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Tsai CC, Yang YCSH, Chen YF, Huang LY, Yang YN, Lee SY, Wang WL, Lee HL, Whang-Peng J, Lin HY, Wang K. Integrins and Actions of Androgen in Breast Cancer. Cells 2023; 12:2126. [PMID: 37681860 PMCID: PMC10486718 DOI: 10.3390/cells12172126] [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: 07/05/2023] [Revised: 08/16/2023] [Accepted: 08/19/2023] [Indexed: 09/09/2023] Open
Abstract
Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvβ3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvβ3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvβ3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed.
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Affiliation(s)
- Chung-Che Tsai
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Chen S. H. Yang
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan;
| | - Yi-Fong Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
| | - Lin-Yi Huang
- Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (L.-Y.H.); (Y.-N.Y.)
| | - Yung-Ning Yang
- Department of Pediatrics, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (L.-Y.H.); (Y.-N.Y.)
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
| | - Sheng-Yang Lee
- Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei 11031, Taiwan;
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wen-Long Wang
- Department of Life Science, Fu Jen Catholic University, New Taipei City 242, Taiwan;
| | - Hsin-Lun Lee
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 110, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | | | - Hung-Yun Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.T.); (Y.-F.C.)
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan;
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
| | - Kuan Wang
- Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
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Agri-Food By-Products in Cancer: New Targets and Strategies. Cancers (Basel) 2022; 14:cancers14225517. [PMID: 36428610 PMCID: PMC9688227 DOI: 10.3390/cancers14225517] [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: 09/21/2022] [Revised: 10/27/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
The globalization and the changes in consumer lifestyles are forcing us to face a deep transformation in food demand and in the organization of the entire food production system. In this new era, the food-loss and food-waste security nexus is relevant in the global debate and avoiding unsustainable waste in agri-food systems as well as the supply chain is a big challenge. "Food waste" is useful for the recovery of its valuable components, thus it can assume the connotation of a "food by-product". Sustainable utilization of agri-food waste by-products provides a great opportunity. Increasing evidence shows that agri-food by-products are a source of different bioactive molecules that lower the inflammatory state and, hence, the aggressiveness of several proliferative diseases. This review aims to summarize the effects of agri-food by-products derivatives, already recognized as promising therapeutics in human diseases, including different cancer types, such as breast, prostate, and colorectal cancer. Here, we examine products modulating or interfering in the signaling mediated by the epidermal growth factor receptor.
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Groenendyk J, Stoletov K, Paskevicius T, Li W, Dai N, Pujol M, Busaan E, Ng HH, Boukouris AE, Saleme B, Haromy A, Cui K, Hu M, Yan Y, Zhang R, Michelakis E, Chen XZ, Lewis JD, Tang J, Agellon LB, Michalak M. Loss of the fructose transporter SLC2A5 inhibits cancer cell migration. Front Cell Dev Biol 2022; 10:896297. [PMID: 36268513 PMCID: PMC9578049 DOI: 10.3389/fcell.2022.896297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Metastasis is the primary cause of cancer patient death and the elevation of SLC2A5 gene expression is often observed in metastatic cancer cells. Here we evaluated the importance of SLC2A5 in cancer cell motility by silencing its gene. We discovered that CRISPR/Cas9-mediated inactivation of the SLC2A5 gene inhibited cancer cell proliferation and migration in vitro as well as metastases in vivo in several animal models. Moreover, SLC2A5-attenuated cancer cells exhibited dramatic alterations in mitochondrial architecture and localization, uncovering the importance of SLC2A5 in directing mitochondrial function for cancer cell motility and migration. The direct association of increased abundance of SLC2A5 in cancer cells with metastatic risk in several types of cancers identifies SLC2A5 as an important therapeutic target to reduce or prevent cancer metastasis.
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Affiliation(s)
- Jody Groenendyk
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | | | | | - Wenjuan Li
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Ning Dai
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Myriam Pujol
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Erin Busaan
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Hoi Hei Ng
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | | | - Bruno Saleme
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Alois Haromy
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Kaisa Cui
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Miao Hu
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China
| | - Yanan Yan
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China
| | - Rui Zhang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China
| | | | - Xing-Zhen Chen
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
| | - John D. Lewis
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Jingfeng Tang
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China
| | - Luis B. Agellon
- School of Human Nutrition, McGill University, Montreal, QC, Canada
- *Correspondence: Luis B. Agellon, ; Marek Michalak,
| | - Marek Michalak
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Luis B. Agellon, ; Marek Michalak,
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Yu Z, Zhang X, Pei X, Cao W, Ye J, Wang J, Sun L, Yu F, Wang J, Li N, Lee K, Barth S, Yang VC, He H. Antibody-siRNA conjugates (ARCs) using multifunctional peptide as a tumor enzyme cleavable linker mediated effective intracellular delivery of siRNA. Int J Pharm 2021; 606:120940. [PMID: 34310959 DOI: 10.1016/j.ijpharm.2021.120940] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 10/20/2022]
Abstract
The tissue-specific targeted delivery and efficient cellular uptake of siRNAs are the main obstacles to their clinical application. Antibody-siRNA-conjugates (ARCs) can deliver siRNA by exploiting the targeting property of antibodies like antibody-drug conjugates (ADCs). However, the effective conjugation of antibodies and siRNAs and the release of siRNAs specifically at target sites have posed challenges to the development of ARCs. In this study, the successful conjugation of antibodies and siRNAs was achieved using a multifunctional peptide as a linker, composed of a cell-penetrating peptide (CPP) and a substrate peptide (SP), which is highly expressed in solid tumors. The resulting antibody-multifunctional peptide (SP-CPP)-siRNA system delivered the siRNA to target tumor cells by the specific binding of the antibody. Once the enzymes on the tumor cell surface hydrolyzed the substrate peptide linker, siRNA-CPP was released from ARCs. The released siRNA-CPP entered the targeted cells via the cellular penetrating ability of CPP, resulting in improved siRNA-mediated gene silencing efficiency, verified both in vitro and in vivo. After intravenous administration, the designed ARCs achieved approximately 66.7% EGFP (Enhanced Green Fluorescent Protein) downregulation efficiency in nude mice xenografted with the HCT116-EGFP tumor model. The proposed system provides a prospective choice for ARC production and the safe and efficient delivery of siRNAs.
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Affiliation(s)
- Zhili Yu
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xiaojuan Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Xing Pei
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Weiran Cao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Junxiao Ye
- College of Pharmacy, Tsinghua University, Beijing 100084, China
| | - Jianxin Wang
- Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
| | - Lu Sun
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Fei Yu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Jiancheng Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, XueYuan Rd 38, Haidian Dist, Beijing 100191, China
| | - Nan Li
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Kyuri Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
| | - Stefan Barth
- South African Research Chair in Cancer Biotechnology, Institute of Infectious Disease and Molecular Medicine (IDM), Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
| | - Victor C Yang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA
| | - Huining He
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
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Michmerhuizen AR, Spratt DE, Pierce LJ, Speers CW. ARe we there yet? Understanding androgen receptor signaling in breast cancer. NPJ Breast Cancer 2020; 6:47. [PMID: 33062889 PMCID: PMC7519666 DOI: 10.1038/s41523-020-00190-9] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 08/27/2020] [Indexed: 12/30/2022] Open
Abstract
The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.
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Affiliation(s)
- Anna R Michmerhuizen
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI USA
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI USA
| | - Daniel E Spratt
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI USA
| | - Lori J Pierce
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI USA
| | - Corey W Speers
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI USA
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Carafa V, Poziello A, Della Torre L, Giovannelli P, Di Donato M, Safadeh E, Yu Z, Baldi A, Castoria G, Tomaselli D, Mai A, Rotili D, Nebbioso A, Altucci L. Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer. Int J Mol Sci 2019; 20:ijms20225654. [PMID: 31726691 PMCID: PMC6888689 DOI: 10.3390/ijms20225654] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/05/2019] [Accepted: 11/08/2019] [Indexed: 01/13/2023] Open
Abstract
Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure–activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine.
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Affiliation(s)
- Vincenzo Carafa
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Angelita Poziello
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Laura Della Torre
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Pia Giovannelli
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Marzia Di Donato
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Elham Safadeh
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Zhijun Yu
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Alfonso Baldi
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
| | - Gabriella Castoria
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
| | - Daniela Tomaselli
- Dipartimento di Chimica e Tecnologie del Farmaco “Sapienza” Università di Roma, 00185 Roma, Italy;
| | - Antonello Mai
- Dipartimento di Chimica e Tecnologie del Farmaco “Sapienza” Università di Roma, 00185 Roma, Italy;
- Correspondence: (A.M.); (D.R.); (A.N.); (L.A.); Tel.: +39-0649-913-392 (A.M.); +39-0649-913-891 (D.R.); +39-0815-665-682 (A.N.); +39-0815-667-569 (L.A.); Fax: +39-064-9693-268 (A.M. & D.R.); +39-081-450-169 (A.N. & L.A.)
| | - Dante Rotili
- Dipartimento di Chimica e Tecnologie del Farmaco “Sapienza” Università di Roma, 00185 Roma, Italy;
- Correspondence: (A.M.); (D.R.); (A.N.); (L.A.); Tel.: +39-0649-913-392 (A.M.); +39-0649-913-891 (D.R.); +39-0815-665-682 (A.N.); +39-0815-667-569 (L.A.); Fax: +39-064-9693-268 (A.M. & D.R.); +39-081-450-169 (A.N. & L.A.)
| | - Angela Nebbioso
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
- Correspondence: (A.M.); (D.R.); (A.N.); (L.A.); Tel.: +39-0649-913-392 (A.M.); +39-0649-913-891 (D.R.); +39-0815-665-682 (A.N.); +39-0815-667-569 (L.A.); Fax: +39-064-9693-268 (A.M. & D.R.); +39-081-450-169 (A.N. & L.A.)
| | - Lucia Altucci
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy; (V.C.); (A.P.); (L.D.T.); (P.G.); (M.D.D.); (E.S.); (Z.Y.); (G.C.)
- Correspondence: (A.M.); (D.R.); (A.N.); (L.A.); Tel.: +39-0649-913-392 (A.M.); +39-0649-913-891 (D.R.); +39-0815-665-682 (A.N.); +39-0815-667-569 (L.A.); Fax: +39-064-9693-268 (A.M. & D.R.); +39-081-450-169 (A.N. & L.A.)
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Albasri AM, Elkablawy MA. Clinicopathological and prognostic significance of androgen receptor overexpression in colorectal cancer. Experience from Al-Madinah Al-Munawarah, Saudi Arabia. Saudi Med J 2019; 40:893-900. [PMID: 31522216 PMCID: PMC6790489 DOI: 10.15537/smj.2019.9.24204] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/11/2019] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVES To examine the androgen receptor (AR) status in colorectal cancer (CRC) patients by the immunohistochemical method and to correlate the findings with all available clinicopathological parameters of prognostic significance. METHODS Archival tumor samples were studied using immunohistochemistry for AR expression in 324 patients with CRC. Patients were diagnosed at the Pathology Department at a tertiary care Hospital, Al-Madinah Al-Munawarah, Saudi Arabia, between January 2006 and December 2017. RESULTS There is a complete lack of AR expression in normal colonic mucosa; however, AR was expressed in 16 cases (40%) of colorectal adenoma. In CRC, AR expression was high in 118 cases (36.4%). There were no significant correlations between AR expression and gender, age, tumor histologic type, and tumor location. However, AR expression revealed a significant correlation with tumor size (p=0.026), tumor differentiation (p=0.047), American Joint Committee on Cancer (AJCC) staging (p=0.043), lymph node positivity (p=0.018), lymphovascular invasion (p=0.018), and distant metastasis (p=0.049). In univariate Kaplan-Meier survival analysis, there was a significant (p=0.002) difference in overall survival between AR positive and negative tumors in favor of the latter. In multivariate (COX) models, high AR expression (p=0.002), AJCC (p less than 0.001), and lymphovascular invasion (p less than 0.001) were the only significant independent prognostic indicators of overall survival in CRC.Conlusion: Our study showed that the patients with higher AR expression had a significantly poorer survival rate, AR expression had the potential to be a prognostic marker of CRC.
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Affiliation(s)
- Abdulkader M Albasri
- Pathology Department, Faculty of Medicine, Taibah University, Al-Madinah Al-Munawarah, Kingdom of Saudi Arabia. E-mail.
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Teruya K, Kusumoto Y, Eto H, Nakamichi N, Shirahata S. Selective Suppression of Cell Growth and Programmed Cell Death-Ligand 1 Expression in HT1080 Fibrosarcoma Cells by Low Molecular Weight Fucoidan Extract. Mar Drugs 2019; 17:E421. [PMID: 31331053 PMCID: PMC6669552 DOI: 10.3390/md17070421] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/12/2019] [Accepted: 07/14/2019] [Indexed: 12/14/2022] Open
Abstract
Low molecular weight fucoidan extract (LMF), prepared by an abalone glycosidase digestion of a crude fucoidan extracted from Cladosiphon novae-caledoniae Kylin, exhibits various biological activities, including anticancer effect. Various cancers express programmed cell death-ligand 1 (PD-L1), which is known to play a significant role in evasion of the host immune surveillance system. PD-L1 is also expressed in many types of normal cells for self-protection. Previous research has revealed that selective inhibition of PD-L1 expressed in cancer cells is critical for successful cancer eradication. In the present study, we analyzed whether LMF could regulate PD-L1 expression in HT1080 fibrosarcoma cells. Our results demonstrated that LMF suppressed PD-L1/PD-L2 expression and the growth of HT1080 cancer cells and had no effect on the growth of normal TIG-1 cells. Thus, LMF differentially regulates PD-L1 expression in normal and cancer cells and could serve as an alternative complementary agent for treatment of cancers with high PD-L1 expression.
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Affiliation(s)
- Kiichiro Teruya
- Faculty of Agriculture, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
- Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
| | - Yoshihiro Kusumoto
- Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Hiroshi Eto
- Daiichi Sangyo Co., Ltd., 6-7-2 Nishitenma, Kita-ku, Osaka 530-0047, Japan
| | - Noboru Nakamichi
- Daiichi Sangyo Co., Ltd., 6-7-2 Nishitenma, Kita-ku, Osaka 530-0047, Japan
| | - Sanetaka Shirahata
- Faculty of Agriculture, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
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Bleach R, McIlroy M. The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology. Front Endocrinol (Lausanne) 2018; 9:594. [PMID: 30416486 PMCID: PMC6213369 DOI: 10.3389/fendo.2018.00594] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/19/2018] [Indexed: 12/16/2022] Open
Abstract
Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19-29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.
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Affiliation(s)
| | - Marie McIlroy
- Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
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10
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Park JY, Baek MH, Park Y, Kim YT, Nam JH. Investigation of hormone receptor expression and its prognostic value in endometrial stromal sarcoma. Virchows Arch 2018; 473:61-69. [DOI: 10.1007/s00428-018-2358-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/30/2018] [Accepted: 04/05/2018] [Indexed: 10/14/2022]
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11
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Teng Y, Cai Y, Pi W, Gao L, Shay C. Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. J Hematol Oncol 2017; 10:118. [PMID: 28606127 PMCID: PMC5469135 DOI: 10.1186/s13045-017-0485-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 06/02/2017] [Indexed: 12/31/2022] Open
Abstract
Background Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticancer activity in multiple cancer types including prostate cancer. However, the molecular mechanisms of action of CYT997 in prostate cancer have not been well characterized. Methods Src knockdown cells were achieved by lentiviral-mediated interference. The drug effects on cell proliferation were measured by MTS. The drug effects on cell viability and death were determined by Cell Titer-Glo® Luminescent cell viability kit and flow cytometry with Zombie Aqua™ staining. The drug effects on apoptosis were assessed by Cell Death Detection Elisa kit and Western blot with a cleaved PARP antibody. The drug effects on cell invasion were examined by Matrigel-coated Boyden chambers. Oxidative stress was detected by DCFH-DA staining and electrochemical biosensor. Mouse models generated by subcutaneous or intracardiac injection were used to investigate the in vivo drug efficacy in tumor growth and metastasis. Results CYT997 effectively inhibited proliferation, survival, and invasion of prostate cancer cells via blocking multiple oncogenic signaling cascades but not the Src pathway. Inhibition of Src expression by small hairpin RNA or inactivation of Src by dasatinib increased the CYT997-induced cytotoxicity of in vitro. Moreover, the combination of dasatinib and CYT997 exhibited a superior inhibitory effect on tumor growth and metastasis compared with either of the drugs alone. Conclusion Our findings demonstrate that blockage of Src augments the anticancer effect of CYT997 on prostate cancer and suggest that co-treatment of dasatinib and CYT997 may represent an effective therapeutic regimen for limiting prostate cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0485-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yong Teng
- Department of Oral Biology, Augusta University, Augusta, GA, 30912, USA. .,Georgia Cancer Center, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. .,Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
| | - Yafei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wenhu Pi
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.,Department of Radiation Oncology, Indiana University, Indianapolis, IN, 46202, USA
| | - Lixia Gao
- Department of Oral Biology, Augusta University, Augusta, GA, 30912, USA
| | - Chloe Shay
- Department of Pediatrics, Emory Children's Center, Emory University, Atlanta, GA, 30322, USA
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12
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Castoria G, Auricchio F, Migliaccio A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis. FASEB J 2016; 31:1289-1300. [PMID: 28031322 DOI: 10.1096/fj.201601047r] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 12/19/2016] [Indexed: 01/11/2023]
Abstract
In this review, we focus on the role played by the protein partners of ligand-activated extranuclear androgen receptor (AR) in the final effects of hormone action, such as proliferation, migration, and neuritogenesis. The choice of AR partner, at least in part, depends on cell type. Androgen-activated receptor directly associates with cytoplasmic Src tyrosine kinase in epithelial cells, whereas in mesenchymal and neuronal cells, it prevalently interacts with filamin A. In the former, proliferation represents the final hormonal outcome, whereas in the latter, either migration or neuritogenesis, respectively, occurs. Furthermore, AR partner filamin A is replaced with Src when mesenchymal cells are stimulated with very low androgen concentrations. Consequently, the migratory effect is replaced by mitogenesis. Use of peptides that prevent receptor/partner assembly abolishes the effects that are dependent on their association and offers new therapeutic approaches to AR-related diseases. Perturbation of migration is often associated with metastatic spreading in cancer. In turn, cell cycle aberration causes tumors to grow faster, whereas toxic signaling triggers neurodegenerative events in the CNS. Here, we provide examples of new tools that interfere in rapid androgen effects, including migration, proliferation, and neuronal differentiation, together with their potential therapeutic applications in AR-dependent diseases-mainly prostate cancer and neurodegenerative disorders.-Castoria, G., Auricchio, F., Migliaccio, A. Extranuclear partners of androgen receptor: at the crossroads of proliferation, migration, and neuritogenesis.
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Affiliation(s)
- Gabriella Castoria
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Ferdinando Auricchio
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics, and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy
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Di Zazzo E, Galasso G, Giovannelli P, Di Donato M, Di Santi A, Cernera G, Rossi V, Abbondanza C, Moncharmont B, Sinisi AA, Castoria G, Migliaccio A. Prostate cancer stem cells: the role of androgen and estrogen receptors. Oncotarget 2016; 7:193-208. [PMID: 26506594 PMCID: PMC4807992 DOI: 10.18632/oncotarget.6220] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 12/22/2022] Open
Abstract
Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment. In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.
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Affiliation(s)
- Erika Di Zazzo
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Giovanni Galasso
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Pia Giovannelli
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Marzia Di Donato
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Annalisa Di Santi
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Gustavo Cernera
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Valentina Rossi
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Ciro Abbondanza
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | | | - Antonio Agostino Sinisi
- Endocrinology Section, Department of Cardio-Thoracic and Respiratory Diseases, II University of Naples, Naples, Italy
| | - Gabriella Castoria
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
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Patel A, Sabbineni H, Clarke A, Somanath PR. Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis. Life Sci 2016; 157:52-61. [PMID: 27245276 DOI: 10.1016/j.lfs.2016.05.036] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/25/2016] [Accepted: 05/27/2016] [Indexed: 12/21/2022]
Abstract
The Src-family kinases (SFKs), an intracellularly located group of non-receptor tyrosine kinases are involved in oncogenesis. The importance of SFKs has been implicated in the promotion of tumor cell motility, proliferation, inhibition of apoptosis, invasion and metastasis. Recent evidences indicate that specific effects of SFKs on epithelial-to-mesenchymal transition (EMT) as well as on endothelial and stromal cells in the tumor microenvironment can have profound effects on tumor microinvasion and metastasis. Although, having been studied extensively, these novel features of SFKs may contribute to greater understanding of benefits from Src inhibition in various types of cancers. Here we review the novel role of SFKs, particularly c-Src in mediating EMT, modulation of tumor endothelial-barrier, transendothelial migration (microinvasion) and metastasis of cancer cells, and discuss the utility of Src inhibitors in vascular normalization and cancer therapy.
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Affiliation(s)
- Ami Patel
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States
| | - Harika Sabbineni
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States; Charlie Norwood VA Medical Center, Augusta, GA, United States
| | - Andrea Clarke
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States
| | - Payaningal R Somanath
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States; Charlie Norwood VA Medical Center, Augusta, GA, United States; Department of Medicine, Vascular Biology Center and Cancer Center, Augusta University, Augusta, GA, United States.
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15
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Caiazza F, Murray A, Madden SF, Synnott NC, Ryan EJ, O'Donovan N, Crown J, Duffy MJ. Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells. Endocr Relat Cancer 2016; 23:323-34. [PMID: 26932782 DOI: 10.1530/erc-16-0068] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/01/2016] [Indexed: 12/22/2022]
Abstract
The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC50 values for the second-generation anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.
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Affiliation(s)
- Francesco Caiazza
- School of MedicineUniversity College Dublin, Ireland Centre for Colorectal DiseaseSt. Vincent's University Hospital, Dublin, Ireland
| | - Alyson Murray
- School of MedicineUniversity College Dublin, Ireland
| | - Stephen F Madden
- Population Health SciencesDepartment of Psychology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Elizabeth J Ryan
- School of MedicineUniversity College Dublin, Ireland Centre for Colorectal DiseaseSt. Vincent's University Hospital, Dublin, Ireland
| | - Norma O'Donovan
- National Institute for Cellular Biotechnology (NICB)Dublin City University, Dublin, Ireland
| | - John Crown
- School of MedicineUniversity College Dublin, Ireland Department of Medical OncologySt. Vincent's University Hospital, Dublin, Ireland
| | - Michael J Duffy
- School of MedicineUniversity College Dublin, Ireland UCD Clinical Research CentreSt. Vincent's University Hospital, Dublin, Ireland
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Archibald M, Pritchard T, Nehoff H, Rosengren RJ, Greish K, Taurin S. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer. Int J Nanomedicine 2016; 11:179-200. [PMID: 26811677 PMCID: PMC4712974 DOI: 10.2147/ijn.s97286] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.
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Affiliation(s)
- Monica Archibald
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Tara Pritchard
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Hayley Nehoff
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Rhonda J Rosengren
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
| | - Khaled Greish
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
- Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Sebastien Taurin
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
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17
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Chen H, Shen J, Choy E, Hornicek FJ, Duan Z. Targeting protein kinases to reverse multidrug resistance in sarcoma. Cancer Treat Rev 2015; 43:8-18. [PMID: 26827688 DOI: 10.1016/j.ctrv.2015.11.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/27/2015] [Accepted: 11/30/2015] [Indexed: 12/28/2022]
Abstract
Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.
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Affiliation(s)
- Hua Chen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States; Department of Emergency Surgery, ShenZhen People's Hospital, 2nd Clinical Medical College of Jinan University, No. 1017 Dongmenbei Road, Shenzhen, Guangdong Province 518020, China
| | - Jacson Shen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Edwin Choy
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, United States.
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18
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Kanda T, Jiang X, Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol 2014; 20:9229-9236. [PMID: 25071315 PMCID: PMC4110552 DOI: 10.3748/wjg.v20.i28.9229] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/07/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these "difficult to treat" cancers.
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Di Donato M, Giovannelli P, Cernera G, Di Santi A, Marino I, Bilancio A, Galasso G, Auricchio F, Migliaccio A, Castoria G. Non-genomic androgen action regulates proliferative/migratory signaling in stromal cells. Front Endocrinol (Lausanne) 2014; 5:225. [PMID: 25646090 PMCID: PMC4298220 DOI: 10.3389/fendo.2014.00225] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 12/08/2014] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is the major cause of cancer-related death among the male population of Western society, and androgen-deprivation therapy (ADT) represents the first line in PCa treatment. However, although androgen receptor (AR) expression is maintained throughout the various stages of PCa, ADT frequently fails. Clinical studies have demonstrated that different androgen/AR signaling pathways operate in target tissues. AR stimulates growth and transformation of target cells, but under certain conditions slows down their proliferation. In this review, we discuss the role of AR in controlling different functions of mesenchymal and transformed mesenchymal cells. Findings here presented support the role of AR in suppressing proliferation and stimulating migration of stromal cells, with implications for current approaches to cancer therapy.
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Affiliation(s)
- Marzia Di Donato
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Pia Giovannelli
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Gustavo Cernera
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Annalisa Di Santi
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Irene Marino
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Antonio Bilancio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Giovanni Galasso
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Ferdinando Auricchio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Antimo Migliaccio
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
| | - Gabriella Castoria
- Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Naples, Italy
- *Correspondence: Gabriella Castoria, Department of Biochemistry, Biophysics and General Pathology, II University of Naples, Via L. De Crecchio 7, Naples 80138, Italy e-mail:
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