arabidopsis thaliana, on cell survival and metastatic properties of breast cancer cells. Our data show that HSP70 sustains cell viability in MCF-7 and MDA-MB-231 breast tumoral cells and increases Cyclin D1 and Survivin expression. The extracellular HSP70 triggers cell migration and the activation of MMPs particularly in MDA-MB-231 cells. Furthermore, under UV-induced stress condition, the low levels of phospho-AKT were increased by exogenous HSP70, together with the upregulation of Cyclin D1, particularly in the tumoral cell phenotype. On the other hand, UV increased TP53 expression, and the coincubation of HSP70 lowers the TP53 levels similar to the control. These findings correlate with the cytoprotective and antiapoptotic role of HSPs, as reported in different cellular contexts. This is the first study on mammary cells that highlights how the heterologous HSP70 from Arabidopsis thaliana sustains cell survival prevalently in breast cancer cell types, thus maintaining their metastatic potential. Therefore, targeting HSP70 would be of clinical importance since HSP70 blocking selectively targets tumor cells, in which it supports cell growth and survival. Mol Cancer Ther; 15(5); 1063-73. ©2016 AACR.
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Affiliation(s)
- Alessandra Nigro
- Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Loredana Mauro
- Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Francesca Giordano
- Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Salvatore Panza
- Health Center, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Rina Iannacone
- ALSIA-Research Center Metapontum Agrobios, Metaponto, Matera, Italy
| | - Grazia Maria Liuzzi
- Department of Biosciences, Biotechnologies and Biopharmaceutics, Aldo Moro University, Bari, Italy
| | - Saveria Aquila
- Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy. Health Center, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Francesca De Amicis
- Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy. Health Center, University of Calabria, Arcavacata di Rende (CS), Italy
| | | | - Cesare Indiveri
- Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende (CS), Italy
| | - Maria Luisa Panno
- Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
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23
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Busch S, Sims AH, Stål O, Fernö M, Landberg G. Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance. Cancer Res 2016; 75:1457-69. [PMID: 25833830 DOI: 10.1158/0008-5472.can-14-1583] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
One third of the patients with estrogen receptor α (ERα)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ERα and TGFβ signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFβ signaling. In this study, we analyzed TGFβ receptor type 2 (TGFBR2) expression and correlated it with ERα status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ERα-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERα phosphorylation, tamoxifen-induced transcriptional activation of TGFβ, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGFβ signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERα-positive forms of this disease.
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Affiliation(s)
- Susann Busch
- Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden
| | - Andrew H Sims
- Applied Bioinformatics of Cancer, University of Edinburgh, Cancer Research UK Centre, United Kingdom
| | - Olle Stål
- Department of Clinical and Experimental Medicine, Institution of Surgery and Clinical Oncology, Linköpings Universitet, Linköping, Sweden
| | - Mårten Fernö
- Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden
| | - Göran Landberg
- Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden. Molecular Pathology, Breakthrough Breast Cancer Research Unit, University of Manchester, United Kingdom.
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24
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Kiyama R, Wada-Kiyama Y. Estrogenic endocrine disruptors: Molecular mechanisms of action. ENVIRONMENT INTERNATIONAL 2015; 83:11-40. [PMID: 26073844 DOI: 10.1016/j.envint.2015.05.012] [Citation(s) in RCA: 192] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 05/26/2015] [Accepted: 05/27/2015] [Indexed: 05/20/2023]
Abstract
A comprehensive summary of more than 450 estrogenic chemicals including estrogenic endocrine disruptors is provided here to understand the complex and profound impact of estrogen action. First, estrogenic chemicals are categorized by structure as well as their applications, usage and effects. Second, estrogenic signaling is examined by the molecular mechanism based on the receptors, signaling pathways, crosstalk/bypassing and autocrine/paracrine/homeostatic networks involved in the signaling. Third, evaluation of estrogen action is discussed by focusing on the technologies and protocols of the assays for assessing estrogenicity. Understanding the molecular mechanisms of estrogen action is important to assess the action of endocrine disruptors and will be used for risk management based on pathway-based toxicity testing.
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Affiliation(s)
- Ryoiti Kiyama
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | - Yuko Wada-Kiyama
- Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan
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25
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Xiao JJ, Zhao WJ, Zhang XT, Zhao WL, Wang XX, Yin SH, Jiang F, Zhao YX, Chen FN, Li SL. Bergapten promotes bone marrow stromal cell differentiation into osteoblasts in vitro and in vivo. Mol Cell Biochem 2015; 409:113-22. [DOI: 10.1007/s11010-015-2517-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/11/2015] [Indexed: 10/23/2022]
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26
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De Amicis F, Aquila S, Morelli C, Guido C, Santoro M, Perrotta I, Mauro L, Giordano F, Nigro A, Andò S, Panno ML. Bergapten drives autophagy through the up-regulation of PTEN expression in breast cancer cells. Mol Cancer 2015; 14:130. [PMID: 26148846 PMCID: PMC4498523 DOI: 10.1186/s12943-015-0403-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 06/29/2015] [Indexed: 12/12/2022] Open
Abstract
Background Bergapten (5-methoxypsoralen), a natural psoralen derivative present in many fruits and vegetables, has shown antitumoral effects in a variety of cell types. In this study, it has been addressed how Bergapten in breast cancer cells induces autophagic process. Results In MCF7 and ZR-75 breast cancer cells Bergapten exhibited anti-survival response by inducing the autophagic process increasing Beclin1, PI3KIII, UVRAG, AMBRA expression and conversion of LC3-I to LC3-II. LC3-GFP, Acridine orange assay and transmission electron microscopy even confirmed the increased autophagosome formations in treated cells. Bergapten-induced autophagy is dependent by PTEN up-regulation, since silencing this gene, the induction of Beclin1 and the p-AKT/p-mTOR signal down-regulation were reversed. PTEN is transcriptionally regulated by Bergapten through the involvement of p38MAPK/NF-Y, as evidenced by the use of p38MAPK inhibitor SB203580, site-direct mutagenesis of NF-Y element and NF-Y siRNA. Furthermore NF-Y knockdown prevented Bergapten-induced acid vesicular organelle accumulations (AVOs), strengthening the role of this element in mediating autophagy. Conclusions Our data indicate PTEN as a key target of Bergapten action in breast cancer cells for the induction of autophagy. These findings add further details on the mechanism of action of Bergapten, therefore suggesting that phytochemical compounds may be implemented in the novel strategies for breast cancer treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0403-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy. .,Health Center, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Saveria Aquila
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy. .,Health Center, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Carmela Guido
- Health Center, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Marta Santoro
- Health Center, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Ida Perrotta
- Department of Biology, Ecology and Earth Science (Di.B.E.S.T.), University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Loredana Mauro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Alessandra Nigro
- Department of Biology, Ecology and Earth Science (Di.B.E.S.T.), University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy. .,Health Center, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
| | - Maria L Panno
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Arcavacata di Rende, Cosenza, Italy.
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27
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Liu Y, Ao X, Jia Z, Bai XY, Xu Z, Hu G, Jiang X, Chen M, Wu H. FOXK2 transcription factor suppresses ERα-positive breast cancer cell growth through down-regulating the stability of ERα via mechanism involving BRCA1/BARD1. Sci Rep 2015; 5:8796. [PMID: 25740706 PMCID: PMC4350111 DOI: 10.1038/srep08796] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 02/04/2015] [Indexed: 01/05/2023] Open
Abstract
Estrogen receptors (ERs) are critical regulators of breast cancer development. Identification of molecules that regulate the function of ERs may facilitate the development of more effective breast cancer treatment strategies. In this study, we showed that the forkhead transcription factor FOXK2 interacted with ERα, and inhibited ERα-regulated transcriptional activities by enhancing the ubiquitin-mediated degradation of ERα. This process involved the interaction between FOXK2 and BRCA1/BARD1, the E3 ubiquitin ligase of ERα. FOXK2 interacted with BARD1 and acted as a scaffold protein for BRCA1/BARD1 and ERα, leading to enhanced degradation of ERα, which eventually accounted for its decreased transcriptional activity. Consistent with these observations, overexpression of FOXK2 inhibited the transcriptional activity of ERα, decreased the transcription of ERα target genes, and suppressed the proliferation of ERα-positive breast cancer cells. In contract, knockdown of FOXK2 in MCF-7 cells promoted cell proliferation. However, when ERα was also knocked down, knockdown of FOXK2 had no effect on cell proliferation. These findings suggested that FOXK2 might act as a negative regulator of ERα, and its association with both ERα and BRCA1/BARD1 could lead to the down-regulation of ERα transcriptional activity, effectively regulating the function of ERα.
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Affiliation(s)
- Ying Liu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xiang Ao
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Zhaojun Jia
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xiao-Yan Bai
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Zhaowei Xu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Gaolei Hu
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Xiao Jiang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Min Chen
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China
| | - Huijian Wu
- 1] School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China [2] School of Life Science and Medicine, Dalian University of Technology, Panjin 114221, Liaoning, China
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28
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De Amicis F, Guido C, Santoro M, Lanzino M, Panza S, Avena P, Panno ML, Perrotta I, Aquila S, Andò S. A novel functional interplay between Progesterone Receptor-B and PTEN, via AKT, modulates autophagy in breast cancer cells. J Cell Mol Med 2014; 18:2252-65. [PMID: 25216078 PMCID: PMC4224558 DOI: 10.1111/jcmm.12363] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/02/2014] [Indexed: 12/20/2022] Open
Abstract
The tumour suppressor activity of the phosphatase and tensin homologue on chromosome 10 (PTEN) is subject of intense investigative efforts, although limited information on its regulation in breast cancer is available. Herein, we report that, in breast cancer cells, progesterone (OHPg), through its cognate receptor PR-B, positively modulates PTEN expression by inducing its mRNA and protein levels, and increasing PTEN-promoter activity. The OHPg-dependent up-regulation of PTEN gene activity requires binding of the PR-B to an Sp1-rich region within the PTEN gene promoter. Indeed, ChIP and EMSA analyses showed that OHPg treatment induced the occupancy of PTEN promoter by PR and Sp1 together with transcriptional coactivators such as SRC1 and CBP. PR-B isoform knockdown abolished the complex formation indicating its specific involvement. The OHPg/PR-B dependent induction of PTEN causes the down-regulation of PI3K/AKT signal, switching on the autophagy process through an enhanced expression of UVRAG and leading to a reduced cell survival. Altogether these findings highlight a novel functional connection between OHPg/PR-B and tumour suppressor pathways in breast cancer.
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Affiliation(s)
- Francesca De Amicis
- Centro Sanitario, University of Calabria, Arcavacata di Rende (CS), Italy; Department of Pharmacy, Health Science and Nutrition, University of Calabria, Arcavacata di Rende (CS), Italy
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29
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Panno ML, Giordano F. Effects of psoralens as anti-tumoral agents in breast cancer cells. World J Clin Oncol 2014; 5:348-358. [PMID: 25114850 PMCID: PMC4127606 DOI: 10.5306/wjco.v5.i3.348] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 05/14/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer.
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30
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Mauro L, Pellegrino M, De Amicis F, Ricchio E, Giordano F, Rizza P, Catalano S, Bonofiglio D, Sisci D, Panno ML, Andò S. Evidences that estrogen receptor α interferes with adiponectin effects on breast cancer cell growth. Cell Cycle 2013; 13:553-64. [PMID: 24335340 DOI: 10.4161/cc.27455] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, anti-inflammatory, antiatherogenic, and antiproliferative properties. In addition, it appears to play an important role also in the development and progression of several obesity-related malignancies, including breast cancer. Here, we demonstrated that adiponectin induces a dichotomic effect on breast cancer growth. Indeed, it stimulates growth in ERα+ MCF-7 cells while inhibiting proliferation of ERα- MDA-MB-231 cells. Notably, only in MCF-7 cells adiponectin exposure exerts a rapid activation of MAPK phosphorylation, which is markedly reduced when knockdown of the ERα gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ERα siRNA prevents this effect. Moreover, MAPK activation induced by adiponectin was reversed by IGF-IR siRNA. Coimmunoprecipitation studies show the existence of a multiprotein complex involving AdipoR1, APPL1, ERα, IGF-IR, and c-Src that is responsible for MAPK signaling activation in ERα+ positive breast cancer cells. It is well known that in addition to the rapid effects through non-genomic mechanisms, ERα also mediates nuclear genomic actions. In this concern, we demonstrated that adiponectin is able to transactivate ERα in MCF-7 cells. We showed the classical features of ERα transactivation: nuclear localization, downregulation of mRNA and protein levels, and upregulation of estrogen-dependent genes. Thus, our study clarifies the molecular mechanism through which adiponectin modulates breast cancer cell growth, providing evidences on the cell-type dependency of adiponectin action in relationship to ERα status.
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Affiliation(s)
- Loredana Mauro
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Michele Pellegrino
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Emilia Ricchio
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Francesca Giordano
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Pietro Rizza
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Diego Sisci
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
| | - Maria Luisa Panno
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy
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Xie YH, Wang SW, Zhang Y, Edvinsson L, Xu CB. Nuclear Factor-kappaB-Mediated Endothelin Receptor Up-Regulation Increases Renal Artery Contractility in Rats. Basic Clin Pharmacol Toxicol 2013; 113:401-10. [PMID: 24034179 DOI: 10.1111/bcpt.12123] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 08/06/2013] [Indexed: 01/21/2023]
Abstract
Increased renal artery contractility leads to renal vasospasm and ischaemia as well as kidney damage. This study was designed to examine the hypothesis that organ culture of renal arteries induces transcriptional up-regulation of endothelin type A (ETA ) and type B2 (ETB2 ) receptors in the smooth muscle cells via activation of nuclear factor-kappaB (NF-κB) and subsequently increases renal artery contractility. Rat renal artery segments were organ-cultured for 6 or 24 hr to increase endothelin receptor-mediated contraction. To dissect molecular mechanisms involved in this process, inhibitors for NF-κB signalling pathway (MG-132 and BMS345541), transcription (actinomycin D) and translation (cycloheximide) were used during organ culture. Endothelin receptors were studied using a sensitive myograph (functional contractility), real-time PCR (mRNA analysis) and immunohistochemistry (protein localization). Compared with fresh segments, contractile responses to endothelin-1 (non-selective endothelin receptor agonist) and sarafotoxin 6c (selective ETB receptor agonist) were significantly increased in the segments after 24 hr of organ culture; ETB2 receptor-mediated maximal contraction increased from 2.7 ± 0.5 to 135.3 ± 5.1 (p < 0.001), and potency (pEC50 ) of ETA receptor agonist increased from 8.20 ± 0.04 to 8.72 ± 0.07 (p < 0.001). This was in parallel with increased corresponding mRNA and protein expression for ETA and ETB2 receptors. BMS345541, MG-132, actinomycin D or cyclohexamide, respectively, suppressed the up-regulation of ETA and ETB2 receptors. Immunostaining performed with specific antibody showed that IκB was phosphorylated during organ culture. In conclusion, activation of NF-κB mediates up-regulation of ETA and ETB2 receptors and subsequently increases renal artery contractility, which may contribute to renal vasospasm and ischaemia as well as kidney damage.
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Affiliation(s)
- Yan-Hua Xie
- Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Si-Wang Wang
- Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yaping Zhang
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Lars Edvinsson
- Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden
| | - Cang-Bao Xu
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi, China.,Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden
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32
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Synthesis of novel psoralen analogues and their in vitro antitumor activity. Bioorg Med Chem 2013; 21:5047-53. [DOI: 10.1016/j.bmc.2013.06.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 06/19/2013] [Accepted: 06/20/2013] [Indexed: 11/21/2022]
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