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1
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M Ezzat S, M Merghany R, M Abdel Baki P, Ali Abdelrahim N, M Osman S, A Salem M, Peña-Corona SI, Cortés H, Kiyekbayeva L, Leyva-Gómez G, Sharifi-Rad J, Calina D. Nutritional Sources and Anticancer Potential of Phenethyl Isothiocyanate: Molecular Mechanisms and Therapeutic Insights. Mol Nutr Food Res 2024; 68:e2400063. [PMID: 38600885 DOI: 10.1002/mnfr.202400063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Indexed: 04/12/2024]
Abstract
Phenethyl isothiocyanate (PEITC), a compound derived from cruciferous vegetables, has garnered attention for its anticancer properties. This review synthesizes existing research on PEITC, focusing on its mechanisms of action in combatting cancer. PEITC has been found to be effective against various cancer types, such as breast, prostate, lung, colon, and pancreatic cancers. Its anticancer activities are mediated through several mechanisms, including the induction of apoptosis (programmed cell death), inhibition of cell proliferation, suppression of angiogenesis (formation of new blood vessels that feed tumors), and reduction of metastasis (spread of cancer cells to new areas). PEITC targets crucial cellular signaling pathways involved in cancer progression, notably the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), Protein Kinase B (Akt), and Mitogen-Activated Protein Kinase (MAPK) pathways. These findings suggest PEITC's potential as a therapeutic agent against cancer. However, further research is necessary to determine the optimal dosage, understand its bioavailability, and assess potential side effects. This will be crucial for developing PEITC-based treatments that are both effective and safe for clinical use in cancer therapy.
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Affiliation(s)
- Shahira M Ezzat
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Rana M Merghany
- Pharmacognosy Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), 33 El-Bohouth Street, Dokki, Giza, Egypt
| | - Passent M Abdel Baki
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt
| | - Nariman Ali Abdelrahim
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Sohaila M Osman
- Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Mohamed A Salem
- Department of Pharmacognosy and Natural Products, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr St., Shibin El Kom, Menoufia, 32511, Egypt
| | - Sheila I Peña-Corona
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México, Mexico
| | - Lashyn Kiyekbayeva
- Department of Pharmaceutical Technology, Pharmaceutical School, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania
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Hoch CC, Shoykhet M, Weiser T, Griesbaum L, Petry J, Hachani K, Multhoff G, Bashiri Dezfouli A, Wollenberg B. Isothiocyanates in medicine: A comprehensive review on phenylethyl-, allyl-, and benzyl-isothiocyanates. Pharmacol Res 2024; 201:107107. [PMID: 38354869 DOI: 10.1016/j.phrs.2024.107107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 02/05/2024] [Accepted: 02/10/2024] [Indexed: 02/16/2024]
Abstract
In recent years, isothiocyanates (ITCs), bioactive compounds primarily derived from Brassicaceae vegetables and herbs, have gained significant attention within the biomedical field due to their versatile biological effects. This comprehensive review provides an in-depth exploration of the therapeutic potential and individual biological mechanisms of the three specific ITCs phenylethyl isothiocyanate (PEITC), allyl isothiocyanate (AITC), and benzyl isothiocyanate (BITC), as well as their collective impact within the formulation of ANGOCIN® Anti-Infekt N (Angocin). Angocin comprises horseradish root (Armoracia rusticanae radix, 80 mg) and nasturtium (Tropaeoli majoris herba, 200 mg) and is authorized for treating inflammatory diseases affecting the respiratory and urinary tract. The antimicrobial efficacy of this substance has been confirmed both in vitro and in various clinical trials, with its primary effectiveness attributed to ITCs. PEITC, AITC, and BITC exhibit a wide array of health benefits, including potent anti-inflammatory, antioxidant, and antimicrobial properties, along with noteworthy anticancer potentials. Moreover, we highlight their ability to modulate critical biochemical pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription (STAT) pathways, shedding light on their involvement in cellular apoptosis and their intricate role to guide immune responses.
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Affiliation(s)
- Cosima C Hoch
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Maria Shoykhet
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Tobias Weiser
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Lena Griesbaum
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Julie Petry
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany
| | - Khouloud Hachani
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany; Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Gabriele Multhoff
- Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Ali Bashiri Dezfouli
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany; Central Institute for Translational Cancer Research, Technical University of Munich (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Barbara Wollenberg
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany.
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Shoaib S, Khan FB, Alsharif MA, Malik MS, Ahmed SA, Jamous YF, Uddin S, Tan CS, Ardianto C, Tufail S, Ming LC, Yusuf N, Islam N. Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers. Cancers (Basel) 2023; 15:2390. [PMID: 37190316 PMCID: PMC10137050 DOI: 10.3390/cancers15082390] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.
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Affiliation(s)
- Shoaib Shoaib
- Department of Biochemistry, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India
| | - Farheen Badrealam Khan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Meshari A. Alsharif
- Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - M. Shaheer Malik
- Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Saleh A. Ahmed
- Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
- Department of Chemistry, Faculty of Applied Sciences, Assiut University, Assiut 71515, Egypt
| | - Yahya F. Jamous
- Vaccines and Bioprocessing Center, King Abdulaziz City for Science and Technology (KACST), Riyadh 12354, Saudi Arabia
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Laboratory of Animal Center, Qatar University, Doha 2731, Qatar
| | - Ching Siang Tan
- School of Pharmacy, KPJ Healthcare University College, Nilai 71800, Malaysia;
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia; (C.A.); (L.C.M.)
| | - Saba Tufail
- Department of Biochemistry, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India
| | - Long Chiau Ming
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia; (C.A.); (L.C.M.)
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
- School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
| | - Nabiha Yusuf
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Najmul Islam
- Department of Biochemistry, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh 202002, India
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Liu Y, Yu Y, Li S, Sun M, Li F. Comparative transcriptomic analysis of gill reveals genes belonging to mTORC1 signaling pathway associated with the resistance trait of shrimp to VP AHPND. Front Immunol 2023; 14:1150628. [PMID: 37143674 PMCID: PMC10151482 DOI: 10.3389/fimmu.2023.1150628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/27/2023] [Indexed: 05/06/2023] Open
Abstract
Selective breeding for acute hepatopancreatic necrosis disease (AHPND) resistant shrimp is an effective way to deal with heavy losses to shrimp aquaculture caused by AHPND. However, knowledge about the molecular mechanism of susceptibility or resistance to AHPND is very limited. We herein performed a comparative transcriptomic analysis of gill tissue between AHPND susceptible and resistant families of the white Pacific shrimp Litopenaeus vannamei during Vibrio parahaemolyticus (VPAHPND) infection. A total of 5,013 genes that were differentially expressed between the two families at 0 and 6 h post-infection, and 1,124 DEGs were shared for both two time points. Both GO and KEGG analyses in each or two time point's comparisons showed DEGs involved in endocytosis, protein synthesis and cell inflammation were significantly enriched. Several immune DEGs including PRRs, antioxidants and AMPs were also identified. The susceptible shrimp showed enhanced endocytosis, higher aminoacyl-tRNA ligase activity and occurrence of inflammatory response, while the resistant shrimp had much more strong ability in ribosome biogenesis, antioxidant activity and pathogen recognition and clearance. These genes and processes were mostly associated with mTORC1 signaling pathway, which could reflect differences in cell growth, metabolism and immune response between the two families. Our findings indicate a close link between mTORC1 signaling-related genes and Vibrio-resistance phenotype of shrimp, and provide new clues for further research on resistance strategy of shrimp to AHPND.
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Affiliation(s)
- Yuan Liu
- Chinese Academy of Sciences (CAS) and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China
| | - Yang Yu
- Chinese Academy of Sciences (CAS) and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China
| | - Shihao Li
- Chinese Academy of Sciences (CAS) and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China
| | - Mingzhe Sun
- Chinese Academy of Sciences (CAS) and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China
| | - Fuhua Li
- Chinese Academy of Sciences (CAS) and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, China
- *Correspondence: Fuhua Li,
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CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy. NPJ Syst Biol Appl 2022; 8:5. [PMID: 35132075 PMCID: PMC8821627 DOI: 10.1038/s41540-022-00214-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 01/05/2022] [Indexed: 12/04/2022] Open
Abstract
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy due to the lack of reliable biomarkers, effective treatment, and chemoresistance. Improving the diagnosis and the development of targeted therapies is still needed. The molecular pathomechanisms driving HGSC progression are not fully understood though crucial for effective diagnosis and identification of novel targeted therapy options. The oncogene CTCFL (BORIS), the paralog of CTCF, is a transcriptional factor highly expressed in ovarian cancer (but in rarely any other tissue in females) with cancer-specific characteristics and therapeutic potential. In this work, we seek to understand the regulatory functions of CTCFL to unravel new target genes with clinical relevance. We used in vitro models to evaluate the transcriptional changes due to the presence of CTCFL, followed by a selection of gene candidates using de novo network enrichment analysis. The resulting mechanistic candidates were further assessed regarding their prognostic potential and druggability. We show that CTCFL-driven genes are involved in cytoplasmic membrane functions; in particular, the PI3K-Akt initiators EGFR1 and VEGFA, as well as ITGB3 and ITGB6 are potential drug targets. Finally, we identified the CTCFL targets ACTBL2, MALT1 and PCDH7 as mechanistic biomarkers to predict survival in HGSC. Finally, we elucidated the value of CTCFL in combination with its targets as a prognostic marker profile for HGSC progression and as putative drug targets.
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Khodavandi A, Alizadeh F, Razis AFA. Association between dietary intake and risk of ovarian cancer: a systematic review and meta-analysis. Eur J Nutr 2021; 60:1707-1736. [PMID: 32661683 DOI: 10.1007/s00394-020-02332-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 07/07/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE It is unclear how dietary intake influences the ovarian cancer. The present paper sets out to systematically review and meta-analyze research on dietary intake to identify cases having high- or low-risk ovarian cancer. METHODS Scopus, PubMed, and Wiley Online Libraries were searched up to the date November 24, 2019. Two reviewers were requested to independently extract study characteristics and to assess the bias and applicability risks with reference to the study inclusion criteria. Meta-analyses were performed to specify the relationship between dietary intake and the risk of ovarian cancer identifying 97 cohort studies. RESULTS No significant association was found between dietary intake and risk of ovarian cancer. The results of subgroup analyses indicated that green leafy vegetables (RR = 0.91, 95%, 0.85-0.98), allium vegetables (RR = 0.79, 95% CI 0.64-0.96), fiber (RR = 0.89, 95% CI 0.81-0.98), flavonoids (RR = 0.83, 95% CI 0.78-0.89) and green tea (RR = 0.61, 95% CI 0.49-0.76) intake could significantly reduce ovarian cancer risk. Total fat (RR = 1.10, 95% CI 1.02-1.18), saturated fat (RR = 1.11, 95% CI 1.01-1.22), saturated fatty acid (RR = 1.19, 95% CI 1.04-1.36), cholesterol (RR = 1.13, 95% CI 1.04-1.22) and retinol (RR = 1.14, 95% CI 1.00-1.30) intake could significantly increase ovarian cancer risk. In addition, acrylamide, nitrate, water disinfectants and polychlorinated biphenyls were significantly associated with an increased risk of ovarian cancer. CONCLUSION These results could support recommendations to green leafy vegetables, allium vegetables, fiber, flavonoids and green tea intake for ovarian cancer prevention.
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Affiliation(s)
- Alireza Khodavandi
- Department of Biology, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
| | - Fahimeh Alizadeh
- Department of Microbiology, Yasooj Branch, Islamic Azad University, Yasooj, Iran
| | - Ahmad Faizal Abdull Razis
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
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Lin YC, Chen TH, Huang YM, Wei PL, Lin JC. Involvement of microRNA in Solid Cancer: Role and Regulatory Mechanisms. Biomedicines 2021; 9:biomedicines9040343. [PMID: 33805515 PMCID: PMC8065716 DOI: 10.3390/biomedicines9040343] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) function as the post-transcriptional factor that finetunes the gene expression by targeting to the specific candidate. Mis-regulated expression of miRNAs consequently disturbs gene expression profile, which serves as the pivotal mechanism involved in initiation or progression of human malignancy. Cancer-relevant miRNA is potentially considered the therapeutic target or biomarker toward the precise treatment of cancer. Nevertheless, the regulatory mechanism underlying the altered expression of miRNA in cancer is largely uncovered. Detailed knowledge regarding the influence of miRNAs on solid cancer is critical for exploring its potential of clinical application. Herein, we elucidate the regulatory mechanism regarding how miRNA expression is manipulated and its impact on the pathogenesis of distinct solid cancer.
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Affiliation(s)
- Ying-Chin Lin
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Tso-Hsiao Chen
- Division of Nephrology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
| | - Yu-Min Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Gastrointestinal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (P.-L.W.); (J.-C.L.); Tel.: +886-2-2736-1661 (ext. 3330) (J.-C.L.)
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Gaikwad S, Srivastava SK. Role of Phytochemicals in Perturbation of Redox Homeostasis in Cancer. Antioxidants (Basel) 2021; 10:83. [PMID: 33435480 PMCID: PMC7827008 DOI: 10.3390/antiox10010083] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, research on reactive oxygen species (ROS) has revealed their critical role in the initiation and progression of cancer by virtue of various transcription factors. At certain threshold values, ROS act as signaling molecules leading to activation of oncogenic pathways. However, if perturbated beyond the threshold values, ROS act in an anti-tumor manner leading to cellular death. ROS mediate cellular death through various programmed cell death (PCD) approaches such as apoptosis, autophagy, ferroptosis, etc. Thus, external stimulation of ROS beyond a threshold is considered a promising therapeutic strategy. Phytochemicals have been widely regarded as favorable therapeutic options in many diseased conditions. Over the past few decades, mechanistic studies on phytochemicals have revealed their effect on ROS homeostasis in cancer. Considering their favorable side effect profile, phytochemicals remain attractive treatment options in cancer. Herein, we review some of the most recent studies performed using phytochemicals and, we further delve into the mechanism of action enacted by individual phytochemicals for PCD in cancer.
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Affiliation(s)
| | - Sanjay K. Srivastava
- Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA;
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Juárez-Avelar I, Rodríguez T, García-García AP, Rodríguez-Sosa M. Macrophage migration inhibitory factor (MIF): Its role in the genesis and progression of colorectal cancer. IMMUNOTHERAPY IN RESISTANT CANCER: FROM THE LAB BENCH WORK TO ITS CLINICAL PERSPECTIVES 2021:173-193. [DOI: 10.1016/b978-0-12-822028-3.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Ramachandran S, Srivastava SK. Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy. Mol Ther Oncolytics 2020; 19:19-32. [PMID: 33024816 PMCID: PMC7527685 DOI: 10.1016/j.omto.2020.08.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%-77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.
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Affiliation(s)
- Sharavan Ramachandran
- Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Sanjay K. Srivastava
- Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
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Ranjan A, Kaushik I, Srivastava SK. Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy. Cells 2020; 9:2141. [PMID: 32971907 PMCID: PMC7563195 DOI: 10.3390/cells9092141] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 09/11/2020] [Accepted: 09/16/2020] [Indexed: 12/23/2022] Open
Abstract
Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
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Affiliation(s)
- Alok Ranjan
- Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (A.R.); (I.K.)
| | - Itishree Kaushik
- Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (A.R.); (I.K.)
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Center for Tumor Immunology and Targeted Cancer Therapy, Abilene, TX 79601, USA
| | - Sanjay K. Srivastava
- Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (A.R.); (I.K.)
- Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Center for Tumor Immunology and Targeted Cancer Therapy, Abilene, TX 79601, USA
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12
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Sivakumar M, Surendar S, Jayakumar M, Seedevi P, Sivasankar P, Ravikumar M, Anbazhagan M, Murugan T, Siddiqui SS, Loganathan S. Parthenium hysterophorus Mediated Synthesis of Silver Nanoparticles and its Evaluation of Antibacterial and Antineoplastic Activity to Combat Liver Cancer Cells. J CLUST SCI 2020. [DOI: 10.1007/s10876-020-01775-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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13
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Role of microRNAs as Clinical Cancer Biomarkers for Ovarian Cancer: A Short Overview. Cells 2020; 9:cells9010169. [PMID: 31936634 PMCID: PMC7016727 DOI: 10.3390/cells9010169] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 12/28/2019] [Accepted: 01/06/2020] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer has the highest mortality rate among gynecological cancers. Early clinical signs are missing and there is an urgent need to establish early diagnosis biomarkers. MicroRNAs are promising biomarkers in this respect. In this paper, we review the most recent advances regarding the alterations of microRNAs in ovarian cancer. We have briefly described the contribution of miRNAs in the mechanisms of ovarian cancer invasion, metastasis, and chemotherapy sensitivity. We have also summarized the alterations underwent by microRNAs in solid ovarian tumors, in animal models for ovarian cancer, and in various ovarian cancer cell lines as compared to previous reviews that were only focused the circulating microRNAs as biomarkers. In this context, we consider that the biomarker screening should not be limited to circulating microRNAs per se, but rather to the simultaneous detection of the same microRNA alteration in solid tumors, in order to understand the differences between the detection of nucleic acids in early vs. late stages of cancer. Moreover, in vitro and in vivo models should also validate these microRNAs, which could be very helpful as preclinical testing platforms for pharmacological and/or molecular genetic approaches targeting microRNAs. The enormous quantity of data produced by preclinical and clinical studies regarding the role of microRNAs that act synergistically in tumorigenesis mechanisms that are associated with ovarian cancer subtypes, should be gathered, integrated, and compared by adequate methods, including molecular clustering. In this respect, molecular clustering analysis should contribute to the discovery of best biomarkers-based microRNAs assays that will enable rapid, efficient, and cost-effective detection of ovarian cancer in early stages. In conclusion, identifying the appropriate microRNAs as clinical biomarkers in ovarian cancer might improve the life quality of patients.
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14
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Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin Cancer Biol 2019; 59:147-160. [PMID: 31128298 DOI: 10.1016/j.semcancer.2019.05.012] [Citation(s) in RCA: 454] [Impact Index Per Article: 75.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/28/2019] [Accepted: 05/21/2019] [Indexed: 01/09/2023]
Abstract
Ovarian cancer (OC) is a lethal gynecological cancer. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the regulation of cell survival, growth, and proliferation. Irregularities in the major components of the PI3K/AKT/mTOR signaling pathway are common in human cancers. Despite the availability of strong pre-clinical and clinical data of PI3K/AKT/mTOR pathway inhibitors in OC, there is no FDA approved inhibitor available for the treatment of OC. Here, we outline the importance of PI3K/AKT/mTOR signaling pathway in OC tumorigenesis, proliferation and progression, and pre-clinical and clinical experience with several PI3K/AKT/mTOR pathway inhibitors in OC.
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Affiliation(s)
- Meran Keshawa Ediriweera
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka.
| | - Kamani Hemamala Tennekoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka
| | - Sameera Ranganath Samarakoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, Cumaratunga Munidasa Mawatha, Colombo 03, Sri Lanka
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15
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ROS-Mediated Cancer Cell Killing through Dietary Phytochemicals. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9051542. [PMID: 31217841 PMCID: PMC6536988 DOI: 10.1155/2019/9051542] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) promote carcinogenesis by inducing genetic mutations, activating oncogenes, and raising oxidative stress, which all influence cell proliferation, survival, and apoptosis. Cancer cells display redox imbalance due to increased ROS level compared to normal cells. This unique feature in cancer cells may, therefore, be exploited for targeted therapy. Over the past few decades, natural compounds have attracted attention as potential cancer therapies because of their ability to maintain cellular redox homeostasis with minimal toxicity. Preclinical studies show that bioactive dietary polyphenols exert antitumor effects by inducing ROS-mediated cytotoxicity in cancer cells. These bioactive compounds also regulate cell proliferation, survival, and apoptotic and antiapoptotic signalling pathways. In this review, we discuss (i) how ROS is generated and (ii) regulated and (iii) the cell signalling pathways affected by ROS. We also discuss (iv) the various dietary phytochemicals that have been implicated to have cancer therapeutic effects through their ROS-related functions.
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16
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Moradi-Marjaneh R, Hassanian SM, Mehramiz M, Rezayi M, Ferns GA, Khazaei M, Avan A. Reactive oxygen species in colorectal cancer: The therapeutic impact and its potential roles in tumor progression via perturbation of cellular and physiological dysregulated pathways. J Cell Physiol 2018; 234:10072-10079. [PMID: 30515827 DOI: 10.1002/jcp.27881] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 11/15/2018] [Indexed: 01/17/2023]
Abstract
Reactive oxygen species (ROS) are produced by mitochondria during metabolism. In physiological states, the production of ROS and their elimination by antioxidants are kept in balance. However, in pathological states, elevated levels of ROS interact with susceptible cellular target compounds including lipids, proteins, and DNA and deregulate oncogenic signaling pathways that are involved in colorectal cancer (CRC) carcinogenesis. Although antioxidant compounds have been successfully used in the treatment of CRC as prevention approaches, they have also been shown in some cases to promote disease progression. In this review, we focus on the role of ROS in gastrointestinal homeostasis, CRC progression, diagnosis, and therapy with particular emphasis on ROS-stimulated pathways.
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Affiliation(s)
- Reyhaneh Moradi-Marjaneh
- Torbat Heydarieh University of Medical Sciences, Torbat Heydarieh, Iran.,Department of Physiology and Neurogenic inflammation research center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehraneh Mehramiz
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Brighton, UK
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Physiology and Neurogenic inflammation research center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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17
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Soundararajan P, Kim JS. Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers. Molecules 2018; 23:E2983. [PMID: 30445746 PMCID: PMC6278308 DOI: 10.3390/molecules23112983] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 12/16/2022] Open
Abstract
Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.
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Affiliation(s)
- Prabhakaran Soundararajan
- Genomics Division, Department of Agricultural Bio-Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wansan-gu, Jeonju 54874, Korea.
| | - Jung Sun Kim
- Genomics Division, Department of Agricultural Bio-Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wansan-gu, Jeonju 54874, Korea.
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18
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BAG3 Protein Is Involved in Endothelial Cell Response to Phenethyl Isothiocyanate. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5967890. [PMID: 29955247 PMCID: PMC6000881 DOI: 10.1155/2018/5967890] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/15/2018] [Accepted: 04/17/2018] [Indexed: 01/15/2023]
Abstract
Phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived compound, is a versatile cancer chemopreventive agent that displays the ability to inhibit tumor growth during initiation, promotion, and progression phases in several animal models of carcinogenesis. In this report, we dissect the cellular events induced by noncytotoxic concentrations of PEITC in human umbilical vein endothelial cells (HUVECs). In the early phase, PEITC treatment elicited cells' morphological changes that comprise reduction in cell volume and modification of actin organization concomitantly with a rapid activation of the PI3K/Akt pathway. Downstream to PI3K, PEITC also induces the activity of Rac1 and activation of c-Jun N-terminal kinase (JNK), well-known regulators of actin cytoskeleton dynamics. Interestingly, PEITC modifications of the actin cytoskeleton were abrogated by pretreatment with JNK inhibitor, SP600125. JNK signaling led also to the activation of the c-Jun transcription factor, which is involved in the upregulation of several genes; among them is the BAG3 protein. This protein, a member of the BAG family of heat shock protein (Hsp) 70 cochaperones, is able to sustain survival in different tumor cell lines and neoangiogenesis by directly regulating the endothelial cell cycle. Furthermore, BAG3 is involved in maintaining actin folding. Our findings indicate that BAG3 protein expression is induced in endothelial cells upon exposure to a noncytotoxic concentration of PEITC and its expression is requested for the recovery of normal cell size and morphology after the stressful stimuli. This assigns an additional role for BAG3 protein in the endothelial cells after a stress event.
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19
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Natural scaffolds in anticancer therapy and precision medicine. Biotechnol Adv 2018; 36:1563-1585. [PMID: 29729870 DOI: 10.1016/j.biotechadv.2018.04.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 04/08/2018] [Accepted: 04/26/2018] [Indexed: 12/21/2022]
Abstract
The diversity of natural compounds is essential for their mechanism of action. The source, structures and structure activity relationship of natural compounds contributed to the development of new classes of chemotherapy agents for over 40 years. The availability of combinatorial chemistry and high-throughput screening has fueled the challenge to identify novel compounds that mimic nature's chemistry and to predict their macromolecular targets. Combining conventional and targeted therapies helped to successfully overcome drug resistance and prolong disease-free survival. Here, we aim to provide an overview of preclinical investigated natural compounds alone and in combination to further improve personalization of cancer treatment.
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20
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Su M, Qian C, Hu Y, Lu W, Huang R, Chen M, Chen J. Inhibitory effect of the low-toxic exogenous aryl hydrocarbon receptor modulator 3'3-diindolylmethane on gastric cancer in mice. Oncol Lett 2017; 14:8100-8105. [PMID: 29344254 DOI: 10.3892/ol.2017.7185] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 08/08/2017] [Indexed: 12/14/2022] Open
Abstract
3'3-Diindolylmethane (DIM) has been proved to exhibit anticancer properties in many solid tumors. In our previous study, we demonstrated that DIM inhibited SGC7901 cell proliferation by inducing apoptosis and delaying cell cycle progression. Herein, we further explored the anti-tumor effect of DIM on SGC-7901 tumor bearing mice. Tumors were excised, weighed, and tested by western blot and TdT-UTP nick-end labeling (TUNEL) assay. Blood samples were collected for biochemical analysis. The expression levels of AhR and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) protein were evaluated by western-blot assay. Our data show that with the increase of DIM dose (0, 5, 10, 20 mg/kg/day), AhR protein gradually decreased as CYP1A1 protein increased. The weight of the tumors found in the treated animals was significantly lower than that of the control group (0.845±0.096 vs. 1.275±0.236 g, 0.768±0.161 vs. 1.275±0.236 g, 0.607±0.106 vs. 1.275±0.236 g, P<0.05). TUNEL test showed that DIM induced increased apoptosis in the treatment groups in a dose-dependent manner. Blood tests also indicated that DIM showed no toxic effect on animal weight or liver and kidney function. These results indicated that DIM agent could be a safe and potent drug in therapy of gastric cancer.
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Affiliation(s)
- Mingli Su
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chenchen Qian
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yumin Hu
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Wenhua Lu
- Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Rongkang Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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21
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Shao WY, Yang YL, Yan H, Huang Q, Liu KJ, Zhang S. Phenethyl isothiocyanate suppresses the metastasis of ovarian cancer associated with the inhibition of CRM1-mediated nuclear export and mTOR-STAT3 pathway. Cancer Biol Ther 2017; 18:26-35. [PMID: 27981892 PMCID: PMC5323014 DOI: 10.1080/15384047.2016.1264540] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 09/03/2016] [Accepted: 11/20/2016] [Indexed: 02/05/2023] Open
Abstract
Epithelial ovarian cancer is prone to metastasizing at an early stage, but their mechanisms remain unclear. CRM1 is an important nuclear exportin and inhibitors targeting CRM1 has been explored as an anti-cancer strategy. In previous study, we observed that PEITC could combine with the hydrophobic pocket of CRM1. In this study, we focused on the effects of PEITC on EOC and its mechanisms. Results showed that IC50 values of PEITC on SKOV3 and HO8910 cell line were 42.14 μM and 37.29 μM, respectively. PEITC inhibits the migration and invasion of SKOV3 and HO8910 cells in vitro. Oral administration of 10 μmol PEITC suppressed the metastasis of EOC in a xenograft mouse model in vivo. PEITC treatment decreased the expressions of CRM1 and mTOR (cargo protein of CRM1) in EOC cell lines and in xenograft mouse tissues. Moreover, CRM1-mediated nuclear export was attenuated by PEITC, mTOR accumulated in nucleus, expressions of mTORS2448 and downstream effectors STAT3S727, MMP2 and MMP9 were decreased in a dose- and time-dependent manner. Furthermore, immunohistochemical analysis showed that CRM1 and mTOR were increased in EOC tissues compared with benign ovarian tumors, and related with advanced stage, type II EOC, positive peritoneal cytology and decreased overall survival. In addition, CRM1 was positively correlated with mTOR levels. In conclusion, our data demonstrated that PEITC suppresses the metastasis of EOC through inhibiting CRM1-mediated nuclear export, subsequently suppressing the mTOR-STAT3 pathway. Both CRM1 and mTOR were increased in EOC patients, providing a rationale for further clinical investigation of PEITC in EOC treatment.
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Affiliation(s)
- Wen Yu Shao
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Yong Liang Yang
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Huan Yan
- Department of Obstetrics and Gynecology, RenJi Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Qian Huang
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Kai Jiang Liu
- Department of Gynecological Oncology, RenJi Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Shu Zhang
- Department of Obstetrics and Gynecology, RenJi Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
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22
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Ye J, Chen W, Wu ZY, Zhang JH, Fei H, Zhang LW, Wang YH, Chen YP, Yang XM. Upregulated CTHRC1 promotes human epithelial ovarian cancer invasion through activating EGFR signaling. Oncol Rep 2016; 36:3588-3596. [PMID: 27779718 DOI: 10.3892/or.2016.5198] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 10/17/2016] [Indexed: 11/06/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the major cause of deaths from gynecologic malignancies, and metastasis is the main cause of cancer related death. Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that has the ability to inhibit collagen matrix synthesis. In this study, we found that high CTHRC1 expression was associated with poor prognosis of EOC. In vitro experiments showed that CTHRC1 promoted migration and invasion of ovarian cancer cells. CTHRC1 had no effect on ovarian cancer cells viability. Additionally, EGFR inhibitors reduced the promotion effects of CTHRC1 on EOC cell invasion. After silencing of CTHRC1, downregulated expression of phosphorylation of EGFR/ERK1/2/AKT was observed in ovarian cancer cells. Taken together, our results suggest a role for CTHRC1 in the progression of ovarian cancer and identified CTHRC1 as a potentially important predictor for human ovarian cancer prognosis.
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Affiliation(s)
- Jun Ye
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - Wei Chen
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - Zhi-Yong Wu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China
| | - Jin-Hui Zhang
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - He Fei
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - Li-Wen Zhang
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - Ya-Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, P.R. China
| | - Ya-Ping Chen
- The Fifth People's Hospital of Shanghai, Shanghai 200240, P.R. China
| | - Xiao-Mei Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, P.R. China
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23
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Ranjan A, Gupta P, Srivastava SK. Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis. Cancer Res 2016; 76:877-890. [PMID: 26627008 PMCID: PMC4755811 DOI: 10.1158/0008-5472.can-15-1233] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 11/13/2015] [Indexed: 01/01/2023]
Abstract
Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the antimetastatic potential of penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, penfluridol treatment significantly reduced the expression of integrin α6, integrin β4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of penfluridol in three different in vivo tumor models. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin β4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC.
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Affiliation(s)
- Alok Ranjan
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Parul Gupta
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Sanjay K Srivastava
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas.
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24
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Hong YH, Uddin MH, Jo U, Kim B, Song J, Suh DH, Kim HS, Song YS. ROS Accumulation by PEITC Selectively Kills Ovarian Cancer Cells via UPR-Mediated Apoptosis. Front Oncol 2015; 5:167. [PMID: 26284193 PMCID: PMC4517521 DOI: 10.3389/fonc.2015.00167] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2015] [Accepted: 07/08/2015] [Indexed: 12/11/2022] Open
Abstract
Unfolded protein response (UPR) is crucial for both survival and death of mammalian cells, which is regulated by reactive oxygen species (ROS) and nutrient depletion. In this study, we demonstrated the effect of ROS-accumulation, induced by β-phenethyl isothiocyanate (PEITC), on UPR-mediated apoptosis in ovarian cancer cells. We used ovarian cancer cell lines, PA-1 and SKOV-3, with different p53 status (wild- and null-type, respectively). PEITC caused increased ROS-accumulation and inhibited proliferation selectively in ovarian cancer cells, and glutathione (GSH) depletion in SKOV-3. However, PEITC did not cause any effect in normal ovarian epithelial cells and peripheral blood mononuclear cells. After 48 h of PEITC treatment (5 μM), apoptotic cell death was shown to increase significantly in the ovarian cancer cells and not in the normal cells. The key regulator of UPR-mediated apoptosis, CHOP/GADD153 and endoplasmic reticulum resident chaperone BiP/GRP78 were parallely up-regulated with activation of two major sensors of the UPR [PERK and ATF-6 in PA-1; PERK, and IRE1α in SKOV-3) in response to ROS accumulation induced by PEITC (5 μM). ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the effect of PEITC on UPR signatures (P-PERK, IRE1α, CHOP/GADD153, and BiP/GRP78), suggesting the involvement of ROS in UPR-mediated apoptosis. Altogether, PEITC induces UPR-mediated apoptosis in ovarian cancer cells via accumulation of ROS in a cancer-specific manner.
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Affiliation(s)
- Yoon-Hee Hong
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - Md. Hafiz Uddin
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Untek Jo
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Boyun Kim
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - Jiyoung Song
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
| | - Dong Hoon Suh
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hee Seung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
| | - Yong Sang Song
- Gynecological Oncology Laboratory, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, South Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
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Abstract
Cancer results from aberrant signaling pathways that result in uncontrolled cellular proliferation. The epidemiological studies have shown a strong inverse correlation between dietary consumption of cruciferous vegetables and incidences of cancer. Isothiocyanates (ITCs) are present in cruciferous vegetables like broccoli, cabbage, watercress, etc. and are identified as the major active constituents. Several mechanistic studies have demonstrated chemopreventive and chemotherapeutic activity of ITCs against various tumor types. ITCs exert anticancer activity by suppressing various critical hallmarks of cancer like cellular proliferation, angiogenesis, apoptosis, metastasis, etc., in vitro as well as in preclinical animal model. ITCs also generate reactive oxygen species to induce apoptosis in cancer cells. Due to promising preclinical results, few ITCs have also advanced to clinical trials. This chapter provides a candid review on the chemopreventive and chemotherapeutic activity of various major ITCs.
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Affiliation(s)
- Neel M Fofaria
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - Alok Ranjan
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, USA
| | - Sung-Hoon Kim
- Cancer Preventive Material Development Research Center, College of Korean Medicine, Department of Pathology, Kyung Hee University, Seoul, South Korea.
| | - Sanjay K Srivastava
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, USA; Cancer Preventive Material Development Research Center, College of Korean Medicine, Department of Pathology, Kyung Hee University, Seoul, South Korea.
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Qin CZ, Zhang X, Wu LX, Wen CJ, Hu L, Lv QL, Shen DY, Zhou HH. Advances in molecular signaling mechanisms of β-phenethyl isothiocyanate antitumor effects. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:3311-3322. [PMID: 25798652 DOI: 10.1021/jf504627e] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
β-Phenethyl isothiocyanate (PEITC) is an important phytochemical from cruciferous vegetables and is being evaluated for chemotherapeutic activity in early phase clinical trials. Moreover, studies in cell culture and in animals found that the anticarcinogenic activities of PEITC involved all the major stages of tumor growth: initiation, promotion, and progression. A number of mechanisms have been proposed for the chemopreventive activities of this compound. Here, we focus on the major molecular signaling pathways for the anticancer activities of PEITC. These include (1) activation of apoptosis pathways; (2) induction of cell cycle arrest; and (3) inhibition of the survival pathways. Furthermore, we also discussed the regulation of drug-metabolizing enzymes, including cytochrome P450s, metabolizing enzymes, and multidrug resistance.
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Affiliation(s)
- Chong-Zhen Qin
- †Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- ‡Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Xue Zhang
- §Institute of Life Sciences, Chongqing Medical University, Chongqing, Chongqing 400016, China
| | - Lan-Xiang Wu
- §Institute of Life Sciences, Chongqing Medical University, Chongqing, Chongqing 400016, China
| | - Chun-Jie Wen
- §Institute of Life Sciences, Chongqing Medical University, Chongqing, Chongqing 400016, China
| | - Lei Hu
- †Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- ‡Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Qiao-Li Lv
- †Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- ‡Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Dong-Ya Shen
- †Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- ‡Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
| | - Hong-Hao Zhou
- †Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
- ‡Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, P. R. China
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Gupta P, Wright SE, Srivastava SK. PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth. Oncoimmunology 2015; 4:e981449. [PMID: 25949878 PMCID: PMC4404818 DOI: 10.4161/2162402x.2014.981449] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/20/2014] [Accepted: 10/22/2014] [Indexed: 01/26/2023] Open
Abstract
Breast tumors are heterogeneous with a complex etiology. The immune system plays a crucial role in the development of tumors and can facilitate tumor growth pleiotropically. Myeloid derived suppressor cells (MDSCs) generate reactive oxygen species (ROS) and cytokines to suppress T cells, dendritic cells and natural killer (NK) cells. Hence, the inhibition of MDSCs could be an important strategy for anticancer therapeutics. Phenethyl isothiocyanate (PEITC), a bioactive compound present in cruciferous vegetables, is known to have anticancer properties. However, the effects of PEITC administration on the immune system have not been previously reported. In the current study, we evaluated the effects of administering PEITC to immunocompromised NOD-SCID IL2Rγ-/- (SCID/NSG) host mice bearing MDA-MB-231 xenografts on MDSCs in the peripheral blood. Our results reveal that oral administration of 12 μmol PEITC attenuated tumor growth by 76%. This was marked tumor-inhibitory phenotype was associated with a significant reduction in the levels of MDSCs bearing the surface markers CD33, CD34 and CD11b in PEITC treated mice, indicating that overall tumor growth suppression by PEITC correlates with inhibition of MDSCs. To the best of our knowledge, this is the first study showing effects of PEITC on MDSCs.
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Affiliation(s)
- Parul Gupta
- Department of Biomedical Sciences and Cancer Biology Center; Texas Tech University Health Sciences Center; Amarillo, TX USA
| | - Stephen E. Wright
- Department of Biomedical Sciences and Cancer Biology Center; Texas Tech University Health Sciences Center; Amarillo, TX USA
- Department of Internal Medicine; Texas Tech University Health Sciences Center; Amarillo, TX USA
- Harrington Cancer Center; Amarillo, TX USA
| | - Sanjay K. Srivastava
- Department of Biomedical Sciences and Cancer Biology Center; Texas Tech University Health Sciences Center; Amarillo, TX USA
- Cancer Preventive Material Development Research Center; College of Korean Medicine; Department of Pathology; Kyunghee University; Dongdaemun-ku, Seoul, South Korea
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Gupta P, Srivastava SK. Inhibition of Integrin-HER2 signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression. Oncotarget 2015; 5:1812-28. [PMID: 24729020 PMCID: PMC4039119 DOI: 10.18632/oncotarget.1743] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
HER2, an oncogenic receptor is overexpressed in about 25-30% of breast cancer patients. HER2 has been shown to play role in tumor promotion by having cross-talk with multiple oncogenic pathways in cancer cells. Our results show that Cucurbitacin B (CuB), a triterpenoid steroidal compound inhibited the growth of various breast cancer cells with an IC50 ranging from 18-50nM after 48 and 72 h of treatment. Our study also revealed the significant inhibitory effects of CuB on HER2 and integrin signaling in breast cancer. Notably, CuB inhibited ITGA6 and ITGB4 (integrin α6 & integrin β4), which are overexpressed in breast cancer. Furthermore, CuB also induced the expression of major ITGB1and ITGB3, which are known to cause integrin-mediated cell death. In addition, we observed that TGFβ treatment resulted in the increased association of HER2 with ITGA6 and this association was inhibited by CuB treatment. Efficacy of CuB was tested in vivo using two different orthotopic models of breast cancer. MDA-MB-231 and 4T-1 cells were injected orthotopically in the mammary fat pad of female athymic nude mice or BALB/c mice respectively. Our results showed that CuB administration inhibited MDA-MB-231 orthotopic tumors by 55%, and 4T-1 tumors by 40%. The 4T-1 cells represent stage IV breast cancer and form very aggressive tumors. CuB mediated breast tumor growth suppression was associated with the inhibition of HER2/integrin signaling. Our results suggest novel targets of CuB in breast cancer in vitro and in vivo.
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Affiliation(s)
- Parul Gupta
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA
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Gupta P, Wright SE, Kim SH, Srivastava SK. Phenethyl isothiocyanate: a comprehensive review of anti-cancer mechanisms. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1846:405-424. [PMID: 25152445 PMCID: PMC4260992 DOI: 10.1016/j.bbcan.2014.08.003] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 08/11/2014] [Accepted: 08/13/2014] [Indexed: 01/22/2023]
Abstract
The epidemiological evidence suggests a strong inverse relationship between dietary intake of cruciferous vegetables and the incidence of cancer. Among other constituents of cruciferous vegetables, isothiocyanates (ITC) are the main bioactive chemicals present. Phenethyl isothiocyanate (PEITC) is present as gluconasturtiin in many cruciferous vegetables with remarkable anti-cancer effects. PEITC is known to not only prevent the initiation phase of carcinogenesis process but also to inhibit the progression of tumorigenesis. PEITC targets multiple proteins to suppress various cancer-promoting mechanisms such as cell proliferation, progression and metastasis. Pre-clinical evidence suggests that combination of PEITC with conventional anti-cancer agents is also highly effective in improving overall efficacy. Based on accumulating evidence, PEITC appears to be a promising agent for cancer therapy and is already under clinical trials for leukemia and lung cancer. This is the first review which provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of PEITC as a future anti-cancer agent.
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Affiliation(s)
- Parul Gupta
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Stephen E Wright
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Sung-Hoon Kim
- Cancer Preventive Material Development Research Center, College of Korean Medicine, Department of Pathology, Kyunghee University, 1 Hoegi-dong, Dongdaemun-ku, Seoul 131-701, South Korea.
| | - Sanjay K Srivastava
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; Cancer Preventive Material Development Research Center, College of Korean Medicine, Department of Pathology, Kyunghee University, 1 Hoegi-dong, Dongdaemun-ku, Seoul 131-701, South Korea.
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30
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Marioni G, Ottaviano G, Lionello M, Fasanaro E, Staffieri C, Giacomelli L, Gattazzo S, Staffieri A, Blandamura S. A panel of biomarkers for predicting response to postoperative RT for laryngeal cancer? Am J Otolaryngol 2014; 35:771-8. [PMID: 25064017 DOI: 10.1016/j.amjoto.2014.06.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 06/10/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Postoperative radiotherapy (PORT) improves locoregional control and survival rates for patients with advanced laryngeal carcinoma (LSCC), but reported outcomes after PORT for LSCC vary considerably. Predictive markers (including biomarkers) are needed for LSCC to orient the choice of the most appropriate adjuvant therapy for individual patients. The aim of this study was to identify a panel of LSCC tissue markers (considering EGFR, mTOR, survivin, Bcl-2, angiogenin, endoglin [CD105], nm23-H1) capable of pinpointing patients at higher risk of recurrence among 33 LSCC cases treated with PORT. METHODS/RESULTS Univariate analysis found 4 biomarkers (mTOR, nuclear survivin, CD105, non-nuclear nm23-H1) significantly associated with LSCC recurrence. A collinearity emerged between mTOR and CD105 expressions. The predictive role of two different panels (panel 1: mTOR, nuclear survivin, non-nuclear nm23-H1; panel 2: CD105, nuclear survivin, non-nuclear nm23-H1) was considered. According to the Hosmer and Lemeshow scale, panel 1 demonstrated an outstanding discriminatory power (AUC 0.903) in predicting LSCC recurrence after PORT. Panel 2 had an excellent discriminatory power too (AUC 0.899). CONCLUSIONS Both panels of biomarkers showed an important discriminatory power in pinpointing patients at higher risk of recurrence after PORT for LSCC who could reasonably benefit from adjuvant postoperative chemo-RT.
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Zhou X, Hu Y, Dai L, Wang Y, Zhou J, Wang W, Di W, Qiu L. MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer. PLoS One 2014; 9:e96718. [PMID: 24816687 PMCID: PMC4016102 DOI: 10.1371/journal.pone.0096718] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 04/10/2014] [Indexed: 12/31/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention.
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Affiliation(s)
- Xingchen Zhou
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Yuan Hu
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Lan Dai
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Yunfei Wang
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Jinhua Zhou
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - WenWen Wang
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Wen Di
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Lihua Qiu
- Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
- * E-mail:
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Zhao SF, Zhang X, Zhang XJ, Shi XQ, Yu ZJ, Kan QC. Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells. Asian Pac J Cancer Prev 2014; 15:3363-8. [DOI: 10.7314/apjcp.2014.15.8.3363] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Gupta P, Kim B, Kim SH, Srivastava SK. Molecular targets of isothiocyanates in cancer: recent advances. Mol Nutr Food Res 2014; 58:1685-707. [PMID: 24510468 DOI: 10.1002/mnfr.201300684] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 12/16/2013] [Accepted: 12/17/2013] [Indexed: 12/14/2022]
Abstract
Cancer is a multistep process resulting in uncontrolled cell division. It results from aberrant signaling pathways that lead to uninhibited cell division and growth. Various recent epidemiological studies have indicated that consumption of cruciferous vegetables, such as garden cress, broccoli, etc., reduces the risk of cancer. Isothiocyanates (ITCs) have been identified as major active constituents of cruciferous vegetables. ITCs occur in plants as glucosinolate and can readily be derived by hydrolysis. Numerous mechanistic studies have demonstrated the anticancer effects of ITCs in various cancer types. ITCs suppress tumor growth by generating reactive oxygen species or by inducing cycle arrest leading to apoptosis. Based on the exciting outcomes of preclinical studies, few ITCs have advanced to the clinical phase. Available data from preclinical as well as available clinical studies suggest ITCs to be one of the promising anticancer agents available from natural sources. This is an up-to-date exhaustive review on the preventive and therapeutic effects of ITCs in cancer.
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Affiliation(s)
- Parul Gupta
- Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA
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Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2014; 12:931-47. [PMID: 24287781 DOI: 10.1038/nrd4002] [Citation(s) in RCA: 2591] [Impact Index Per Article: 235.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.
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Affiliation(s)
- Chiara Gorrini
- 1] The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada. [2]
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Gupta B, Chiang L, Chae K, Lee DH. Phenethyl isothiocyanate inhibits hypoxia-induced accumulation of HIF-1α and VEGF expression in human glioma cells. Food Chem 2013; 141:1841-6. [DOI: 10.1016/j.foodchem.2013.05.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/16/2013] [Accepted: 05/02/2013] [Indexed: 01/11/2023]
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Lionello M, Lovato A, Staffieri A, Blandamura S, Turato C, Giacomelli L, Staffieri C, Marioni G. The EGFR-mTOR pathway and laryngeal cancer angiogenesis. Eur Arch Otorhinolaryngol 2013; 271:757-64. [PMID: 24065188 DOI: 10.1007/s00405-013-2691-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 09/04/2013] [Indexed: 02/07/2023]
Abstract
Epidermal growth factor receptor (EGFR) is a trans-membrane tyrosine kinase taking part in cell transformation and tumor progression. One of the downstream pathways controlled by EGFR involves the mammalian target of rapamycin (mTOR), a proto-oncogene activated in several cell functions. Recent evidence seems to confirm that both EGFR and mTOR regulate angiogenesis. The aim of this study was to investigate the expression of EGFR and mTOR in laryngeal squamous cell carcinoma (LSCC) cells in a retrospective clinical setting and their correlation with tumor neo-angiogenesis, judged on the grounds of CD105-assessed microvascular density (MVD), and prognosis. We considered 76 consecutive patients with LSCC treated with surgery alone. Immunohistochemical expressions of EGFR, mTOR, and CD105 were measured using image analysis and findings underwent statistical analysis using univariate and multivariate models. We found that nodal status correlated significantly with patient prognosis in terms of disease-free survival (DFS) (p = 0.01). There was a strong direct correlation between mTOR and EGFR expression (p = 0.0003), and between mTOR and CD105-assessed MVD (p = 0.0025). Patients with a CD105-assessed MVD >5.28 % had a significantly higher recurrence rate (RR) (p = 0.026), and a significantly shorter DFS (p = 0.025). On multivariate analysis, only N stage [hazard ratio (HR) 3.54, p = 0.009] and CD105-assessed MVD (HR 2.87, p = 0.027) maintained their independent prognostic significance in terms of DFS. Judging from our promising findings, the EGFR-mTOR pathway should be investigated further to understand its role in LSCC neo-angiogenesis.
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Affiliation(s)
- Marco Lionello
- Otolaryngology Section, Department of Neurosciences, University of Padova, Padova, Italy,
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The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 2013; 14:8213-27. [PMID: 23591839 PMCID: PMC3645739 DOI: 10.3390/ijms14048213] [Citation(s) in RCA: 140] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 03/28/2013] [Accepted: 04/01/2013] [Indexed: 12/11/2022] Open
Abstract
Ovarian cancer is the fifth most common cause of death due to cancer in women despite being the tenth in incidence. Unfortunately, the five-year survival rate is only 45%, which has not improved much in the past 30 years. Even though the majority of women have successful initial therapy, the low rate of survival is due to the eventual recurrence and succumbing to their disease. With the recent release of the Cancer Genome Atlas for ovarian cancer, it was shown that the PI3K/AKT/mTOR pathway was one of the most frequently mutated or altered pathways in patients’ tumors. Researching how the PI3K/AKT/mTOR pathway affects the progression and tumorigensis of ovarian cancer will hopefully lead to new therapies that will increase survival for women. This review focuses on recent research on the PI3K/AKT/mTOR pathway and its role in the progression and tumorigensis of ovarian cancer.
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