|
1
|
Koerner L, Schmiel M, Yang TP, Peifer M, Buettner R, Pasparakis M. NEMO- and RelA-dependent NF-κB signaling promotes small cell lung cancer. Cell Death Differ 2023; 30:938-951. [PMID: 36653597 PMCID: PMC10070460 DOI: 10.1038/s41418-023-01112-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/28/2022] [Accepted: 01/06/2023] [Indexed: 01/19/2023] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKK/NF-κB signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMO/IKKγ, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-κB signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-κB family member p65/RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKK/NF-κB signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-κB levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKK/NF-κB signaling plays an important role in promoting SCLC, identifying the IKK/NF-κB pathway as a promising therapeutic target.
Collapse
Affiliation(s)
- Lioba Koerner
- Institute for Genetics, University of Cologne, 50674, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Marcel Schmiel
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.,Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Tsun-Po Yang
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Martin Peifer
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.,Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.,Center for Molecular Medicine (CMMC), Medical Faculty and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.,Center for Molecular Medicine (CMMC), Medical Faculty and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Manolis Pasparakis
- Institute for Genetics, University of Cologne, 50674, Cologne, Germany. .,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany. .,Center for Molecular Medicine (CMMC), Medical Faculty and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
| |
Collapse
|
|
2
|
Attalla S, Taifour T, Muller W. Tailoring therapies to counter the divergent immune landscapes of breast cancer. Front Cell Dev Biol 2023; 11:1111796. [PMID: 36910138 PMCID: PMC9992199 DOI: 10.3389/fcell.2023.1111796] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/25/2023] [Indexed: 02/24/2023] Open
Abstract
Breast cancer remains a significant clinical concern affecting millions of women worldwide. Immunotherapy is a rapidly growing drug class that has revolutionized cancer treatment but remains marginally successful in breast cancer. The success of immunotherapy is dependent on the baseline immune responses as well as removing the brakes off pre-existing anti-tumor immunity. In this review, we summarize the different types of immune microenvironment observed in breast cancer as well as provide approaches to target these different immune subtypes. Such approaches have demonstrated pre-clinical success and are currently under clinical evaluation. The impact of combination of these approaches with already approved chemotherapies and immunotherapies may improve patient outcome and survival.
Collapse
Affiliation(s)
- Sherif Attalla
- Department Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.,Goodman Cancer Institute, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Tarek Taifour
- Goodman Cancer Institute, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.,Department Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - William Muller
- Department Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.,Goodman Cancer Institute, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.,Department Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
3
|
Alam M, Hasan GM, Ansari MM, Sharma R, Yadav DK, Hassan MI. Therapeutic implications and clinical manifestations of thymoquinone. PHYTOCHEMISTRY 2022; 200:113213. [PMID: 35472482 DOI: 10.1016/j.phytochem.2022.113213] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 06/14/2023]
Abstract
Thymoquinone (TQ), a natural phytochemical predominantly found in Nigella sativa, has been investigated for its numerous health benefits. TQ showed anti-cancer, anti-oxidant, and anti-inflammatory properties, validated in various disease models. The anti-cancer potential of TQ is goverened by anti-proliferation, cell cycle arrest, apoptosis induction, ROS production, anti-metastasis and anti-angiogenesis, inhibition of cell migration and invasion action. Additionally, TQ exhibited antitumor activity via the modulation of multiple pathways and molecular targets, including Akt, ERK1/2, STAT3, and NF-κB. The present review highlighted the anticancer potential of TQ . We summarize the anti-cancer, anti-oxidant, and anti-inflammatory properties of TQ, focusing on its molecular targets and its promising action in cancer therapy. We further described the molecular mechanisms by which TQ prevents signaling pathways that mediate cancer progression, invasion, and metastasis.
Collapse
Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj, 11942, Saudi Arabia
| | - Md Meraj Ansari
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, SAS Nagar, Mohali, Punjab, 160062, India
| | - Rishi Sharma
- Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Dharmendra Kumar Yadav
- College of Pharmacy, Gachon University of Medicine and Science, Hambakmoeiro, Yeonsu-gu, Incheon City, 21924, South Korea.
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
| |
Collapse
|
|
4
|
Xie W, Jiang Q, Wu X, Wang L, Gao B, Sun Z, Zhang X, Bu L, Lin Y, Huang Q, Li J, Guo J. IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis. Cell Death Differ 2022; 29:1528-1540. [PMID: 35066576 PMCID: PMC9345937 DOI: 10.1038/s41418-022-00940-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 12/15/2022] Open
Abstract
IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion of Ikbke markedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion of IKBKE attenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies.
Collapse
|
|
5
|
Natural Products for Cancer Therapy: A Review of Their Mechanism of Actions and Toxicity in the Past Decade. J Trop Med 2022; 2022:5794350. [PMID: 35309872 PMCID: PMC8933079 DOI: 10.1155/2022/5794350] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/13/2021] [Accepted: 02/19/2022] [Indexed: 12/12/2022] Open
Abstract
The ethnopharmacological information gathered over many centuries and the presence of diverse metabolites have made the medicinal plants as the prime source of drugs. Despite the positive attributes of natural products, there are many questions pertaining to their mechanism of actions and molecular targets that impede their development as therapeutic agents. One of the major challenges in cancer research is the toxicity exerted by investigational agents towards the host. An understanding of their molecular targets, underlying mechanisms can reveal their anticancer efficacy, help in optimal therapeutic dose selection, to mitigate their side effects and toxicity towards the host. The purpose of this review is to collate details on natural products that are recently been investigated extensively in the past decade for their anticancer potential. Besides, critical analysis of their molecular targets and underlying mechanisms on multiple cancer cell lines, an in-depth probe of their toxicological screening on rodent models is outlined as well to observe the prevalence of their toxicity towards host. This review can provide valuable insights for researchers in developing methods, strategies during preclinical and clinical evaluation of anticancer candidates.
Collapse
|
|
6
|
Eftekhar SP, Kazemi S, Moghadamnia AA. Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro. Hum Exp Toxicol 2022; 41:9603271221145422. [PMID: 36510676 DOI: 10.1177/09603271221145422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration (Cmax), area under the curve (AUC), and time of maximum concentration (Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.
Collapse
Affiliation(s)
- Seyed Parsa Eftekhar
- Department of Pharmacology and Toxicology, School of Medicine, 114456Babol University of Medical Sciences, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, 114456Babol University of Medical Sciences, Babol, Iran
| | - Ali Akbar Moghadamnia
- Department of Pharmacology and Toxicology, School of Medicine, 114456Babol University of Medical Sciences, Babol, Iran
| |
Collapse
|
|
7
|
Apoptotic and Non-Apoptotic Modalities of Thymoquinone-Induced Lymphoma Cell Death: Highlight of the Role of Cytosolic Calcium and Necroptosis. Cancers (Basel) 2021; 13:cancers13143579. [PMID: 34298792 PMCID: PMC8304872 DOI: 10.3390/cancers13143579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 01/17/2023] Open
Abstract
Simple Summary Diffuse large B cell lymphoma (DLBCL) represents the most common type of non-Hodgkin lymphoma with a high curability rate. However, 40% of patients will relapse or exhibit refractory disease, and compromised apoptotic pathways is among the prognosis-worsening factors. Therefore, drugging non-apoptotic modalities might be therapeutically promising. Thymoquinone (TQ) has been reported to promote apoptosis in cancer cells. Herein, we show that TQ selectively kills DLBCL cells, either cell lines or primary lymphoma cells bearing resistance features to standard treatment. Investigations show that, although TQ induced apoptotic markers, non-apoptotic death was the major mechanism responsible for TQ-induced cellular demise. We demonstrate critical and selective roles of cytosolic calcium and necroptosis in TQ-induced non-apoptotic cell death. Finally, TQ exhibits an improved selectivity profile over conventional chemotherapy. Collectively, this work provides new insights into the mode of action of TQ and points to the therapeutic relevance of non-apoptotic modalities as a fail-safe mechanism for pro-apoptotic DLBCL therapies. Abstract Targeting non-apoptotic modalities might be therapeutically promising in diffuse large B cell lymphoma (DLBCL) patients with compromised apoptotic pathways. Thymoquinone (TQ) has been reported to promote apoptosis in cancer cells, but little is known about its effect on non-apoptotic pathways. This work investigates TQ selectivity against DLBCL cell lines and the cell death mechanisms. TQ reduces cell viability and kills cell lines with minimal toxicity on normal hematological cells. Mechanistically, TQ promotes the mitochondrial caspase pathway and increases genotoxicity. However, insensitivity of most cell lines to caspase inhibition by z-VAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) pointed to a critical role of non-apoptotic signaling. In cells dying through non-apoptotic death, TQ increases endoplasmic reticulum (ER) stress markers and substantially increases cytosolic calcium ([Ca2+]c) through ER calcium depletion and activation of store-operated calcium entry (SOCE). Chelation of [Ca2+]c, but not SOCE inhibitors, reduces TQ-induced non-apoptotic cell death, highlighting the critical role of calcium in a non-apoptotic effect of TQ. Investigations showed that TQ-induced [Ca2+]c signaling is primarily initiated by necroptosis upstream to SOCE, and inhibition necroptosis by necrostatin-1 alone or with z-VAD-fmk blocks the cell death. Finally, TQ exhibits an improved selectivity profile over standard chemotherapy agents, suggesting a therapeutic relevance of the pro-necroptotic effect of TQ as a fail-safe mechanism for DLBCL therapies targeting apoptosis.
Collapse
|
|
8
|
Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis. Cancers (Basel) 2021; 13:cancers13133329. [PMID: 34283045 PMCID: PMC8268413 DOI: 10.3390/cancers13133329] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Rlip knockout has been reported to prevent cancer in highly cancer-susceptible mice lacking p53, and Rlip knockdown kills many types of cancer cells. In humans, breast cancer shows diverse characteristics, including HER2-driven subtypes and viral-driven subtypes. HER2 can be targeted; however, escape of the cancer from targeted therapies remains a problem. In this work we evaluated the capacity of Rlip knockout to prevent breast cancer in genetically engineered mouse models of HER2-driven breast cancer (Erbb2 model) and polyomavirus-driven breast cancer (PyVT model). We found that in Erbb2 mice, Rlip knockout significantly delayed oncogenesis and reduced the expression of genes associated with poor prognosis in patients. In PyVT mice, Rlip knockout did not delay oncogenesis or tumor growth, but Rlip knockdown reduced tumor metastasis to the lung. We conclude that Rlip inhibitors may significantly improve survival in HER2-positive patients, but are unlikely to offer benefits to patients with polyomavirus-associated tumors. Abstract We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.
Collapse
|
|
9
|
Kurley SJ, Tischler V, Bierie B, Novitskiy SV, Noske A, Varga Z, Zürrer-Härdi U, Brandt S, Carnahan RH, Cook RS, Muller WJ, Richmond A, Reynolds AB. A requirement for p120-catenin in the metastasis of invasive ductal breast cancer. J Cell Sci 2021; 134:jcs250639. [PMID: 33097605 PMCID: PMC7990862 DOI: 10.1242/jcs.250639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/02/2020] [Indexed: 12/15/2022] Open
Abstract
We report here the effects of targeted p120-catenin (encoded by CTNND1; hereafter denoted p120) knockout (KO) in a PyMT mouse model of invasive ductal (mammary) cancer (IDC). Mosaic p120 ablation had little effect on primary tumor growth but caused significant pro-metastatic alterations in the tumor microenvironment, ultimately leading to a marked increase in the number and size of pulmonary metastases. Surprisingly, although early effects of p120-ablation included decreased cell-cell adhesion and increased invasiveness, cells lacking p120 were almost entirely unable to colonized distant metastatic sites in vivo The relevance of this observation to human IDC was established by analysis of a large clinical dataset of 1126 IDCs. As reported by others, p120 downregulation in primary IDC predicted worse overall survival. However, as in the mice, distant metastases were almost invariably p120 positive, even in matched cases where the primary tumors were p120 negative. Collectively, our results demonstrate a strong positive role for p120 (and presumably E-cadherin) during metastatic colonization of distant sites. On the other hand, downregulation of p120 in the primary tumor enhanced metastatic dissemination indirectly via pro-metastatic conditioning of the tumor microenvironment.
Collapse
Affiliation(s)
- Sarah J Kurley
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Verena Tischler
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Brian Bierie
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Sergey V Novitskiy
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Aurelia Noske
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Zsuzsanna Varga
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Ursina Zürrer-Härdi
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Simone Brandt
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Robert H Carnahan
- Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA
- Goodman Cancer Centre, Montreal, Quebec, H3A 1A3, Canada
| | - Rebecca S Cook
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - William J Muller
- Goodman Cancer Centre, Montreal, Quebec, H3A 1A3, Canada
- Departments of Biochemistry and Medicine, McGill University, Montreal, Quebec, H3A OG4, Canada
| | - Ann Richmond
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA
| | - Albert B Reynolds
- Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA
| |
Collapse
|
|
10
|
Elgohary S, Elkhodiry AA, Amin NS, Stein U, El Tayebi HM. Thymoquinone: A Tie-Breaker in SARS-CoV2-Infected Cancer Patients? Cells 2021; 10:302. [PMID: 33540625 PMCID: PMC7912962 DOI: 10.3390/cells10020302] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022] Open
Abstract
Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-2) pandemic, arace to develop a vaccine has been initiated, considering the massive and rather significant economic and healthcare hits that this virus has caused. The pathophysiology occurring following COVID-19(coronavirus disease-2019) infection has givenhints regarding the supportive and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications. Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients are at higher risk of viral infection and more likely to develop serious complications due to their immunocompromised state, the fact that they are already administering multiple medications, as well as combined comorbidity compared to the general population. It may seem impossible to find a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19 infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive COVID-19 therapy and cancer therapy, and finally, its anticancer effects.
Collapse
Affiliation(s)
- Sawsan Elgohary
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Aya A. Elkhodiry
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Nada S. Amin
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Hend M. El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt; (S.E.); (A.A.E.); (N.S.A.)
| |
Collapse
|
|
11
|
Long F, Lin H, Zhang X, Zhang J, Xiao H, Wang T. Atractylenolide-I Suppresses Tumorigenesis of Breast Cancer by Inhibiting Toll-Like Receptor 4-Mediated Nuclear Factor-κB Signaling Pathway. Front Pharmacol 2020; 11:598939. [PMID: 33363472 PMCID: PMC7753112 DOI: 10.3389/fphar.2020.598939] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/30/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide-I (AT-I), a novel TLR4-antagonizing agent, is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear. Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments. Results: We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit N-Nitroso-N-methylurea-induced rat mammary tumor progression through TLR4/NF-κB pathway. Conclusion: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.
Collapse
Affiliation(s)
- Fangyi Long
- Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Hong Lin
- Department of Pharmacy, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiqian Zhang
- Department of Pharmacy, Chengdu Third People's Hospital and College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Jianhui Zhang
- Department of Breast Cancer, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hongtao Xiao
- Department of Pharmacy, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Wang
- Department of Pharmacy, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
|
12
|
New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs. Differentiation 2020; 118:4-23. [PMID: 33189416 DOI: 10.1016/j.diff.2020.10.003] [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: 10/02/2020] [Revised: 10/12/2020] [Accepted: 10/25/2020] [Indexed: 01/17/2023]
Abstract
In the early 1960's, at Professor Bern's laboratory, University of California, Berkeley) in the US, Takasugi discovered ovary-independent, persistent vaginal changes in mice exposed neonatally to estrogen, which resulted in vaginal cancer later in life. Reproductive abnormalities in rodents were reported as a result of perinatal exposure to various estrogenic chemicals. Ten years later, vaginal cancers were reported in young women exposed in utero to the synthetic estrogen diethylstilbestrol (DES) and this has been called the "DES syndrome". The developing organism is particularly sensitive to developmental exposure to estrogens inducing long-term changes in various organs including the reproductive organs. The molecular mechanism underlying the persistent vaginal changes induced by perinatal estrogen exposure was partly demonstrated. Persistent phosphorylation and sustained expression of EGF-like growth factors, lead to estrogen receptor α (ESR1) activation, and then persistent vaginal epithelial cell proliferation. Agents which are weakly estrogenic by postnatal criteria may have major developmental effects, especially during a critical perinatal period. The present review outlines various studies conducted by four generations of investigators all under the influence of Prof. Bern. The studies include reports of persistent changes induced by neonatal androgen exposure, analyses of estrogen responsive genes, factors determining epithelial differentiation in the Müllerian duct, ESR and growth factor signaling, and polyovular follicles in mammals. This review is then expanded to the studies on the effects of environmental estrogens on wildlife and endocrine disruption in Daphnids.
Collapse
|
|
13
|
Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer. BMC Cancer 2020; 20:970. [PMID: 33028251 PMCID: PMC7542116 DOI: 10.1186/s12885-020-07450-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown. Therefore, we aimed to investigate the therapeutic potential of increasing macrophage NF-κB activity in immunocompetent mouse models of ovarian cancer. METHODS We have generated a transgenic mouse model, termed IKFM, which allows doxycycline-inducible overexpression of a constitutively active form of IKK2 (cIKK2) specifically within macrophages. The IKFM model was used to evaluate effects of increasing macrophage NF-κB activity in syngeneic murine TBR5 and ID8-Luc models of ovarian cancer in two temporal windows: 1) in established tumors, and 2) during tumor implantation and early tumor growth. Tumor weight, ascites volume, ascites supernatant and cells, and solid tumor were collected at sacrifice. Populations of macrophages and T cells within solid tumor and/or ascites were analyzed by immunofluorescent staining and qPCR, and soluble factors in ascitic fluid were analyzed by ELISA. Comparisons of control versus IKFM groups were performed by 2-tailed Mann-Whitney test, and a P-value < 0.05 was considered statistically significant. RESULTS Increased expression of the cIKK2 transgene in TAMs from IKFM mice was confirmed at the mRNA and protein levels. Tumors from IKFM mice, regardless of the timing of doxycycline (dox) administration, demonstrated greater necrosis and immune infiltration than control tumors. Analysis of IKFM ascites and tumors showed sustained shifts in macrophage populations away from the M2 and towards the anti-tumor M1 phenotype. There were also increased tumor-infiltrating CD3+/CD8+ T cells in IKFM mice, accompanied by higher levels of CXCL9, a T cell activating factor secreted by macrophages, in IKFM ascitic fluid. CONCLUSIONS In syngeneic ovarian cancer models, increased canonical NF-κB signaling in macrophages promoted anti-tumor TAM phenotypes and increased cytotoxic T cell infiltration, which was sufficient to limit tumor progression. This may present a novel translational approach for ovarian cancer treatment, with the potential to increase responses to T cell-directed therapy in future studies.
Collapse
|
|
14
|
Helm JS, Rudel RA. Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast. Arch Toxicol 2020. [PMID: 32399610 DOI: 10.1007/s00204-020-02752-z)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.
Collapse
Affiliation(s)
- Jessica S Helm
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA
| | - Ruthann A Rudel
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA.
| |
Collapse
|
|
15
|
Helm JS, Rudel RA. Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast. Arch Toxicol 2020; 94:1511-1549. [PMID: 32399610 PMCID: PMC7261741 DOI: 10.1007/s00204-020-02752-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022]
Abstract
Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.
Collapse
Affiliation(s)
- Jessica S Helm
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA
| | - Ruthann A Rudel
- Silent Spring Institute, 320 Nevada Street, Suite 302, Newton, MA, 02460, USA.
| |
Collapse
|
|
16
|
Senthil Kumar KJ, Gokila Vani M, Hsieh HW, Lin CC, Liao JW, Chueh PJ, Wang SY. MicroRNA-708 activation by glucocorticoid receptor agonists regulate breast cancer tumorigenesis and metastasis via downregulation of NF-κB signaling. Carcinogenesis 2019; 40:335-348. [PMID: 30726934 DOI: 10.1093/carcin/bgz011] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/06/2019] [Accepted: 01/22/2019] [Indexed: 02/06/2023] Open
Abstract
Therapeutic administration of glucocorticoids (GCs) is frequently used as add-on chemotherapy for palliative purposes during breast cancer treatment. Recent studies have shown that GC treatment induces microRNA-708 in ovarian cancer cells, resulting in impaired tumor cell proliferation and metastasis. However, the regulatory functions of GCs on miR-708 and its downstream target genes in human breast cancer cells (BCCs) are poorly understood. In this study, we found that treatment with either the synthetic GC dexamethasone (DEX) or the natural GC mimic, antcin A (ATA) significantly increased miR-708 expression by transactivation of glucocorticoid receptor alpha (GRα) in MCF-7 and MDA-MB-231 human BCCs. Induction of miR-708 by GR agonists resulted in inhibition of cell proliferation, cell-cycle progression, cancer stem cell (CSC)-like phenotype and metastasis of BCCs. In addition, GR agonist treatment or miR-708 mimic transfection remarkably inhibited IKKβ expression and suppressed nuclear factor-kappaB (NF-κB) activity and its downstream target genes, including COX-2, cMYC, cyclin D1, Matrix metalloproteinase (MMP)-2, MMP-9, CD24, CD44 and increased p21CIP1 and p27KIP1 that are known to be involved in proliferation, cell-cycle progression, metastasis and CSC marker protein. BCCs xenograft models indicate that treatment with GR agonists significantly reduced tumor growth, weight and volume. Overall, our data strongly suggest that GR agonists induced miR-708 and downstream suppression of NF-κB signaling, which may be applicable as a novel therapeutic intervention in breast cancer treatment.
Collapse
Affiliation(s)
- K J Senthil Kumar
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - M Gokila Vani
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | | | | | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathology, National Chung Hsing University, Taichung, Taiwan
| | - Pin-Ju Chueh
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Sheng-Yang Wang
- Department of Forestry, National Chung Hsing University, Taichung, Taiwan.,National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.,Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
| |
Collapse
|
|
17
|
Zhu N, Xiang Y, Zhao X, Cai C, Chen H, Jiang W, Wang Y, Zeng C. Thymoquinone suppresses platelet-derived growth factor-BB-induced vascular smooth muscle cell proliferation, migration and neointimal formation. J Cell Mol Med 2019; 23:8482-8492. [PMID: 31638340 PMCID: PMC6850929 DOI: 10.1111/jcmm.14738] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 08/24/2019] [Accepted: 08/31/2019] [Indexed: 02/06/2023] Open
Abstract
The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are mainly responsible for vascular occlusion diseases, such as pulmonary arterial hypertension and restenosis. Our previous study demonstrated thymoquinone (TQ) attenuated monocrotaline‐induced pulmonary arterial hypertension. The aim of the present study is to systematically examine inhibitory effects of TQ on platelet‐derived growth factor‐BB (PDGF‐BB)–induced proliferation and migration of VSMCs in vitro and neointimal formation in vivo and elucidate the potential mechanisms. Vascular smooth muscle cells were isolated from the aorta in rats. Cell viability and proliferation were measured in VSMCs using the MTT assay. Cell migration was detected by wound healing assay and Transwell assay. Alpha‐smooth muscle actin (α‐SMA) and Ki‐67‐positive cells were examined by immunofluorescence staining. Reactive oxygen species (ROS) generation and apoptosis were measured by flow cytometry and terminal deoxyribonucleotide transferase–mediated dUTP nick end labelling (TUNEL) staining, respectively. Molecules including the mitochondria‐dependent apoptosis factors, matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), PTEN/AKT and mitogen‐activated protein kinases (MAPKs) were determined by Western blot. Neointimal formation was induced by ligation in male Sprague Dawley rats and evaluated by HE staining. Thymoquinone inhibited PDGF‐BB–induced VSMC proliferation and the increase in α‐SMA and Ki‐67‐positive cells. Thymoquinone also induced apoptosis via mitochondria‐dependent apoptosis pathway and p38MAPK. Thymoquinone blocked VSMC migration by inhibiting MMP2. Finally, TQ reversed neointimal formation induced by ligation in rats. Thus, TQ is a potential candidate for the prevention and treatment of occlusive vascular diseases.
Collapse
Affiliation(s)
- Ning Zhu
- Department of Cardiology, The Wenzhou Third Clinical Institute Affiliated To Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Yijia Xiang
- Department of Cardiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, China
| | - Xuyong Zhao
- Department of Cardiology, The Wenzhou Third Clinical Institute Affiliated To Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Changhong Cai
- Department of Cardiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, China
| | - Hao Chen
- Department of Cardiology, The Wenzhou Third Clinical Institute Affiliated To Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Wenbing Jiang
- Department of Cardiology, The Wenzhou Third Clinical Institute Affiliated To Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Yi Wang
- Department of Cardiology, The Wenzhou Third Clinical Institute Affiliated To Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China
| | - Chunlai Zeng
- Department of Cardiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, China
| |
Collapse
|
|
18
|
Glass EB, Masjedi S, Dudzinski SO, Wilson AJ, Duvall CL, Yull FE, Giorgio TD. Optimizing Mannose "Click" Conjugation to Polymeric Nanoparticles for Targeted siRNA Delivery to Human and Murine Macrophages. ACS OMEGA 2019; 4:16756-16767. [PMID: 31646220 PMCID: PMC6796989 DOI: 10.1021/acsomega.9b01465] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/19/2019] [Indexed: 06/09/2023]
Abstract
"Smart", dual pH-responsive, and endosomolytic polymeric nanoparticles have demonstrated great potential for localized drug delivery, especially for siRNA delivery to the cytoplasm of cells. However, targeted delivery to a specific cell phenotype requires an additional level of functionality. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a highly selective bioconjugation reaction that can be performed in conjunction with other polymerization techniques without adversely affecting reaction kinetics, but there exists some concern for residual copper causing cytotoxicity. To alleviate these concerns, we evaluated conjugation efficiency, residual copper content, and cell viability in relation to copper catalyst concentration. Our results demonstrated an optimal range for minimizing cytotoxicity while maintaining high levels of conjugation efficiency, and these conditions produced polymers with increased targeting to M2-polarized macrophages, as well as successful delivery of therapeutic siRNA that reprogrammed the macrophages to a proinflammatory phenotype.
Collapse
Affiliation(s)
- Evan B Glass
- Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, Tennessee 37232, United States
| | - Shirin Masjedi
- Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, Tennessee 37232, United States
| | - Stephanie O Dudzinski
- Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, Tennessee 37232, United States
| | - Andrew J Wilson
- Department of Obstetrics & Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Craig L Duvall
- Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, Tennessee 37232, United States
| | - Fiona E Yull
- Department of Pharmacology and Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37232, United States
- Department of Obstetrics & Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Todd D Giorgio
- Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, Tennessee 37232, United States
- Department of Pharmacology and Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37232, United States
| |
Collapse
|
|
19
|
Krylova NG, Drobysh MS, Semenkova GN, Kulahava TA, Pinchuk SV, Shadyro OI. Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress. Mol Cell Biochem 2019; 462:195-206. [PMID: 31493190 DOI: 10.1007/s11010-019-03622-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 02/23/2019] [Indexed: 01/01/2023]
Abstract
Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood-brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20-50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70-100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.
Collapse
Affiliation(s)
- N G Krylova
- Department of Biophysics, Faculty of Physics, Belarusian State University, 4 Nezavisimosti ave., 220030, Minsk, Belarus
| | - M S Drobysh
- Department of Radiation Chemistry and Pharmaceutical Technologies, Faculty of Chemistry, Belarusian State University, 14 Leningradskaya st., 220030, Minsk, Belarus
| | - G N Semenkova
- Department of Radiation Chemistry and Pharmaceutical Technologies, Faculty of Chemistry, Belarusian State University, 14 Leningradskaya st., 220030, Minsk, Belarus
| | - T A Kulahava
- Department of Biophysics, Faculty of Physics, Belarusian State University, 4 Nezavisimosti ave., 220030, Minsk, Belarus.
| | - S V Pinchuk
- Institute of Biophysics and Cell Engineering of National Academy of Sciences of Belarus, 27 Academicheskaya st., 220072, Minsk, Belarus
| | - O I Shadyro
- Department of Radiation Chemistry and Pharmaceutical Technologies, Faculty of Chemistry, Belarusian State University, 14 Leningradskaya st., 220030, Minsk, Belarus
| |
Collapse
|
|
20
|
Li J, Li K, Gao J, Guo X, Lu M, Li Z, Li D. Maternal exposure to an n-3 polyunsaturated fatty acid diet decreases mammary cancer risk of female offspring in adulthood. Food Funct 2019; 9:5768-5777. [PMID: 30327803 DOI: 10.1039/c8fo01006d] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Maternal exposure to dietary factors during pregnancy influences the risk of many adult-onset diseases in the later life of offspring. Here, we investigated the effects of maternal n-3 polyunsaturated fatty acid (PUFA) diet on breast cancer risk of female offspring. Pregnant C57BL/6J mice were fed a normal diet (control group), or a high-fat diet rich in safflower oil (SO), fish oil (FO) or flaxseed oil (FSO) (n = 10) throughout gestation and lactation. Their female offspring were fed an AIN-93G diet from weaning. Tumor incidences in offspring induced by 7,12-dimethylbenz[α]anthracene (DMBA) were higher in high-fat groups than in the control group, and were lower in FO and FSO groups than in the SO group. The plasma concentrations of 17β-estradiol (E2), in both pregnant dams and offspring, were significantly lower in FO and FSO groups compared with the SO group. The FO and FSO offspring showed delayed puberty onset, and their mammary glands contained decreased numbers of epithelial terminal end buds (TEBs, targets for malignant transformation) compared with SO offspring. Reduced cell proliferation and increased apoptosis in FO and FSO offspring were observed compared with SO offspring. In line with these changes, maternal exposure to FO promoted the expression of long noncoding RNA (lncRNA) in p53 and apoptosis signaling pathways and inhibited that in NF-κB and Jak-STAT signaling pathways, while FSO promoted the expression of lncRNA in p53 signaling pathways and inhibited that in NF-κB, Jak-STAT and MAPK signaling pathways. In conclusion, maternal exposure to a high-fat diet rich in n-3 PUFAs, both marine- and plant-based, has a protective effect on mammary tumor risk of female offspring in later life.
Collapse
Affiliation(s)
- Jiaomei Li
- Department of Food Science and Nutrition, Zhejiang University, Zhejiang, China.
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Chang C, Xi L, Zhang J, Zhao W, Liu Z, Guo J, Xu C. Roles of Cyclin A, Myc, Jun and Ppm1l in tumourigenic transformation of NIH3T3 cell. J Genet 2018; 97:1155-1168. [PMID: 30555065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
To analyse the mechanism of tumourigenic transformation of NIH3T3 cells at the transcriptional level, we used cancerogen 3-methylcholanthrene (3-MCA) and cancerogenic substance phorbol-12-myristate-13-acetate (PMA) to transform NIH3T3 cells and the assessment of transformation was performed using Giemsa staining and methylcellulose colony formation assay. Changes in gene expression profile were detected by Mouse Genome 430 2.0 microarray; and quantitative real-time polymerase chain reaction and Western blotting were used to verify the expression changes of mRNAs and proteins, respectively. With the aid of bioinformatics method, five signalling pathways were identified to participate in different stages of NIH3T3 cell transformation. Further, our study suggested that oncogenes Cyclin A, Myc, Jun and the tumour suppressor gene Ppm1l may play important roles in these pathways.
Collapse
Affiliation(s)
- Cuifang Chang
- State Key Laboratory Cultivation Base for Cell Differentiation Regulation, Henan Normal University, Xinxiang 453007, People's Republic of China.
| | | | | | | | | | | | | |
Collapse
|
|
22
|
|
|
23
|
Kabil N, Bayraktar R, Kahraman N, Mokhlis HA, Calin GA, Lopez-Berestein G, Ozpolat B. Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer. Breast Cancer Res Treat 2018; 171:593-605. [PMID: 29971628 DOI: 10.1007/s10549-018-4847-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 05/30/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND/PURPOSE Triple-negative breast cancer (TNBC) is the most aggressive and chemoresistant subtype of breast cancer. Therefore, new molecular targets and treatments need to be developed to improve poor patient prognosis and survival. We have previously shown that eukaryotic elongation factor 2 kinase (eEF-2K) is highly expressed in TNBC cells, is associated with poor patient survival and prognosis, and promotes cell proliferation, migration, and invasion. In vivo targeting of eEF-2K significantly reduces the tumor growth of orthotopic TNBC xenograft mouse models, suggesting that eEF-2K may serve as a potential novel therapeutic target. METHODS/RESULTS In the current study, we identified thymoquinone (TQ), an active ingredient of Nigella sativa, as a potential safe and effective eEF-2K inhibitor in TNBC. We demonstrated for the first time that TQ inhibits the protein and mRNA expression of eEF-2K, as well as the clinically relevant downstream targets, including Src/FAK and Akt, and induces the tumor suppressor miR-603, in response to NF-kB inhibition. This effect was associated with a significant decrease in the proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, systemic in vivo injection of TQ (20 and 100 mg/kg) significantly reduced the growth of MDA-MB-231 tumors and inhibited the eEF-2K expression in an orthotopic tumor model in mice. CONCLUSION Our study provides first evidence that TQ treatment inhibits cell proliferation, migration/invasion, and tumor growth, in part through the inhibition of eEF-2K signaling in TNBC. Thus, our findings suggest that systemic TQ treatment may be used as a targeted therapeutic strategy for the inhibition of eEF-2K in TNBC tumor growth and progression.
Collapse
Affiliation(s)
- Nashwa Kabil
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA
| | - Recep Bayraktar
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA
| | - Nermin Kahraman
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA
| | - Hamada A Mokhlis
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX, 77030, USA. .,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| |
Collapse
|
|
24
|
Collignon E, Canale A, Al Wardi C, Bizet M, Calonne E, Dedeurwaerder S, Garaud S, Naveaux C, Barham W, Wilson A, Bouchat S, Hubert P, Van Lint C, Yull F, Sotiriou C, Willard-Gallo K, Noel A, Fuks F. Immunity drives TET1 regulation in cancer through NF-κB. SCIENCE ADVANCES 2018; 4:eaap7309. [PMID: 29938218 PMCID: PMC6010319 DOI: 10.1126/sciadv.aap7309] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 05/09/2018] [Indexed: 05/27/2023]
Abstract
Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to TET1 regulation. We further demonstrate that TET1 repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between TET1 expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice, TET1 is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the TET1 promoter. We lastly show that these findings extend to other cancer types, including melanoma, lung, and thyroid cancers. Together, our data suggest a novel mode of regulation for TET1 in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.
Collapse
Affiliation(s)
- Evelyne Collignon
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| | - Annalisa Canale
- Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)–Cancer, University of Liège, Liège, Belgium
| | - Clémence Al Wardi
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| | - Martin Bizet
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| | - Emilie Calonne
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| | - Sarah Dedeurwaerder
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| | - Soizic Garaud
- Molecular Immunology Unit, Institut Jules Bordet, ULB, Brussels, Belgium
| | - Céline Naveaux
- Molecular Immunology Unit, Institut Jules Bordet, ULB, Brussels, Belgium
| | - Whitney Barham
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Andrew Wilson
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Sophie Bouchat
- Service of Molecular Virology, Department of Molecular Biology, U-CRC, ULB, Gosselies, Belgium
| | - Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Carine Van Lint
- Service of Molecular Virology, Department of Molecular Biology, U-CRC, ULB, Gosselies, Belgium
| | - Fiona Yull
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA
| | - Christos Sotiriou
- Breast Cancer Translational Research Laboratory, Jules Bordet Institute, ULB, Brussels, Belgium
| | | | - Agnès Noel
- Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)–Cancer, University of Liège, Liège, Belgium
| | - François Fuks
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)–Cancer Research Center (U-CRC), ULB, Brussels, Belgium
| |
Collapse
|
|
25
|
Ballout F, Habli Z, Rahal ON, Fatfat M, Gali-Muhtasib H. Thymoquinone-based nanotechnology for cancer therapy: promises and challenges. Drug Discov Today 2018; 23:1089-1098. [PMID: 29374534 DOI: 10.1016/j.drudis.2018.01.043] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 12/22/2017] [Accepted: 01/17/2018] [Indexed: 12/17/2022]
Abstract
Thymoquinone (TQ), the active ingredient of black seed, is a promising anticancer molecule that inhibits cancer cell growth and progression in vitro and in vivo. Despite the promising anticancer activities of TQ, its translation to the clinic is limited by its poor bioavailability and hydrophobicity. As such, we and others encapsulated TQ in nanoparticles to improve its delivery and limit undesirable cytotoxicity. These TQ-nanoparticle formulations showed improved anticancer and anti-inflammatory activities when compared with free TQ. Here, we provide an overview of the various TQ-nanoparticle formulations, highlight their superior efficacy and discuss up-to-date solutions to further enhance TQ bioavailability and anticancer activity, thus improving potential for clinical translation.
Collapse
Affiliation(s)
- Farah Ballout
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1103, Lebanon
| | - Zeina Habli
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1103, Lebanon
| | - Omar Nasser Rahal
- School of Medicine, Saba University School of Medicine, Saba, Dutch Caribbean 5016121, The Netherlands
| | - Maamoun Fatfat
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1103, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1103, Lebanon; Department of Biology, Faculty of Arts and Sciences and Center for Drug Discovery, Faculty of Medicine, American University of Beirut, Lebanon.
| |
Collapse
|
|
26
|
Velloso FJ, Bianco AFR, Farias JO, Torres NEC, Ferruzo PYM, Anschau V, Jesus-Ferreira HC, Chang THT, Sogayar MC, Zerbini LF, Correa RG. The crossroads of breast cancer progression: insights into the modulation of major signaling pathways. Onco Targets Ther 2017; 10:5491-5524. [PMID: 29200866 PMCID: PMC5701508 DOI: 10.2147/ott.s142154] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer is the disease with highest public health impact in developed countries. Particularly, breast cancer has the highest incidence in women worldwide and the fifth highest mortality in the globe, imposing a significant social and economic burden to society. The disease has a complex heterogeneous etiology, being associated with several risk factors that range from lifestyle to age and family history. Breast cancer is usually classified according to the site of tumor occurrence and gene expression profiling. Although mutations in a few key genes, such as BRCA1 and BRCA2, are associated with high breast cancer risk, the large majority of breast cancer cases are related to mutated genes of low penetrance, which are frequently altered in the whole population. Therefore, understanding the molecular basis of breast cancer, including the several deregulated genes and related pathways linked to this pathology, is essential to ensure advances in early tumor detection and prevention. In this review, we outline key cellular pathways whose deregulation has been associated with breast cancer, leading to alterations in cell proliferation, apoptosis, and the delicate hormonal balance of breast tissue cells. Therefore, here we describe some potential breast cancer-related nodes and signaling concepts linked to the disease, which can be positively translated into novel therapeutic approaches and predictive biomarkers.
Collapse
Affiliation(s)
| | | | | | | | | | - Valesca Anschau
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | | | - Ted Hung-Tse Chang
- Cancer Genomics Group, International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
| | | | - Luiz F Zerbini
- Cancer Genomics Group, International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
| | - Ricardo G Correa
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| |
Collapse
|
|
27
|
Asaduzzaman Khan M, Tania M, Fu S, Fu J. Thymoquinone, as an anticancer molecule: from basic research to clinical investigation. Oncotarget 2017; 8:51907-51919. [PMID: 28881699 PMCID: PMC5584300 DOI: 10.18632/oncotarget.17206] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/05/2017] [Indexed: 02/07/2023] Open
Abstract
Thymoquinone is an anticancer phytochemical commonly found in black cumin. In this review, we discuss the potential of thymoquinone as anticancer molecule, its mechanism of action and future usage in clinical applications. Thymoquinone exhibits anticancer activity via numerous mechanisms of action, specifically by showing selective antioxidant and oxidant activity, interfering with DNA structure, affecting carcinogenic signaling molecules/pathways and immunomodulation. In vitro activity of thymoquinone has been further implicated in animal models of cancer; however, no clinical application has been proven yet. This is the optimum time to focus on clinical trials for developing thymoquinone as a future drug in cancer therapeutics.
Collapse
Affiliation(s)
- Md. Asaduzzaman Khan
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
- Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Mousumi Tania
- Division of Computer Aided Drug Design, The Red-Green Computing Centre, Dhaka, Bangladesh
| | - Shangyi Fu
- The Honors College, University of Houston, Houston, Texas, United States
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
| |
Collapse
|
|
28
|
Cheng MH, Wong YH, Chang CM, Yang CC, Chen SH, Yuan CL, Kuo HM, Yang CY, Chiu HF. B1, a novel HDAC inhibitor, induces apoptosis through the regulation of STAT3 and NF-κB. Int J Mol Med 2017; 39:1137-1148. [PMID: 28393178 PMCID: PMC5403210 DOI: 10.3892/ijmm.2017.2946] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 03/27/2017] [Indexed: 12/21/2022] Open
Abstract
We previously demonstrated that B1 induced significant cytotoxic effects, cell cycle G1 arrest and apoptosis in human lung cancer A549 cells through the inhibition of DNA topoisomerase II activity. In the present study, we focused on the histone deacetylase (HDAC) modulation of B1 in A549 cells. HDACs, important enzymes affecting epigenetic regulation, play a crucial role in human carcinogenesis. Our findings showed that B1 could suppress the growth of A549 cells in vitro through the inhibition of HDAC activity. Additionally, B1 caused disruption of the mitochondrial membrane potential and induced DNA double-strand breaks (DSBs) in a dose- and time-dependent manner, which consequently led to cell apoptosis. We also observed that B1 inhibited cancer cell migration and angiogenesis-related signal expression, including vascular endothelial growth factor (VEGF) and pro-matrix metalloproteinases-2 and -9 (pro-MMP-2/9). Gelatin zymography suggested that B1 decreased pro-MMP-2 and pro-MMP-9 activity. Transcription factors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB), are vital players in the many steps of carcinogenesis. B1 showed significant dose-response inhibitory effects on cytoplasmic expression and nuclear translocation of both phosphorylated STAT3 (pSTAT3) and NF-κB. It has been well documented that reactivated telomerase confers cancer cells the ability to repair DNA. Real-time PCR results indicated that B1 inhibited STAT3 and NF-κB mRNA expression and telomerase activity. Taken together, our results demonstrated that B1 exerted significant inhibitory effects on HDAC, telomerase activities, oncogenic STAT3 and NF-κB expression. The inhibition of the intricate crosstalk between STAT3 and NF-κB may be a major factor in the molecular action mechanism of B1. The multiple targeting effects of B1 render it a potential new drug for lung cancer therapy.
Collapse
Affiliation(s)
- Meng-Hsuan Cheng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan, R.O.C
| | - Yun-Hong Wong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Chia-Ming Chang
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Chun-Chien Yang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Shih-Hua Chen
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Chun-Lung Yuan
- Department of Chemistry, Republic of China Military Academy, Fengshan, Kaohsiung 83059, Taiwan, R.O.C
| | - Hsiao-Mei Kuo
- Department of Neuroscience, Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, R.O.C
| | - Chun-Yuh Yang
- Faculty of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| | - Hui-Fen Chiu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C
| |
Collapse
|
|
29
|
Wang M, Zhang C, Song Y, Wang Z, Wang Y, Luo F, Xu Y, Zhao Y, Wu Z, Xu Y. Mechanism of immune evasion in breast cancer. Onco Targets Ther 2017; 10:1561-1573. [PMID: 28352189 PMCID: PMC5359138 DOI: 10.2147/ott.s126424] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.
Collapse
Affiliation(s)
| | - Changwang Zhang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | | | | | | | - Yi Zhao
- Department of Breast Surgery
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
| | | |
Collapse
|
|
30
|
Forcados GE, James DB, Sallau AB, Muhammad A, Mabeta P. Oxidative Stress and Carcinogenesis: Potential of Phytochemicals in Breast Cancer Therapy. Nutr Cancer 2017; 69:365-374. [PMID: 28103111 DOI: 10.1080/01635581.2017.1267777] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Breast cancer remains a burden in both developed and developing countries, with higher mortality in developing countries. Attempts to eradicate cancer have not been successful despite the progress made in the development of more novel chemotherapeutic drugs. Reactive-oxygen-species-mediated oxidative stress is known to play a role in breast cancer pathogenesis via genetic and epigenetic modifications, resulting in uncontrolled cell proliferation. Phytochemicals could provide leads for the development of alternative therapeutic agents due to their antioxidant activity, as well as their ability to induce apoptosis in cancer cells. However, most of the studies carried out using in vitro models do not continue with further studies in estrogen-receptor-positive in vivo breast cancer models, or fail to examine the possible biochemical mechanisms of phytochemical-based amelioration. This review examines oxidative-stress-mediated carcinogenesis and the potential of phytochemicals as anticancer agents.
Collapse
Affiliation(s)
- Gilead Ebiegberi Forcados
- a Division of Biochemistry , National Veterinary Research Institute , Vom , Nigeria.,b Department of Biochemistry , Faculty of Science, Ahmadu Bello University , Zaria , Nigeria.,c Department of Anatomy and Physiology , Faculty of Veterinary Sciences, University of Pretoria , Pretoria , South Africa
| | - Dorcas Bolanle James
- b Department of Biochemistry , Faculty of Science, Ahmadu Bello University , Zaria , Nigeria
| | | | - Aliyu Muhammad
- b Department of Biochemistry , Faculty of Science, Ahmadu Bello University , Zaria , Nigeria
| | - Peace Mabeta
- c Department of Anatomy and Physiology , Faculty of Veterinary Sciences, University of Pretoria , Pretoria , South Africa
| |
Collapse
|
|
31
|
Zhu WQ, Wang J, Guo XF, Liu Z, Dong WG. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J Gastroenterol 2016; 22:4149-4159. [PMID: 27122665 PMCID: PMC4837432 DOI: 10.3748/wjg.v22.i16.4149] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 02/26/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the mechanism of thymoquinone (TQ)-induced apoptosis in human gastric cancer cells in vitro and in vivo.
METHODS: HGC27, BGC823, and SGC7901 cells were cultured in vitro and treated with TQ (0, 10, 25, 50, 75, 100, 125 μmol/L) for 12 h, 24 h, and 36 h, and then the proliferation inhibitory rates were detected by methylthiazole tetrazolium assay. Apoptosis was observed after Hoechst staining. The protein expressions of signal transducer and activator of transcription (STAT)3, p-STAT3, STAT5, p-STAT5, phospho-janus-activated kinase 2 (JAK2), JAK2, p-Src, Src, glyceraldehyde-3-phosphate dehydrogenase, lamin-A, survivin, Cyclin D, Bcl-2, Bax, peroxisome proliferator activated receptor, and caspase-3,7,9 were detected by western blot. Cell cycle and apoptosis were determined with flow cytometry. TQ induced dose-dependent apoptotic cell death in HGC27 cells was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) analysis and Hoechst 33258.
RESULTS: TQ inhibited the phosphorylation of STAT3 but not STAT5. TQ-induced downregulation of STAT3 activation was associated with a reduction in JAK2 and c-Src activity. TQ also downregulated the expression of STAT3-regulated genes, such as Bcl-2, cyclin D, survivin, and vascular endothelial growth factor, and activated caspase-3,7,9. Consistent with the in vitro results, TQ was significantly effective as an antitumor agent in a xenograft tumor mouse model.
CONCLUSION: This study provides strong evidence that downregulation of the STAT3 signaling pathway mediates TQ-induced apoptosis in gastric cancer.
Collapse
|
|
32
|
Jiang WG, Sanders AJ, Katoh M, Ungefroren H, Gieseler F, Prince M, Thompson SK, Zollo M, Spano D, Dhawan P, Sliva D, Subbarayan PR, Sarkar M, Honoki K, Fujii H, Georgakilas AG, Amedei A, Niccolai E, Amin A, Ashraf SS, Ye L, Helferich WG, Yang X, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Azmi AS, Keith WN, Bilsland A, Bhakta D, Halicka D, Nowsheen S, Pantano F, Santini D. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin Cancer Biol 2015; 35 Suppl:S244-S275. [PMID: 25865774 DOI: 10.1016/j.semcancer.2015.03.008] [Citation(s) in RCA: 351] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 03/17/2015] [Accepted: 03/18/2015] [Indexed: 12/12/2022]
Abstract
Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.
Collapse
Affiliation(s)
- W G Jiang
- Cardiff University, Cardiff, United Kingdom.
| | | | - M Katoh
- National Cancer Center, Tokyo, Japan
| | - H Ungefroren
- University Hospital Schleswig-Holstein, Lübeck, Germany
| | - F Gieseler
- University Hospital Schleswig-Holstein, Lübeck, Germany
| | - M Prince
- University of Michigan, Ann Arbor, MI, USA
| | | | - M Zollo
- Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples Federico II, Naples, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy
| | - D Spano
- CEINGE Biotecnologie Avanzate, Naples, Italy
| | - P Dhawan
- University of Nebraska Medical Center, Omaha, USA
| | - D Sliva
- Purdue Research Park, Indianapolis, IN, USA
| | | | - M Sarkar
- University of Miami, Miami, FL, USA
| | - K Honoki
- Nara Medical University, Kashihara, Japan
| | - H Fujii
- Nara Medical University, Kashihara, Japan
| | - A G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Athens, Greece
| | - A Amedei
- University of Florence, Florence, Italy
| | | | - A Amin
- United Arab Emirates University, Al Ain, United Arab Emirates and Faculty of Science, Cairo University, Egypt
| | - S S Ashraf
- United Arab Emirates University, Al Ain, United Arab Emirates and Faculty of Science, Cairo University, Egypt
| | - L Ye
- Cardiff University, Cardiff, United Kingdom
| | - W G Helferich
- University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - X Yang
- University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | | | - G Guha
- SASTRA University, Thanjavur, India
| | | | - K Aquilano
- University of Rome Tor Vergata, Rome, Italy
| | - S Chen
- Ovarian and Prostate Cancer Research Trust Laboratory, Surrey, United Kingdom
| | - A S Azmi
- Wayne State University, Detroit, MI, USA
| | - W N Keith
- University of Glasgow, Glasgow, United Kingdom
| | - A Bilsland
- University of Glasgow, Glasgow, United Kingdom
| | - D Bhakta
- SASTRA University, Thanjavur, India
| | - D Halicka
- New York Medical College, Valhalla, NY, USA
| | - S Nowsheen
- Mayo Clinic College of Medicine, Rochester, MN, USA
| | - F Pantano
- University Campus Bio-Medico, Rome, Italy
| | - D Santini
- University Campus Bio-Medico, Rome, Italy
| |
Collapse
|
|
33
|
Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, Azmi AS, Lokeshwar BL, Grue B, Panis C, Boosani CS, Poudyal D, Stafforini DM, Bhakta D, Niccolai E, Guha G, Vasantha Rupasinghe HP, Fujii H, Honoki K, Mehta K, Aquilano K, Lowe L, Hofseth LJ, Ricciardiello L, Ciriolo MR, Singh N, Whelan RL, Chaturvedi R, Ashraf SS, Shantha Kumara HMC, Nowsheen S, Mohammed SI, Keith WN, Helferich WG, Yang X. A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol 2015; 35 Suppl:S151-S184. [PMID: 25951989 PMCID: PMC4635070 DOI: 10.1016/j.semcancer.2015.03.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 03/13/2015] [Accepted: 03/16/2015] [Indexed: 12/15/2022]
Abstract
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
Collapse
Affiliation(s)
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates; Faculty of Science, Cairo University, Cairo, Egypt
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL, United States
| | - Asfar S Azmi
- Department of Pathology, Wayne State Univeristy, Karmanos Cancer Center, Detroit, MI, USA
| | - Bal L Lokeshwar
- Department of Urology, University of Miami, Miller School of Medicine, Miami, FL, United States; Miami Veterans Administration Medical Center, Miami, FL, United States
| | - Brendan Grue
- Department of Environmental Science, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Carolina Panis
- Laboratory of Inflammatory Mediators, State University of West Paraná, UNIOESTE, Paraná, Brazil
| | - Chandra S Boosani
- Department of BioMedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Deepak Poudyal
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, United States
| | - Diana M Stafforini
- Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Dipita Bhakta
- School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | | | - Gunjan Guha
- School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - H P Vasantha Rupasinghe
- Department of Environmental Sciences, Faculty of Agriculture and Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Kapil Mehta
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Leroy Lowe
- Getting to Know Cancer, Truro, Nova Scotia, Canada.
| | - Lorne J Hofseth
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, United States
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Richard L Whelan
- Department of Surgery, St. Luke's Roosevelt Hospital, New York, NY, United States
| | - Rupesh Chaturvedi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - S Salman Ashraf
- Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - H M C Shantha Kumara
- Department of Surgery, St. Luke's Roosevelt Hospital, New York, NY, United States
| | - Somaira Nowsheen
- Medical Scientist Training Program, Mayo Graduate School, Mayo Medical School, Mayo Clinic, Rochester, MN, United States
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
| | | | - Xujuan Yang
- University of Illinois at Urbana Champaign, Champaign, IL, United States
| |
Collapse
|
|
34
|
Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways. Biochem Biophys Rep 2015; 4:397-404. [PMID: 29124230 PMCID: PMC5669446 DOI: 10.1016/j.bbrep.2015.11.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 10/30/2015] [Accepted: 11/04/2015] [Indexed: 01/03/2023] Open
Abstract
Recent reports have shown that antibiotics such as macrolide, aminoglycoside, and tetracyclines have immunomodulatory effects in addition to essential antibiotic effects. These agents may have important effects on the regulation of cytokine and chemokine production. However, the precise mechanism is unknown. This time, we used Multi Plex to measure the production of cytokines and chemokines following tetracycline treatment of lipopolysaccharide (LPS)-induced THP-1 cells. The signaling pathways were investigated with Western blotting analysis. Three tetracyclines significantly suppressed the expression of cytokines and chemokines induced by LPS. Minocycline (50 μg/ml), tigecycline (50 μg/ml), or doxycycline (50 μg/ml) were added after treatment with LPS (10 μg/ml). Tumor necrosis factor-α was downregulated to 16%, 14%, and 8%, respectively, after 60 min compared to treatment with LPS without agents. Interleukin-8 was downregulated to 43%, 32%, and 26% at 60 min. Macrophage inflammatory protein (MIP)-1α was downregulated to 23%, 33%, and 16% at 120 min. MIP-1β was downregulated to 21%, 11%, and 2% at 120 min. Concerning about signaling pathways, the mechanisms of the three tetracyclines might not be the same. Although the three tetracyclines showed some differences in the time course, tetracyclines modulated phosphorylation of the NF-κB pathway, p38 and ERK1/2/MAPK pathways, resulting in inhibition of cytokine and chemokine production. In addition, SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly suppressed the expression of TNF-α and IL-8 in LPS-stimulated THP-1 cells. And further, the NF-κB inhibitor, BAY11-7082, almost completely suppressed LPS-induced these two cytokines production. Thus, more than one signaling pathway may be involved in tetracyclines downregulation of the expression of LPS-induced cytokines and chemokines in THP-1 cells. And among the three signaling pathways, NF-κB pathway might be the dominant pathway on tetracyclines modification the LPS-induced cytokines production in THP-1 cells. In general, minocycline and doxycycline suppressed the production of cytokines and chemokines in LPS-stimulated THP-1 cell lines via mainly the inhibition of phosphorylation of NF-κB pathways. Tigecycline has the same structure as the other tetracyclines, however, it showed the different properties of cytokine modulation in the experimental time course.
Collapse
|
|
35
|
The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer. Tumour Biol 2015; 37:4467-77. [PMID: 26500095 DOI: 10.1007/s13277-015-4307-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
Thymoquinone (TQ) is the active ingredient of Nigella sativa which has a therapeutic potential in cancer therapy and prevention. In this study, TQ has been shown to induce specific cytotoxicity and apoptosis and to inhibit wound healing in triple-negative breast cancer cell line. TQ also inhibited cancer growth in a mouse tumor model. Moreover, TQ and paclitaxel (Pac) combination inhibited cancer growth in cell culture and in mice. Genes involved in TQ and TQ-Pac-mediated cytotoxicity were studied using focused real-time PCR arrays. After bioinformatic analysis, genes in apoptosis, cytokine, and p53 signaling categories were found to be modulated with a high significance in TQ-treated cells (p < 10(-28), p < 10(-8), and p < 10(-6), respectively). Important to note, TQ has been found to regulate the genes involved in the induction of apoptosis through death receptors (p = 5.5 × 10(-5)). Additionally, tumor suppressor genes such as p21, Brca1, and Hic1 were highly upregulated by TQ and TQ-Pac combination. Interestingly, when cells were treated with high dose TQ, several growth factors such as Vegf and Egf were upregulated and several pro-apoptotic factors such as caspases were downregulated possibly pointing out key pathways manipulated by cancer cells to resist against TQ. In cells treated with the combination of TQ and Pac, genes in apoptosis cascade (p < 10(-12)), p53 signaling (p = 10(-5)), and JAK-STAT signaling (p < 10(-3)) were differentially expressed. TQ has also been shown to induce protein levels of cleaved Caspase-3, Caspase-7, and Caspase-12 and PARP and to reduce phosphorylated p65 and Akt1. The in vivo therapeutic potential of TQ-Pac combination and the genetic network involved in this synergy have been shown for the first time to the best of our knowledge.
Collapse
|
|
36
|
Barham W, Chen L, Tikhomirov O, Onishko H, Gleaves L, Stricker TP, Blackwell TS, Yull FE. Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ. BMC Cancer 2015; 15:647. [PMID: 26424146 PMCID: PMC4590702 DOI: 10.1186/s12885-015-1652-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 09/15/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions. METHODS Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium. RESULTS We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue. CONCLUSIONS These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.
Collapse
Affiliation(s)
- Whitney Barham
- Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA.
| | - Lianyi Chen
- Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA.
| | - Oleg Tikhomirov
- Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA.
| | - Halina Onishko
- Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA.
| | - Linda Gleaves
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA.
| | - Thomas P Stricker
- Department of Pathology, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA.
| | - Timothy S Blackwell
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA. .,Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, Nashville, TN, 37232, USA.
| | - Fiona E Yull
- Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. .,Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, Nashville, TN, 37232, USA.
| |
Collapse
|
|
37
|
Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer. J Ovarian Res 2015. [PMID: 26215403 PMCID: PMC4517540 DOI: 10.1186/s13048-015-0177-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Ovarian cancer is the most lethal gynecologic malignancy characterized by the frequent development of resistance to platinum chemotherapy. Finding new drug combinations to overcome platinum resistance is a key clinical challenge. Thymoquinone (TQ) is a component of black seed oil that exerts multiple anti-tumorigenic effects on cells, including inhibition of NF-κB and promotion of DNA damage. We aimed to determine whether TQ enhances cisplatin cytotoxicity in cultured ovarian cancer cells and in an established murine syngeneic model of ovarian cancer. METHODS Ovarian cancer cell viability in vitro was measured by sulforhodamine B (SRB) assays, and drug interactions tested for synergism by isobologram analysis. ID8-NGL mouse ovarian cancer cells stably expressing an NF-κB reporter transgene were injected intra-peritoneally into C57BL/6 mice. After 30 day TQ and/or cisplatin treatment, we measured the following indices: tumor burden (ascites volume, number of peritoneal implants and mesenteric tumor mass); NF-κB reporter activity (luciferase assay); protein expression of the double-strand DNA break marker, pH2AX(ser139), the proliferation markers, Ki67/mib-1 and PCNA, and the apoptosis markers, cleaved caspase-3, cleaved PARP and Bax; and mRNA expression of NF-κB targets, TNF-α and IL-1β. Two-tailed Mann-Whitney tests were used for measuring differences between groups in mouse experiments. RESULTS In SRB assays, TQ and cisplatin synergized in ID8-NGL cells. In mice, cisplatin significantly reduced cell proliferation and increased apoptosis in tumors, resulting in decreased overall tumor burden. Combining TQ with cisplatin further decreased these indices, indicating co-operative effects between the drugs. TQ treatment promoted cisplatin-induced pH2AX expression in cultured cells and in tumors. While NF-κB inhibition by TQ induced anti-tumor effects in vitro, we made the unexpected observation that TQ alone increased both tumor NF-κB activity and formation of ascites in vivo. CONCLUSIONS TQ enhanced cisplatin-mediated cytoxicity in ovarian cancer cells in vitro and in a mouse syngeneic model, effects associated with increased DNA damage. However, our results strongly caution that TQ treatment alone may have an overall deleterious effect in the immunocompetent host through stimulation of ascites. Since TQ is a potential candidate for future clinical trials in ovarian cancer patients, this finding has considerable potential relevance to the clinic.
Collapse
|
|
38
|
Qu Y, Qu B, Wang X, Wu R, Zhang X. Knockdown of NF-κB p65 subunit expression suppresses growth of nude mouse lung tumour cell xenografts by inhibition of Bcl-2 apoptotic pathway. Cell Biochem Funct 2015; 33:320-5. [PMID: 26178579 DOI: 10.1002/cbf.3117] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 04/20/2015] [Accepted: 04/21/2015] [Indexed: 01/22/2023]
Affiliation(s)
- Yun Qu
- Department of Oncology; Shengjing Hospital of China Medical University; Shenyang China
| | - Bo Qu
- Department of Ophthalmology; The 4th Affiliated Hospital of China Medical University; Shenyang China
| | - Xiaofang Wang
- Hospice Ward; Shengjing Hospital of China Medical University; Shenyang China
| | - Rong Wu
- Department of Oncology; Shengjing Hospital of China Medical University; Shenyang China
| | - Xiaoye Zhang
- Department of Oncology; Shengjing Hospital of China Medical University; Shenyang China
| |
Collapse
|
|
39
|
Zaragozá R, García-Trevijano ER, Lluch A, Ribas G, Viña JR. Involvement of Different networks in mammary gland involution after the pregnancy/lactation cycle: Implications in breast cancer. IUBMB Life 2015; 67:227-38. [PMID: 25904072 DOI: 10.1002/iub.1365] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 02/03/2015] [Indexed: 11/06/2022]
Abstract
Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may yield novel therapeutic targets or prognostic markers for breast cancer.
Collapse
Affiliation(s)
- Rosa Zaragozá
- Instituto INCLIVA, Facultad de Medicina/Hospital Clínico, Universidad de Valencia, Valencia, Spain
| | - Elena R García-Trevijano
- Instituto INCLIVA, Facultad de Medicina/Hospital Clínico, Universidad de Valencia, Valencia, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Ana Lluch
- Instituto INCLIVA, Facultad de Medicina/Hospital Clínico, Universidad de Valencia, Valencia, Spain.,Servicio Oncología Médica, Hospital Clínico Universitario Valencia, Valencia, Spain
| | - Gloria Ribas
- Instituto INCLIVA, Facultad de Medicina/Hospital Clínico, Universidad de Valencia, Valencia, Spain.,Servicio Oncología Médica, Hospital Clínico Universitario Valencia, Valencia, Spain
| | - Juan R Viña
- Instituto INCLIVA, Facultad de Medicina/Hospital Clínico, Universidad de Valencia, Valencia, Spain.,Servicio Oncología Médica, Hospital Clínico Universitario Valencia, Valencia, Spain
| |
Collapse
|
|
40
|
Abstract
The nuclear factor kappa B (NF-κB) signalling pathway exhibits both tumour-promoting and tumour-suppressing functions in different tissues and models of carcinogenesis. In particular in epidermal keratinocytes, NF-κB signalling was reported to exert primarily growth inhibitory and tumour-suppressing functions. Here, we show that mice with keratinocyte-restricted p65/RelA deficiency were resistant to 7, 12-dimethylbenz(a)anthracene (DMBA)-/12-O-tetra decanoylphorbol-13 acetate (TPA)-induced skin carcinogenesis. p65 deficiency sensitized epidermal keratinocytes to DNA damage-induced death in vivo and in vitro, suggesting that inhibition of p65-dependent prosurvival functions prevented tumour initiation by facilitating the elimination of cells carrying damaged DNA. In addition, lack of p65 strongly inhibited TPA-induced epidermal hyperplasia and skin inflammation by suppressing the expression of proinflammatory cytokines and chemokines by epidermal keratinocytes. Therefore, p65-dependent NF-κB signalling in keratinocytes promotes DMBA-/TPA-induced skin carcinogenesis by protecting keratinocytes from DNA damage-induced death and facilitating the establishment of a tumour-nurturing proinflammatory microenvironment.
Collapse
Affiliation(s)
- Chun Kim
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Manolis Pasparakis
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Centre for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| |
Collapse
|
|
41
|
Hilakivi-Clarke L. Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. Breast Cancer Res 2015; 16:208. [PMID: 25032259 PMCID: PMC4053091 DOI: 10.1186/bcr3649] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.
Collapse
|
|
42
|
Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. J Interferon Cytokine Res 2015; 35:1-16. [PMID: 25068787 PMCID: PMC4291218 DOI: 10.1089/jir.2014.0026] [Citation(s) in RCA: 337] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 05/23/2014] [Indexed: 12/12/2022] Open
Abstract
Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped into several protein families that are referred to as tumor necrosis factors, interleukins, interferons, and colony-stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis, and metastasis, all phenomena in which cytokines are prominent players. The data here suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer-related disorders.
Collapse
Affiliation(s)
- Marcela Esquivel-Velázquez
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | - Pedro Ostoa-Saloma
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| | | | - Karen E. Nava-Castro
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, SSA, Cuernavaca, Morelos, México
| | - Julieta Ivonne Castro
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, SSA, Cuernavaca, Morelos, México
| | - Jorge Morales-Montor
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México City, México
| |
Collapse
|
|
43
|
Buckman LB, Thompson MM, Lippert RN, Blackwell TS, Yull FE, Ellacott KLJ. Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol Metab 2014; 4:58-63. [PMID: 25685690 PMCID: PMC4314532 DOI: 10.1016/j.molmet.2014.10.001] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 10/09/2014] [Accepted: 10/10/2014] [Indexed: 11/23/2022] Open
Abstract
Objective Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of these cells in the homeostatic response to the diet. The objective of this study was to determine physiologic role of astrocytes in the acute homeostatic response to high-fat feeding. Methods We bred a transgenic mouse model with doxycycline-inducible inhibition of NFkappaB (NFκB) signaling in astrocytes to determine the effect of loss of NFκB-mediated astrocyte activation on acute high-fat hyperphagia. ELISA was used to measure the levels of markers of astrocyte activation, glial-fibrillary acidic protein (GFAP) and S100B, in the medial basal hypothalamus. Results Inhibition of NFκB signaling in astrocytes prevented acute high-fat diet-induced astrocyte activation and resulted in a 15% increase in caloric intake (P < 0.01) in the first 24 h after introduction of the diet. Conclusions These data reveal a novel homeostatic role for astrocytes in the acute physiologic regulation of food intake in response to high-fat feeding.
Collapse
Affiliation(s)
- Laura B Buckman
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, 2213 Garland Ave, Nashville, TN 37232, USA
| | - Misty M Thompson
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, 2213 Garland Ave, Nashville, TN 37232, USA
| | - Rachel N Lippert
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, 2213 Garland Ave, Nashville, TN 37232, USA
| | - Timothy S Blackwell
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, 1161 21st Ave. South, Suite T-1217 MCN, Nashville, TN 37232, USA
| | - Fiona E Yull
- Department of Cancer Biology, Vanderbilt University Medical Center, 691 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232, USA
| | - Kate L J Ellacott
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 702 Light Hall, 2213 Garland Ave, Nashville, TN 37232, USA
| |
Collapse
|
|
44
|
Yeh ES, Vernon-Grey A, Martin H, Chodosh LA. Tetracycline-regulated mouse models of cancer. Cold Spring Harb Protoc 2014; 2014:pdb.top069823. [PMID: 25275112 DOI: 10.1101/pdb.top069823] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Genetically engineered mouse models (GEMMs) have proven essential to the study of mammalian gene function in both development and disease. However, traditional constitutive transgenic mouse model systems are limited by the temporal and spatial characteristics of the experimental promoter used to drive transgene expression. To address this limitation, considerable effort has been dedicated to developing conditional and inducible mouse model systems. Although a number of approaches to generating inducible GEMMs have been pursued, several have been restricted by toxic or undesired physiological side effects of the compounds used to activate gene expression. The development of tetracycline (tet)-dependent regulatory systems has allowed for circumvention of these issues resulting in the widespread adoption of these systems as an invaluable tool for modeling the complex nature of cancer progression.
Collapse
Affiliation(s)
- Elizabeth S Yeh
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
| | - Ann Vernon-Grey
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
| | - Heather Martin
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
| | - Lewis A Chodosh
- Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
| |
Collapse
|
|
45
|
Abstract
The microenvironment of cells controls their phenotype, and thereby the architecture of the emerging multicellular structure or tissue. We have reported more than a dozen microenvironmental factors whose signaling must be integrated in order to effect an organized, functional tissue morphology. However, the factors that prevent integration of signaling pathways that merge form and function are still largely unknown. We have identified nuclear factor kappa B (NFkB) as a transcriptional regulator that disrupts important microenvironmental cues necessary for tissue organization. We compared the gene expression of organized and disorganized epithelial cells of the HMT-3522 breast cancer progression series: the non-malignant S1 cells that form polarized spheres (‘acini’), the malignant T4-2 cells that form large tumor-like clusters, and the ‘phenotypically reverted’ T4-2 cells that polarize as a result of correction of the microenvironmental signaling. We identified 180 genes that display an increased expression in disorganized compared to polarized structures. Network, GSEA and transcription factor binding site analyses suggested that NFkB is a common activator for the 180 genes. NFkB was found to be activated in disorganized breast cancer cells, and inhibition of microenvironmental signaling via EGFR, beta1 integrin, MMPs, or their downstream signals suppressed its activation. The postulated role of NFkB was experimentally verified: Blocking the NFkB pathway with a specific chemical inhibitor or shRNA induced polarization and inhibited invasion of breast cancer cells in 3D cultures. These results may explain why NFkB holds promise as a target for therapeutic intervention: Its inhibition can reverse the oncogenic signaling involved in breast cancer progression and integrate the essential microenvironmental control of tissue architecture.
Collapse
|
|
46
|
Abukhader MM. Thymoquinone in the clinical treatment of cancer: Fact or fiction? Pharmacogn Rev 2014; 7:117-20. [PMID: 24347919 PMCID: PMC3841989 DOI: 10.4103/0973-7847.120509] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 04/05/2013] [Accepted: 10/25/2013] [Indexed: 01/19/2023] Open
Abstract
Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment.
Collapse
Affiliation(s)
- Majed M Abukhader
- Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman
| |
Collapse
|
|
47
|
Kundu J, Chun KS, Aruoma OI, Kundu JK. Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone. Mutat Res 2014; 768:22-34. [PMID: 25847385 DOI: 10.1016/j.mrfmmm.2014.05.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 05/20/2014] [Indexed: 01/16/2023]
Abstract
The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.
Collapse
Affiliation(s)
- Juthika Kundu
- College of Pharmacy, Keimyung University, Daegu 704 701, Republic of Korea
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu 704 701, Republic of Korea
| | - Okezie I Aruoma
- School of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755, USA.
| | - Joydeb Kumar Kundu
- College of Pharmacy, Keimyung University, Daegu 704 701, Republic of Korea.
| |
Collapse
|
|
48
|
Ulasli SS, Celik S, Gunay E, Ozdemir M, Hazman O, Ozyurek A, Koyuncu T, Unlu M. Anticancer Effects of Thymoquinone, Caffeic Acid Phenethyl Ester and Resveratrol on A549 Non-small Cell Lung Cancer Cells Exposed to Benzo(a)pyrene. Asian Pac J Cancer Prev 2013; 14:6159-64. [DOI: 10.7314/apjcp.2013.14.10.6159] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
|
|
49
|
Pronounced transcriptional regulation of apoptotic and TNF–NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells. Mol Cell Biochem 2013; 383:243-51. [DOI: 10.1007/s11010-013-1772-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 08/02/2013] [Indexed: 01/26/2023]
|
|
50
|
Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women. PLoS One 2013; 8:e63204. [PMID: 23704896 PMCID: PMC3660335 DOI: 10.1371/journal.pone.0063204] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 04/02/2013] [Indexed: 12/21/2022] Open
Abstract
Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.
Collapse
|