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1
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Steinlechner M, Strobel L, Leitner K, Pan TL, Feroz B, Marth C, Zeimet AG. Pegylated liposomal doxorubicin combined with trabectedin as a treatment option in uterine sarcomas: a single-institution retrospective analysis. Int J Gynecol Cancer 2024; 34:1196-1202. [PMID: 38688662 PMCID: PMC11347196 DOI: 10.1136/ijgc-2023-005170] [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: 11/30/2023] [Accepted: 04/16/2024] [Indexed: 05/02/2024] Open
Abstract
OBJECTIVE The use of conventional doxorubicin in combination with trabectedin leads to a considerable prolongation of progression-free survival in the treatment of uterine sarcomas but is associated with dose-limiting toxicities. Significant progression-free survival improvement was recently obtained through treatment prolongation with trabectedin single agent. We hypothesize that the therapeutic index of pegylated liposomal doxorubicin combined with trabectedin could be superior to the combination with conventional doxorubicin due to a more favorable toxicity profile. METHODS In this retrospective cohort study, the clinical outcome was analyzed in patients with advanced or recurrent uterine sarcomas with measurable disease treated with pegylated liposomal doxorubicin 30 mg/m2 plus trabectedin 1.5 mg/m2 given every 3 weeks between January 2011 and April 2023 at the University Hospital in Innsbruck. Response evaluation was done every three cycles. Toxicity was evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria on 107 administered cycles. RESULTS A total of 21 patients were included in the study. In 67% (n=14) of patients, pegylated liposomal doxorubicin plus trabectedin was given as first-line treatment. One patient (5%) achieved a complete response and four (19%) a partial response, resulting in an objective response rate of 24%. Four other patients (19%) had stable disease. The median duration of the response was 14 months (range 3-74). Progression was recorded in 12 patients (57%). Median progression-free survival was 6 months (95% CI 1 to 11 months), while median overall survival was 26 months (95% CI 9 to 43 months). A median of 6 (range 1-11) cycles per patient were administered. Regarding grade ≥3 toxicity, neutropenia was recorded in 29%, thrombocytopenia in 14%, and febrile neutropenia in 19% of patients. Hematologic toxicity was the most frequent reason for dose delays (n=16) and dose reductions (n=5). CONCLUSION Our study found an overall clinical benefit for the combination of pegylated liposomal doxorubicin plus trabectedin in metastatic uterine sarcomas of 43% and appears to exhibit a favorable toxicity profile which allows prolonged administration of this regimen.
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Affiliation(s)
- Magdalena Steinlechner
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Laura Strobel
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Katharina Leitner
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Teresa L Pan
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Barin Feroz
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
| | - Alain G Zeimet
- Department of Obstetrics and Gynecology, Medical University Innsbruck, Innsbruck, Austria
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2
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Bhusare N, Gade A, Kumar MS. Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy. J Biochem Mol Toxicol 2024; 38:e23732. [PMID: 38769657 DOI: 10.1002/jbt.23732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 05/22/2024]
Abstract
Achieving targeted, customized, and combination therapies with clarity of the involved molecular pathways is crucial in the treatment as well as overcoming multidrug resistance (MDR) in cancer. Nanotechnology has emerged as an innovative and promising approach to address the problem of drug resistance. Developing nano-formulation-based therapies using therapeutic agents poses a synergistic effect to overcome MDR in cancer. In this review, we aimed to highlight the important pathways involved in the progression of MDR in cancer mediated through nanotechnology-based approaches that have been employed to circumvent them in recent years. Here, we also discussed the potential use of marine metabolites to treat MDR in cancer, utilizing active drug-targeting nanomedicine-based techniques to enhance selective drug accumulation in cancer cells. The discussion also provides future insights for developing complex targeted, multistage responsive nanomedical drug delivery systems for effective cancer treatments. We propose more combinational studies and their validation for the possible marine-based nanoformulations for future development.
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Affiliation(s)
- Nilam Bhusare
- Somaiya Institute for Research and Consultancy, Somaiya Vidyavihar University, Vidyavihar (E), Mumbai, India
| | - Anushree Gade
- Somaiya Institute for Research and Consultancy, Somaiya Vidyavihar University, Vidyavihar (E), Mumbai, India
| | - Maushmi S Kumar
- Somaiya Institute for Research and Consultancy, Somaiya Vidyavihar University, Vidyavihar (E), Mumbai, India
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3
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Povo-Retana A, Landauro-Vera R, Alvarez-Lucena C, Cascante M, Boscá L. Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment-Progresses in Their Use in Combined Cancer Therapy. Molecules 2024; 29:331. [PMID: 38257245 PMCID: PMC10820391 DOI: 10.3390/molecules29020331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 12/30/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects.
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Affiliation(s)
- Adrián Povo-Retana
- Instituto de Investigaciones Biomédicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (R.L.-V.); (C.A.-L.)
| | - Rodrigo Landauro-Vera
- Instituto de Investigaciones Biomédicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (R.L.-V.); (C.A.-L.)
| | - Carlota Alvarez-Lucena
- Instituto de Investigaciones Biomédicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (R.L.-V.); (C.A.-L.)
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine-Institute of Biomedicine (IBUB), Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain;
- Department of Material Science and Physical Chemistry, Research Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, 08028 Barcelona, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols-Morreale (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (R.L.-V.); (C.A.-L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
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4
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Santaniello G, Nebbioso A, Altucci L, Conte M. Recent Advancement in Anticancer Compounds from Marine Organisms: Approval, Use and Bioinformatic Approaches to Predict New Targets. Mar Drugs 2022; 21:md21010024. [PMID: 36662197 PMCID: PMC9862894 DOI: 10.3390/md21010024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/23/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
In recent years, the study of anticancer bioactive compounds from marine sources has received wide interest. Contextually, world regulatory authorities have approved several marine molecules, and new synthetic derivatives have also been synthesized and structurally improved for the treatment of numerous forms of cancer. However, the administration of drugs in cancer patients requires careful evaluation since their interaction with individual biological macromolecules, such as proteins or nucleic acids, determines variable downstream effects. This is reflected in a constant search for personalized therapies that lay the foundations of modern medicine. The new knowledge acquired on cancer mechanisms has certainly allowed advancements in tumor prevention, but unfortunately, due to the huge complexity and heterogeneity of cancer, we are still looking for a definitive therapy and clinical approaches. In this review, we discuss the significance of recently approved molecules originating from the marine environment, starting from their organism of origin to their structure and mechanism of action. Subsequently, these bio-compounds are used as models to illustrate possible bioinformatics approaches for the search of new targets that are useful for improving the knowledge on anticancer therapies.
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Affiliation(s)
- Giovanna Santaniello
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Vico L. De Crecchio 7, 80138 Naples, Italy
| | - Angela Nebbioso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Vico L. De Crecchio 7, 80138 Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Vico L. De Crecchio 7, 80138 Naples, Italy
- BIOGEM, Institute of Molecular Biology and Genetics, Via Camporeale, 83031 Ariano Irpino, Italy
- IEOS, Institute for Endocrinology and Experimental Oncology, CNR, Via Pansini 5, 80131 Napoli, Italy
- Correspondence: (L.A.); (M.C.); Tel.: +39-081-5667564 (M.C.)
| | - Mariarosaria Conte
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Vico L. De Crecchio 7, 80138 Naples, Italy
- Correspondence: (L.A.); (M.C.); Tel.: +39-081-5667564 (M.C.)
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5
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Teodori E, Braconi L, Manetti D, Romanelli MN, Dei S. The Tetrahydroisoquinoline Scaffold in ABC Transporter Inhibitors that Act as Multidrug Resistance (MDR) Reversers. Curr Top Med Chem 2022; 22:2535-2569. [PMID: 36284399 DOI: 10.2174/1568026623666221025111528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/08/2022] [Accepted: 09/27/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND The failure of anticancer chemotherapy is often due to the development of resistance to a variety of anticancer drugs. This phenomenon is called multidrug resistance (MDR) and is related to the overexpression of ABC transporters, such as P-glycoprotein, multidrug resistance- associated protein 1 and breast cancer resistance protein. Over the past few decades, several ABC protein modulators have been discovered and studied as a possible approach to evade MDR and increase the success of anticancer chemotherapy. Nevertheless, the co-administration of pump inhibitors with cytotoxic drugs, which are substrates of the transporters, does not appear to be associated with an improvement in the therapeutic efficacy of antitumor agents. However, more recently discovered MDR reversing agents, such as the two tetrahydroisoquinoline derivatives tariquidar and elacridar, are characterized by high affinity towards the ABC proteins and by reduced negative properties. Consequently, many analogs of these two derivatives have been synthesized, with the aim of optimizing their MDR reversal properties. OBJECTIVE This review aims to describe the MDR modulators carrying the tetraidroisoquinoline scaffold reported in the literature in the period 2009-2021, highlighting the structural characteristics that confer potency and/or selectivity towards the three ABC transport proteins. RESULTS AND CONCLUSION Many compounds have been synthesized in the last twelve years showing interesting properties, both in terms of potency and selectivity. Although clear structure-activity relationships can be drawn only by considering strictly related compounds, some of the compounds reviewed could be promising starting points for the design of new ABC protein inhibitors.
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Affiliation(s)
- Elisabetta Teodori
- Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy
| | - Laura Braconi
- Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy
| | - Dina Manetti
- Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy
| | - Maria Novella Romanelli
- Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy
| | - Silvia Dei
- Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019, Sesto Fiorentino (FI), Italy
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6
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Wang J, Wang P, Zeng Z, Lin C, Lin Y, Cao D, Ma W, Xu W, Xiang Q, Luo L, Wang W, Shi Y, Gao Z, Zhao Y, Liu H, Liu SL. Trabectedin in Cancers: Mechanisms and Clinical Applications. Curr Pharm Des 2022; 28:1949-1965. [PMID: 35619256 DOI: 10.2174/1381612828666220526125806] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/04/2022] [Indexed: 12/09/2022]
Abstract
Trabectedin, a tetrahydroisoquinoline alkaloid, is the first marine antineoplastic agent approved with special anticancer mechanisms involving DNA binding, DNA repair pathways, transcription regulation and regulation of the tumor microenvironment. It has favorable clinical applications, especially for the treatment of patients with advanced soft tissue sarcoma, who failed in anthracyclines and ifosfamide therapy or could not receive these agents. Currently, trabectedin monotherapy regimen and regimens of combined therapy with other agents are both widely used for the treatment of malignancies, including soft tissue sarcomas, ovarian cancer, breast cancer, and non-small-cell lung cancer. In this review, we summarized the basic information and some updated knowledge on trabectedin, including its molecular structure, metabolism in various cancers, pharmaceutical mechanisms, clinical applications, drug combination, and adverse reactions, along with prospections on its possibly more optimal use in cancer treatment.
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Affiliation(s)
- Jiali Wang
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Pengfei Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Zheng Zeng
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Caiji Lin
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Yiru Lin
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Danli Cao
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Wenqing Ma
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Wenwen Xu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Qian Xiang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Lingjie Luo
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Wenxue Wang
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Yongwei Shi
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Zixiang Gao
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Yufan Zhao
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China
| | - Huidi Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, T2N 4N1, Canada
| | - Shu-Lin Liu
- Genomics Research Center (State-Province Key Laboratories of Biomedicine Pharmaceutics of China), College of Pharmacy, and, Harbin Medical University, Harbin, China.,Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, T2N 4N1, Canada
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7
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Allavena P, Belgiovine C, Digifico E, Frapolli R, D'Incalci M. Effects of the Anti-Tumor Agents Trabectedin and Lurbinectedin on Immune Cells of the Tumor Microenvironment. Front Oncol 2022; 12:851790. [PMID: 35299737 PMCID: PMC8921639 DOI: 10.3389/fonc.2022.851790] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Immune cells in the tumor micro-environment (TME) establish a complex relationship with cancer cells and may strongly influence disease progression and response to therapy. It is well established that myeloid cells infiltrating tumor tissues favor cancer progression. Tumor-Associated Macrophages (TAMs) are abundantly present at the TME and actively promote cancer cell proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Active research of the last decade has provided novel therapeutic approaches aimed at depleting TAMs and/or at reprogramming their functional activities. We reported some years ago that the registered anti-tumor agent trabectedin and its analogue lurbinectedin have numerous mechanisms of action that also involve direct effects on immune cells, opening up new interesting points of view. Trabectedin and lurbinectedin share the unique feature of being able to simultaneously kill cancer cells and to affect several features of the TME, most notably by inducing the rapid and selective apoptosis of monocytes and macrophages, and by inhibiting the transcription of several inflammatory mediators. Furthermore, depletion of TAMs alleviates the immunosuppressive milieu and rescues T cell functional activities, thus enhancing the anti-tumor response to immunotherapy with checkpoint inhibitors. In view of the growing interest in tumor-infiltrating immune cells, the availability of antineoplastic compounds showing immunomodulatory effects on innate and adaptive immunity deserves particular attention in the oncology field.
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Affiliation(s)
- Paola Allavena
- Department Immunology, IRCCS Humanitas Clinical and Research Center, Milan, Italy
| | - Cristina Belgiovine
- Department Immunology, IRCCS Humanitas Clinical and Research Center, Milan, Italy
| | - Elisabeth Digifico
- Department Immunology, IRCCS Humanitas Clinical and Research Center, Milan, Italy
| | - Roberta Frapolli
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Maurizio D'Incalci
- Department Immunology, IRCCS Humanitas Clinical and Research Center, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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8
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Yamano A, Asato Y, Natsume N, Iwasaki A, Suenaga K, Teruya T. Odookeanynes A and B, Acetylene-Containing Lipopeptides from an Okeania sp. Marine Cyanobacterium. JOURNAL OF NATURAL PRODUCTS 2022; 85:169-175. [PMID: 34928625 DOI: 10.1021/acs.jnatprod.1c00915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Odookeanynes A (1) and B (2), two acetylene-containing lipopeptides, were isolated from an Okeania sp. marine cyanobacterium collected in Okinawa, Japan. Their structures were elucidated by spectroscopic analysis and Marfey's analysis of acid hydrolysates. Odookeanynes A (1) and B (2) dose-dependently promoted the differentiation of mouse 3T3-L1 preadipocytes in the presence of insulin.
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Affiliation(s)
- Aki Yamano
- Faculty of Education, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
| | - Yuka Asato
- Graduate School of Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
| | - Noriyuki Natsume
- Graduate School of Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
| | - Arihiro Iwasaki
- Department of Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
| | - Kiyotake Suenaga
- Department of Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
| | - Toshiaki Teruya
- Faculty of Education, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
- Graduate School of Science, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
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9
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Jones RL, Herzog TJ, Patel SR, von Mehren M, Schuetze SM, Van Tine BA, Coleman RL, Knoblauch R, Triantos S, Hu P, Shalaby W, McGowan T, Monk BJ, Demetri GD. Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer. Cancer Med 2021; 10:3565-3574. [PMID: 33960681 PMCID: PMC8178483 DOI: 10.1002/cam4.3903] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/15/2021] [Accepted: 03/03/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment. METHODS Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231). RESULTS Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24-2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12-2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75-4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16-3.05]; p = 0.010). CONCLUSIONS For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.
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Affiliation(s)
- Robin L. Jones
- Sarcoma UnitRoyal Marsden Hospital/Institute of Cancer ResearchLondonUK
| | - Thomas J. Herzog
- University of Cincinnati Cancer CenterUniversity of CincinnatiCincinnatiOHUSA
| | - Shreyaskumar R. Patel
- Department of Sarcoma Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonTXUSA
| | | | | | | | | | | | | | - Peter Hu
- Janssen Research & Development, LLCRaritanNJUSA
| | - Waleed Shalaby
- Medical Group OncologyJanssen Scientific Affairs, LLCHorshamPAUSA
| | - Tracy McGowan
- Medical Group OncologyJanssen Scientific Affairs, LLCHorshamPAUSA
| | - Bradley J. Monk
- Arizona Oncology (US Oncology Network)University of Arizona College of Medicine, and Creighton University School of Medicine at St. Joseph's Hospital and Medical CenterPhoenixAZUSA
| | - George D. Demetri
- Sarcoma CenterDepartment of Medical OncologyDana‐Farber Cancer Institute (DFCI)Harvard Medical School and Ludwig Center at HarvardBostonMAUSA
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10
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Mechanisms of Resistance to Conventional Therapies for Osteosarcoma. Cancers (Basel) 2021; 13:cancers13040683. [PMID: 33567616 PMCID: PMC7915189 DOI: 10.3390/cancers13040683] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.
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Lilienthal I, Herold N. Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies. Int J Mol Sci 2020; 21:ijms21186885. [PMID: 32961800 PMCID: PMC7555161 DOI: 10.3390/ijms21186885] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
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Affiliation(s)
- Ingrid Lilienthal
- Division of Paediatric Oncology, Department of Women’s and Children’s Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Correspondence: (I.L.); (N.H.); Tel.: +46-(0)8-52483204 (I.L. & N.H.)
| | - Nikolas Herold
- Division of Paediatric Oncology, Department of Women’s and Children’s Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Paediatric Oncology, Astrid Lindgren’s Children Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
- Correspondence: (I.L.); (N.H.); Tel.: +46-(0)8-52483204 (I.L. & N.H.)
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12
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Yuan B, Liu D, Guan X, Yan Y, Zhang J, Zhang Y, Yang D, Ma M, Lin W. Piperazine ring formation by a single-module NRPS and cleavage by an α-KG-dependent nonheme iron dioxygenase in brasiliamide biosynthesis. Appl Microbiol Biotechnol 2020; 104:6149-6159. [PMID: 32436033 DOI: 10.1007/s00253-020-10678-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/02/2020] [Accepted: 05/10/2020] [Indexed: 10/24/2022]
Abstract
Brasiliamides are a class of piperazine-containing alkaloids produced by Penicillium brasilianum with a range of pharmaceutical activities. The mechanism of brasiliamide biosynthesis, including piperazine ring formation and multiple tailoring modifications, still remains unclear. In this study, the biosynthetic gene cluster of brasiliamides, brs, was identified from the marine-derived fungal strain Penicillium brasilianum WZXY-M122-9. Deletion of a histone deacetylase-encoding gene using a CRISPR/Cas9 gene editing system led to the production of a new compound, namely brasiliamide I (1). The brs-encoded single-module nonribosomal peptide synthetase (NRPS) BrsA is involved in the formation of the piperazine skeleton of brasiliamides. Full-length BrsA protein (113.6 kDa) was purified, and reconstitution of enzymatic activity in vitro confirmed that BrsA stereoselectively accepts L-phenylalanine as the substrate. Multiple deletion of tailoring genes and analysis of purified proteins in vitro enabled us to propose a brasiliamide biosynthetic pathway. In the tailoring steps, an α-ketoglutarate (KG)-dependent nonheme iron dioxygenase, BrsJ, was identified to catalyze piperazine ring cleavage during biosynthesis of brasiliamide A (2). KEY POINTS: The gene cluster encoding brasiliamide biosynthesis, brs, is identified. Deletion of a histone deacetylase-encoding gene produces brasiliamide I. BrsA catalyzes brasiliamide piperazine skeleton formation. BrsJ catalyzes piperazine ring cleavage to produce brasiliamide A. Graphical abstract.
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Affiliation(s)
- Bochuan Yuan
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Dong Liu
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Xin Guan
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Yunchen Yan
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Jianping Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Yiping Zhang
- Technical Innovation Center for Utilization of Marine Biological Resources, Third Institute of Oceanography, MNR, Xiamen, 361005, People's Republic of China
| | - Donghui Yang
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China
| | - Ming Ma
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China.
| | - Wenhan Lin
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, People's Republic of China. .,Institute of Ocean Research, Peking University, Beijing, 100871, People's Republic of China.
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13
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Jimenez PC, Wilke DV, Branco PC, Bauermeister A, Rezende‐Teixeira P, Gaudêncio SP, Costa‐Lotufo LV. Enriching cancer pharmacology with drugs of marine origin. Br J Pharmacol 2020; 177:3-27. [PMID: 31621891 PMCID: PMC6976878 DOI: 10.1111/bph.14876] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 08/13/2019] [Accepted: 09/05/2019] [Indexed: 12/29/2022] Open
Abstract
Marine natural products have proven, over the last half-century, to be effective biological modulators. These molecules have revealed new targets for cancer therapy as well as dissimilar modes of action within typical classes of drugs. In this scenario, innovation from marine-based pharmaceuticals has helped advance cancer chemotherapy in many aspects, as most of these are designated as first-in-class drugs. Here, by examining the path from discovery to development of clinically approved drugs of marine origin for cancer treatment-cytarabine (Cytosar-U®), trabectedin (Yondelis®), eribulin (Halaven®), brentuximab vedotin (Adcetris®), and plitidepsin (Aplidin®)- together with those in late clinical trial phases-lurbinectedin, plinabulin, marizomib, and plocabulin-the present review offers a critical analysis of the contributions given by these new compounds to cancer pharmacotherapy.
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Affiliation(s)
- Paula C. Jimenez
- Departamento de Ciências do MarUniversidade Federal de São PauloSantosSPBrasil
| | - Diego V. Wilke
- Núcleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Departamento de Fisiologia e Farmacologia, Faculdade de MedicinaUniversidade Federal do CearáFortalezaCEBrasil
| | - Paola C. Branco
- Departamento de Farmacologia, Instituto de Ciências BiomédicasUniversidade de São PauloSão PauloSPBrasil
| | - Anelize Bauermeister
- Departamento de Farmacologia, Instituto de Ciências BiomédicasUniversidade de São PauloSão PauloSPBrasil
| | - Paula Rezende‐Teixeira
- Departamento de Farmacologia, Instituto de Ciências BiomédicasUniversidade de São PauloSão PauloSPBrasil
| | - Susana P. Gaudêncio
- UCIBIO, Department of Chemistry, Blue Biotechnology and Biomedicine Lab, Faculty of Science and TechnologyNOVA University of LisbonCaparicaPortugal
| | - Leticia V. Costa‐Lotufo
- Departamento de Farmacologia, Instituto de Ciências BiomédicasUniversidade de São PauloSão PauloSPBrasil
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14
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Carazo A, Mladěnka P, Pávek P. Marine Ligands of the Pregnane X Receptor (PXR): An Overview. Mar Drugs 2019; 17:md17100554. [PMID: 31569349 PMCID: PMC6836225 DOI: 10.3390/md17100554] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 09/27/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
Pregnane X Receptor (PXR) is a ligand-activated transcription factor which binds many structurally different molecules. The receptor is able to regulate the expression of a wide array of genes and is involved in cancer and different key physiological processes such as the metabolism of drugs/xenobiotics and endogenous compounds including lipids and carbohydrates, and inflammation. Algae, sponges, sea squirts, and other marine organisms are some of the species from which structurally new molecules have been isolated that have been subsequently identified in recent decades as ligands for PXR. The therapeutic potential of these natural compounds is promising in different areas and has recently resulted in the registration of trabectedin by the FDA as a novel antineoplastic drug. Apart from being potentially novel drugs, these compounds can also serve as models for the development of new molecules with improved activity. The aim of this review is to succinctly summarize the currently known natural molecules isolated from marine organisms with a proven ability to interact with PXR.
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Affiliation(s)
- Alejandro Carazo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
| | - Petr Pávek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic.
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15
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Jimenez PC, Wilke DV, Costa-Lotufo LV. Marine drugs for cancer: surfacing biotechnological innovations from the oceans. Clinics (Sao Paulo) 2018; 73:e482s. [PMID: 30133563 PMCID: PMC6096976 DOI: 10.6061/clinics/2018/e482s] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/06/2018] [Indexed: 12/31/2022] Open
Abstract
This review will discuss the contributions of marine natural molecules, a source only recently found to have pharmaceutical prospects, to the development of anticancer drugs. Of the seven clinically utilized compounds with a marine origin, four are used for the treatment of cancer. The development of these drugs has afforded valuable knowledge and crucial insights to meet the most common challenges in this endeavor, such as toxicity and supply. In this context, the development of these compounds will be discussed herein to illustrate, with successful examples provided by cytarabine, trabectedin, eribulin and brentuximab vedotin, the steps involved in this process as well as the scientific advances and technological innovation potential associated with developing a new drug from marine resources.
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Affiliation(s)
| | - Diego Veras Wilke
- Nucleo de Pesquisa e Desenvolvimento de Medicamentos (NPDM), Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceara, Fortaleza, CE, BR
| | - Leticia Veras Costa-Lotufo
- Departamento de Farmacologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
- *Corresponding Author. E-mail:
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16
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Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting Transcription Factors for Cancer Treatment. Molecules 2018; 23:molecules23061479. [PMID: 29921764 PMCID: PMC6100431 DOI: 10.3390/molecules23061479] [Citation(s) in RCA: 249] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/11/2018] [Accepted: 06/15/2018] [Indexed: 12/15/2022] Open
Abstract
Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.
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Affiliation(s)
- Mélanie Lambert
- INSERM UMR-S1172-JPARC (Jean-Pierre Aubert Research Center), Lille University and Hospital Center (CHU-Lille), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille, France.
| | - Samy Jambon
- INSERM UMR-S1172-JPARC (Jean-Pierre Aubert Research Center), Lille University and Hospital Center (CHU-Lille), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille, France.
| | - Sabine Depauw
- INSERM UMR-S1172-JPARC (Jean-Pierre Aubert Research Center), Lille University and Hospital Center (CHU-Lille), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille, France.
| | - Marie-Hélène David-Cordonnier
- INSERM UMR-S1172-JPARC (Jean-Pierre Aubert Research Center), Lille University and Hospital Center (CHU-Lille), Institut pour la Recherche sur le Cancer de Lille (IRCL), Place de Verdun, F-59045 Lille, France.
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17
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Watters DJ. Ascidian Toxins with Potential for Drug Development. Mar Drugs 2018; 16:E162. [PMID: 29757250 PMCID: PMC5983293 DOI: 10.3390/md16050162] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 05/05/2018] [Accepted: 05/10/2018] [Indexed: 12/17/2022] Open
Abstract
Ascidians (tunicates) are invertebrate chordates, and prolific producers of a wide variety of biologically active secondary metabolites from cyclic peptides to aromatic alkaloids. Several of these compounds have properties which make them candidates for potential new drugs to treat diseases such as cancer. Many of these natural products are not produced by the ascidians themselves, rather by their associated symbionts. This review will focus mainly on the mechanism of action of important classes of cytotoxic molecules isolated from ascidians. These toxins affect DNA transcription, protein translation, drug efflux pumps, signaling pathways and the cytoskeleton. Two ascidian compounds have already found applications in the treatment of cancer and others are being investigated for their potential in cancer, neurodegenerative and other diseases.
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Affiliation(s)
- Dianne J Watters
- School of Environment and Science, Griffith University, Brisbane, Queensland 4111, Australia.
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18
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Peraldo Neia C, Cavalloni G, Chiorino G, Ostano P, Aglietta M, Leone F. Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line. Oncotarget 2018; 7:86766-86780. [PMID: 27902465 PMCID: PMC5349952 DOI: 10.18632/oncotarget.13575] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 11/09/2016] [Indexed: 12/11/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes. In the PDX model, trabectedin affected ECM-receptor interaction, focal adhesion, complement and coagulation cascades, Hedgehog, MAPK, EGFR signaling via PIP3 pathway, and apoptosis. Among down-regulated genes, we selected SYK and LGALS1; their silencing caused a significantly reduction of migration, but did not affect proliferation in in vitro models. In MT-CHC01 cells, 24 microRNAs were deregulated upon drug treatment, while only 5 microRNAs were perturbed by trabectedin in PDX. The target prediction analysis showed that SYK and LGALS1 are putative targets of up-regulated microRNAs. In conclusion, we described that trabectedin affected genes and microRNAs involved in tumor progression and metastatic processes, reflecting data previously obtained at macroscopically level; in particular, we identified SYK and LGALS1 as new putative targets of trabectedin.
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Affiliation(s)
- Caterina Peraldo Neia
- University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy
| | - Giuliana Cavalloni
- Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy
| | - Giovanna Chiorino
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy
| | - Paola Ostano
- Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy
| | - Massimo Aglietta
- University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy.,Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy
| | - Francesco Leone
- University of Turin Medical School, Department of Oncology, IRCCS-Institute Candiolo, Italy.,Medical Oncology Division, Fondazione del Piemonte per l'Oncologia (FPO), IRCCS-Institute Candiolo, Italy
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19
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Ghouadni A, Delaloge S, Lardelli P, Kahatt C, Byrski T, Blum JL, Gonçalves A, Campone M, Nieto A, Alfaro V, Cullell-Young M, Lubinski J. Higher antitumor activity of trabectedin in germline BRCA2 carriers with advanced breast cancer as compared to BRCA1 carriers: A subset analysis of a dedicated phase II trial. Breast 2017; 34:18-23. [DOI: 10.1016/j.breast.2017.04.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 04/13/2017] [Accepted: 04/16/2017] [Indexed: 11/28/2022] Open
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20
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Joshi P, Vishwakarma RA, Bharate SB. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. Eur J Med Chem 2017; 138:273-292. [PMID: 28675836 DOI: 10.1016/j.ejmech.2017.06.047] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/19/2017] [Accepted: 06/23/2017] [Indexed: 12/11/2022]
Abstract
The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents. The clinical failure of first and second generation P-gp inhibitors (such as verapamil and cyclosporine analogs) has led to the discovery of third generation potent P-gp inhibitors (tariquidar, zosuquidar, laniquidar). Most of these inhibitors are nitrogenous compounds and recently a natural alkaloid CBT-01® (tetrandrine) has advanced to the clinical phase. CBT-01 demonstrated positive results in Phase-I study in combination with paclitaxel, which warranted conducting it's Phase II/III trial. Apart from this, there exist a large number of natural alkaloids possessing potent inhibition of P-gp efflux pump and other related pumps responsible for the development of resistance. Despite the extensive contribution of alkaloids in this area, has never been reviewed. The present review provides a comprehensive account on natural alkaloids possessing P-gp inhibition activity and their potential for multidrug resistance reversal in cancer.
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Affiliation(s)
- Prashant Joshi
- Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy and Scientific & Innovative Research (AcSIR), CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
| | - Ram A Vishwakarma
- Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy and Scientific & Innovative Research (AcSIR), CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
| | - Sandip B Bharate
- Medicinal Chemistry Division, CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy and Scientific & Innovative Research (AcSIR), CSIR - Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
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21
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Gurtner A, Manni I, Piaggio G. NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1860:604-616. [PMID: 27939755 DOI: 10.1016/j.bbagrm.2016.12.005] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/30/2016] [Accepted: 12/05/2016] [Indexed: 12/17/2022]
Abstract
NF-Y is a ubiquitous heterotrimeric transcription factor with a binding affinity for the CCAAT consensus motif, one of the most common cis-acting element in the promoter and enhancer regions of eukaryote genes in direct (CCAAT) or reverse (ATTGG) orientation. NF-Y consists of three subunits, NF-YA, the regulatory subunit of the trimer, NF-YB, and NF-YC, all required for CCAAT binding. Growing evidence in cells and animal models support the notion that NF-Y, driving transcription of a plethora of cell cycle regulatory genes, is a key player in the regulation of proliferation. Proper control of cellular growth is critical for cancer prevention and uncontrolled proliferation is a hallmark of cancer cells. Indeed, during cell transformation aberrant molecular pathways disrupt mechanisms controlling proliferation and many growth regulatory genes are altered in tumors. Here, we review bioinformatics, molecular and functional evidence indicating the involvement of the cell cycle regulator NF-Y in cancer-associated pathways. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.
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Affiliation(s)
- Aymone Gurtner
- Department of Research, Advanced Diagnostics and Technological Innovation, UOSD SAFU, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Isabella Manni
- Department of Research, Advanced Diagnostics and Technological Innovation, UOSD SAFU, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Giulia Piaggio
- Department of Research, Advanced Diagnostics and Technological Innovation, UOSD SAFU, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
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22
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Kishimoto S, Sato M, Tsunematsu Y, Watanabe K. Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids. Molecules 2016; 21:E1078. [PMID: 27548127 PMCID: PMC6274189 DOI: 10.3390/molecules21081078] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/15/2016] [Accepted: 08/15/2016] [Indexed: 01/13/2023] Open
Abstract
Varieties of alkaloids are known to be produced by various organisms, including bacteria, fungi and plants, as secondary metabolites that exhibit useful bioactivities. However, understanding of how those metabolites are biosynthesized still remains limited, because most of these compounds are isolated from plants and at a trace level of production. In this review, we focus on recent efforts in identifying the genes responsible for the biosynthesis of those nitrogen-containing natural products and elucidating the mechanisms involved in the biosynthetic processes. The alkaloids discussed in this review are ditryptophenaline (dimeric diketopiperazine alkaloid), saframycin (tetrahydroisoquinoline alkaloid), strictosidine (monoterpene indole alkaloid), ergotamine (ergot alkaloid) and opiates (benzylisoquinoline and morphinan alkaloid). This review also discusses the engineered biosynthesis of these compounds, primarily through heterologous reconstitution of target biosynthetic pathways in suitable hosts, such as Escherichia coli, Saccharomyces cerevisiae and Aspergillus nidulans. Those heterologous biosynthetic systems can be used to confirm the functions of the isolated genes, economically scale up the production of the alkaloids for commercial distributions and engineer the biosynthetic pathways to produce valuable analogs of the alkaloids. In particular, extensive involvement of oxidation reactions catalyzed by oxidoreductases, such as cytochrome P450s, during the secondary metabolite biosynthesis is discussed in details.
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Affiliation(s)
- Shinji Kishimoto
- Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
| | - Michio Sato
- Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
| | - Yuta Tsunematsu
- Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
| | - Kenji Watanabe
- Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
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23
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Long S, Sousa E, Kijjoa A, Pinto MMM. Marine Natural Products as Models to Circumvent Multidrug Resistance. Molecules 2016; 21:molecules21070892. [PMID: 27399665 PMCID: PMC6273648 DOI: 10.3390/molecules21070892] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 06/27/2016] [Accepted: 07/01/2016] [Indexed: 02/01/2023] Open
Abstract
Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.
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Affiliation(s)
- Solida Long
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto 4050-313, Portugal.
| | - Emília Sousa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto 4050-313, Portugal.
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal.
| | - Anake Kijjoa
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal.
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-123, Portugal.
| | - Madalena M M Pinto
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto 4050-313, Portugal.
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal.
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Abstract
INTRODUCTION Trabectedin is an anti-tumor compound registered in Europe and in several other countries, for the second-line treatment of soft tissue sarcoma (STS) and for ovarian cancer in combination with liposomal doxorubicin. Trabectedin inhibits cancer cell proliferation mainly affecting the transcription regulation. Trabectedin also acts as a modulator of tumor microenvironment by reducing the number of tumor associated macrophages (TAM). Because of its unique mechanism of action, trabectedin has the potential to act as antineoplastic agent also in several solid malignancies, including breast cancer (BC). AREAS COVERED This article reviews the preclinical and clinical data of trabectedin focusing on development in metastatic BC (mBC). Comments regarding the nature and the results of these trials are included. EXPERT OPINION Trabectedin is thought to have a crucial activity with defective DNA-repair machinery and also in modulating the tumor micro-environment and the immune-system of cancer patients. From the current available data, we recognize a potential activity of trabectedin in mBC and support the renewed efforts to better elucidate the value of trabectedin in this indication.
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Affiliation(s)
- Maurizio D'Incalci
- a Department of Oncology , IRCCS - Istituto di Ricerche Farmacologiche Mario Negri , Via La Masa 19, Milan 20156 , Italy
| | - Alberto Zambelli
- b Medical Oncology , Papa Giovanni XXIII Hospital , P.zza OMS 1, Bergamo 24127 , Italy
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Colmegna B, Uboldi S, Frapolli R, Licandro SA, Panini N, Galmarini CM, Badri N, Spanswick VJ, Bingham JP, Kiakos K, Erba E, Hartley JA, D'Incalci M. Increased sensitivity to platinum drugs of cancer cells with acquired resistance to trabectedin. Br J Cancer 2015; 113:1687-93. [PMID: 26633559 PMCID: PMC4701998 DOI: 10.1038/bjc.2015.407] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 10/29/2015] [Accepted: 11/06/2015] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND In order to investigate the mechanisms of acquired resistance to trabectedin, trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo. METHODS Resistant cell lines were obtained by repeated exposures to trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts. RESULTS 402-91/T and A2780/T cells were six-fold resistant to trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks. CONCLUSIONS Our finding that resistance to trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to trabectedin.
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Affiliation(s)
- B Colmegna
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - S Uboldi
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - R Frapolli
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - S A Licandro
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - N Panini
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - C M Galmarini
- Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo, Madrid 28770, Spain
| | - Nadia Badri
- Department of Research and Development (R&D), PharmaMar S.A., Colmenar Viejo, Madrid 28770, Spain
| | - V J Spanswick
- Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
| | - J P Bingham
- Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
| | - Konstantinos Kiakos
- Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
| | - E Erba
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
| | - J A Hartley
- Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
| | - M D'Incalci
- Department of Oncology, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, via La Masa 19, Milan 20156, Italy
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Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol 2015; 77:663-71. [DOI: 10.1007/s00280-015-2918-1] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 11/13/2015] [Indexed: 12/12/2022]
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Savreux-Lenglet G, Depauw S, David-Cordonnier MH. Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts. Int J Mol Sci 2015; 16:26555-81. [PMID: 26556350 PMCID: PMC4661830 DOI: 10.3390/ijms161125971] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 10/25/2015] [Accepted: 10/27/2015] [Indexed: 12/11/2022] Open
Abstract
DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.
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Affiliation(s)
- Gaëlle Savreux-Lenglet
- UMR-S1172-Jean-Pierre Aubert Research Centre (JPARC), INSERM, University of Lille, Lille Hospital, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun F-59045 Lille cedex, France.
| | - Sabine Depauw
- UMR-S1172-Jean-Pierre Aubert Research Centre (JPARC), INSERM, University of Lille, Lille Hospital, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun F-59045 Lille cedex, France.
| | - Marie-Hélène David-Cordonnier
- UMR-S1172-Jean-Pierre Aubert Research Centre (JPARC), INSERM, University of Lille, Lille Hospital, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun F-59045 Lille cedex, France.
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Targeting the EWS-FLI1 transcription factor in Ewing sarcoma. Cancer Chemother Pharmacol 2015; 75:1317-20. [PMID: 25809543 DOI: 10.1007/s00280-015-2726-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 03/10/2015] [Indexed: 12/15/2022]
Abstract
PURPOSE Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS-FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. METHODS Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. RESULTS The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. CONCLUSIONS The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma.
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Le VH, Inai M, Williams RM, Kan T. Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. Nat Prod Rep 2015; 32:328-47. [PMID: 25273374 PMCID: PMC4806878 DOI: 10.1039/c4np00051j] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.
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Affiliation(s)
- V H Le
- Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA.
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Reid A, Martin-Liberal J, Benson C. Trabectedin for advanced soft tissue sarcomas: optimizing use. Ther Clin Risk Manag 2014; 10:1003-11. [PMID: 25540587 PMCID: PMC4270297 DOI: 10.2147/tcrm.s49330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Patients with locally advanced or metastatic soft tissue sarcoma have a poor outlook with median survival in the order of 1 year. There is therefore an urgent need for novel agents to impact this disease. Trabectedin is one such novel agent that has demonstrated activity for patients with advanced soft tissue sarcoma and it was licensed in Europe in 2007 for patients in the second-line setting or first-line in those patients deemed unsuitable to receive cytotoxics. In order to best serve patients with novel agents, it is imperative to understand the mechanism or mechanisms of action and the best ways of assessing response in order to optimize antitumor activity. Frequently, the mechanism of action and the optimal means of assessing response will be different from those of traditional cytotoxics. Trial design should reflect these factors to ensure that active drugs are not wrongly marked as futile. This review discusses a number of factors that may influence the optimization of trabectedin use. These factors include the administration schedule, the optimal timing of trabectedin administration in the disease process, the histopathological and molecular subtypes that may be most sensitive to trabectedin, the challenge of assessing response, particularly using radiology, and, finally, the safety considerations with this agent.
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Affiliation(s)
- Alison Reid
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, UK
| | | | - Charlotte Benson
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, UK
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Tanaka T, Ohashi S, Saito H, Higuchi T, Tabata K, Kosuge Y, Suzuki T, Miyairi S, Kobayashi S. Indirubin derivatives alter DNA binding activity of the transcription factor NF-Y and inhibit MDR1 gene promoter. Eur J Pharmacol 2014; 741:83-9. [DOI: 10.1016/j.ejphar.2014.07.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 06/20/2014] [Accepted: 07/14/2014] [Indexed: 01/04/2023]
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Martínez S, Pérez L, Galmarini CM, Aracil M, Tercero JC, Gago F, Albella B, Bueren JA. Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway. Br J Pharmacol 2014; 170:871-82. [PMID: 23937566 DOI: 10.1111/bph.12331] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 07/22/2013] [Accepted: 07/26/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND AND PURPOSE We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. EXPERIMENTAL APPROACH Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated. KEY RESULTS While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC. CONCLUSIONS AND IMPLICATIONS Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of 'fanconizing' cancer cells in order to make them more sensitive to other anti-tumour drugs.
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Affiliation(s)
- Sandra Martínez
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-28040, Madrid, Spain; Pharmamar S.A., Avda. de los Reyes, 1 - Pol. Ind. La Mina, E-28770, Colmenar Viejo, Madrid, Spain
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Basmadjian C, Zhao Q, Bentouhami E, Djehal A, Nebigil CG, Johnson RA, Serova M, de Gramont A, Faivre S, Raymond E, Désaubry LG. Cancer wars: natural products strike back. Front Chem 2014; 2:20. [PMID: 24822174 PMCID: PMC4013484 DOI: 10.3389/fchem.2014.00020] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 04/04/2014] [Indexed: 12/14/2022] Open
Abstract
Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.
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Affiliation(s)
- Christine Basmadjian
- Therapeutic Innovation Laboratory, UMR7200, CNRS/University of StrasbourgIllkirch, France
- AAREC Filia ResearchClichy, France
| | - Qian Zhao
- Therapeutic Innovation Laboratory, UMR7200, CNRS/University of StrasbourgIllkirch, France
- AAREC Filia ResearchClichy, France
| | - Embarek Bentouhami
- L.C.I.M.N Laboratory, Department of Process Engineering, Faculty of Technology, University Ferhat AbbasSétif, Algeria
| | - Amel Djehal
- Therapeutic Innovation Laboratory, UMR7200, CNRS/University of StrasbourgIllkirch, France
- L.C.I.M.N Laboratory, Department of Process Engineering, Faculty of Technology, University Ferhat AbbasSétif, Algeria
| | - Canan G. Nebigil
- Biotechnology and Cell Signaling Laboratory, UMR 7242, CNRS/ University of StrasbourgIllkirch, France
| | - Roger A. Johnson
- Department of Physiology and Biophysics, State University of New YorkStony Brook, NY, USA
| | | | | | - Sandrine Faivre
- AAREC Filia ResearchClichy, France
- Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HPClichy, France
| | - Eric Raymond
- AAREC Filia ResearchClichy, France
- Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HPClichy, France
| | - Laurent G. Désaubry
- Therapeutic Innovation Laboratory, UMR7200, CNRS/University of StrasbourgIllkirch, France
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Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. Br J Cancer 2014; 111:646-50. [PMID: 24755886 PMCID: PMC4134488 DOI: 10.1038/bjc.2014.149] [Citation(s) in RCA: 167] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 02/25/2014] [Accepted: 02/26/2014] [Indexed: 11/08/2022] Open
Abstract
Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.
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Colmegna B, Uboldi S, Erba E, D'Incalci M. Resistance to minor groove binders. DRUG DISCOVERY TODAY. TECHNOLOGIES 2014; 11:73-79. [PMID: 24847656 DOI: 10.1016/j.ddtec.2014.03.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
In this paper multiple resistance mechanisms to minor groove binders (MGBs) are overviewed. MGBs with antitumor properties are natural products or their derivatives and, as expected, they are all substrates of P-glycoprotein (P-gp). However, a moderate expression of P-gp does not appear to reduce the sensitivity to trabectedin, the only MGB so far approved for clinical use. Resistance to this drug is often related to transcriptional mechanisms and to DNA repair pathways, particularly defects in transcription-coupled nucleotide excision repair (TC-NER). Therefore tumors resistant to trabectedin may become hypersensitive to UV rays and other DNA damaging agents acting in the major groove, such as Platinum (Pt) complexes. If this is confirmed in clinic, that will provide the rationale to combine trabectedin sequentially with Pt derivates.
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Puyo S, Montaudon D, Pourquier P. From old alkylating agents to new minor groove binders. Crit Rev Oncol Hematol 2014; 89:43-61. [DOI: 10.1016/j.critrevonc.2013.07.006] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 06/06/2013] [Accepted: 07/18/2013] [Indexed: 12/20/2022] Open
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Abstract
The immunomodulatory activity of extract fromStyela clavawas studied systematically based on activity trackingin vitroin order to find out novel-structured secondary metabolite. The proliferation rates of mouse splenic lymphocytes and peritoneal macrophages were used as screening index, as well as NO release promoting activities. The crude extract (CE) and its different polar fractions fromS. clavaall exhibited proliferative activity of splenolymphocytes and mouse macrophages, as well as NO release promoting activities, among which petroleum ether fraction (PE) showed the strongest effect. The antioxidant experimentin vitroshowed that CE demonstrated antioxidant ability in 1,1-diphenyl-2-picrylhydrazyl (DPPH) system and the beta carotene-linoleic acid system; the activity of ethyl acetate fraction (ET) was much stronger than that of the others. Further isolated by silica gel column chromatography, ET was classified into seven sub-components (E1~E7) listed in the order of activity asE5>E6>E4>E3>E7>E2>E1. Five compounds were separated as (1) cholesteric-7-en-3β-ol, (2) cholesteric-4-en-3β,6β-diol, (3) cholesterol, (4) batilol, and (5) ceramide, among which (1), (2), and (4) were isolated for the first time fromS. clava.
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Eid SY, El-Readi MZ, Eldin EEMN, Fatani SH, Wink M. Influence of combinations of digitonin with selected phenolics, terpenoids, and alkaloids on the expression and activity of P-glycoprotein in leukaemia and colon cancer cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2013; 21:47-61. [PMID: 23999162 DOI: 10.1016/j.phymed.2013.07.019] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 06/02/2013] [Accepted: 07/26/2013] [Indexed: 06/02/2023]
Abstract
P-glycoprotein (P-gp or MDR1) is an ATP-binding cassette (ABC) transporter. It is involved in the efflux of several anticancer drugs, which leads to chemotherapy failure and multidrug resistance (MDR) in cancer cells. Representative secondary metabolites (SM) including phenolics (EGCG and thymol), terpenoids (menthol, aromadendrene, β-sitosterol-O-glucoside, and β-carotene), and alkaloids (glaucine, harmine, and sanguinarine) were evaluated as potential P-gp inhibitors (transporter activity and expression level) in P-gp expressing Caco-2 and CEM/ADR5000 cancer cell lines. Selected SM increased the accumulation of the rhodamine 123 (Rho123) and calcein-AM (CAM) in a dose dependent manner in Caco-2 cells, indicating that they act as competitive inhibitors of P-gp. Non-toxic concentrations of β-carotene (40μM) and sanguinarine (1μM) significantly inhibited Rho123 and CAM efflux in CEM/ADR5000 cells by 222.42% and 259.25% and by 244.02% and 290.16%, respectively relative to verapamil (100%). Combination of the saponin digitonin (5μM), which also inhibits P-gp, with SM significantly enhanced the inhibition of P-gp activity. The results were correlated with the data obtained from a quantitative analysis of MDR1 expression. Both compounds significantly decreased mRNA levels of the MDR1 gene to 48% (p<0.01) and 46% (p<0.01) in Caco-2, and to 61% (p<0.05) and 1% (p<0.001) in CEM/ADR5000 cells, respectively as compared to the untreated control (100%). Combinations of digitonin with SM resulted in a significant down-regulation of MDR1. Our findings provide evidence that the selected SM interfere directly and/or indirectly with P-gp function. Combinations of different P-gp substrates, such as digitonin alone and together with the set of SM, can mediate MDR reversal in cancer cells.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Alkaloids/pharmacology
- Alkaloids/therapeutic use
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Benzophenanthridines/pharmacology
- Benzophenanthridines/therapeutic use
- Caco-2 Cells
- Colonic Neoplasms/drug therapy
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Digitonin/pharmacology
- Digitonin/therapeutic use
- Dose-Response Relationship, Drug
- Drug Combinations
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Synergism
- Fluoresceins/metabolism
- Humans
- Isoquinolines/pharmacology
- Isoquinolines/therapeutic use
- Leukemia/drug therapy
- Leukemia/genetics
- Leukemia/metabolism
- Phenols/pharmacology
- Phenols/therapeutic use
- Phytochemicals/pharmacology
- Phytochemicals/therapeutic use
- Phytotherapy
- Plant Extracts/pharmacology
- Plant Extracts/therapeutic use
- RNA, Messenger/metabolism
- Rhodamine 123/metabolism
- Terpenes/pharmacology
- Terpenes/therapeutic use
- beta Carotene/pharmacology
- beta Carotene/therapeutic use
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Affiliation(s)
- Safaa Yehia Eid
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
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39
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Di Giandomenico S, Frapolli R, Bello E, Uboldi S, Licandro SA, Marchini S, Beltrame L, Brich S, Mauro V, Tamborini E, Pilotti S, Casali PG, Grosso F, Sanfilippo R, Gronchi A, Mantovani R, Gatta R, Galmarini CM, Sousa-Faro JMF, D'Incalci M. Mode of action of trabectedin in myxoid liposarcomas. Oncogene 2013; 33:5201-10. [PMID: 24213580 DOI: 10.1038/onc.2013.462] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 09/04/2013] [Accepted: 09/05/2013] [Indexed: 12/11/2022]
Abstract
To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.
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Affiliation(s)
- S Di Giandomenico
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - R Frapolli
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - E Bello
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - S Uboldi
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - S A Licandro
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - S Marchini
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - L Beltrame
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
| | - S Brich
- Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - V Mauro
- Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - E Tamborini
- Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - S Pilotti
- Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - P G Casali
- Adult Sarcoma Medical Treatment Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - F Grosso
- Department of Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy
| | - R Sanfilippo
- Adult Sarcoma Medical Treatment Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - A Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - R Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - R Gatta
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | | | | | - M D'Incalci
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
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40
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Protein recognition of the S23906-1-DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Biochem J 2013; 452:147-59. [PMID: 23409959 DOI: 10.1042/bj20120860] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In a view to develop new DNA alkylating antitumour drugs, evaluating the precise mechanism of action and the molecular/cellular consequences of the alkylation is a point of major interest. The benzo-b-acronycine derivative S23906-1 alkylates guanine nucleobases in the minor groove of the DNA helix and presents an original ability to locally open the double helix of DNA, which appears to be associated with its cytotoxic activity. However, the molecular mechanism linking adduct formation to cellular consequences is not precisely known. The objective of the present study was to identify proteins involved in the recognition and mechanism of action of S23906-DNA adducts. We found that GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is a protein that binds to S23906-alkylated single-stranded, double-stranded and telomeric sequences in a drug-dependent and DNA sequence/structure-dependent manner. We used the CASTing (cyclic amplification of sequence targeting) method to identify GAPDH DNA-binding selectivity and then evaluated its binding to such selected S23906-alkylated sequences. At the cellular level, alkylation of S23906-1 results in an increase in the binding of GAPDH and its protein partner HMG (high-mobility group) B1 to the chromatin. Regarding the multiple roles of GAPDH in apoptosis and DNA repair, the cytotoxic and apoptotic activities of GAPDH were evaluated and present opposite effects in two different cellular models.
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41
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D'Angelo D, Borbone E, Palmieri D, Uboldi S, Esposito F, Frapolli R, Pacelli R, D'Incalci M, Fusco A. The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of trabectedin. Eur J Cancer 2012; 49:1142-51. [PMID: 23149213 DOI: 10.1016/j.ejca.2012.10.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 09/18/2012] [Accepted: 10/16/2012] [Indexed: 11/13/2022]
Abstract
Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo. It interacts with the minor groove of DNA, interfering with transcriptional activity and DNA repair pathways. Here, we report a novel mechanism by which trabectedin exerts its cytotoxic effects on carcinoma cells. It is based on its ability to impair the function of the High-Mobility Group A (HMGA) proteins. These proteins have a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. They bind the minor groove of DNA, alter chromatin structure and, thus, regulate the transcription of several genes by enhancing or suppressing the activity of transcription factors. We first report that trabectedin has a higher cytotoxic effect on thyroid and colon carcinoma cells expressing abundant levels of HMGAs in comparison with cells not expressing them. Then, we have shown that trabectedin treatment displaces HMGA proteins from the HMGA-responsive promoters, including ATM promoter, impairing their transcriptional activity. Finally, we report a synergism between Ionising Radiations and trabectedin treatment restricted to the HMGA-overexpressing cancer cells. This result might have important clinical implications since it would suggest the use of trabectedin for the treatment of neoplasias expressing abundant HMGA levels that are frequently associated to chemoresistance and poor prognosis.
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Affiliation(s)
- Daniela D'Angelo
- Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy
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42
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A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 2012; 48:3036-44. [PMID: 22749255 DOI: 10.1016/j.ejca.2012.05.012] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 05/10/2012] [Accepted: 05/10/2012] [Indexed: 02/07/2023]
Abstract
AIMS Approximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. METHODS The current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. RESULTS TRS subtypes were: synovial sarcoma (SS, n=45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n=27), alveolar soft part sarcoma (ASPS, n=4), endometrial stromal sarcoma (ESS, n=3) and clear cell sarcoma (CCS, n=2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1-48; median dose intensity=0.40 mg/m(2)/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR=10%; 95% CI, 4-19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48-70%). Median PFS was 4.1 months (6-month PFS rate=40%). Median overall survival was 17.4 months (survival rate at 12 months=60%). Trabectedin had a manageable safety profile. CONCLUSION Trabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS.
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43
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Dong W, Liu W, Yan Z, Liao X, Guan B, Wang N, Liu Z. Asymmetric synthesis and cytotoxicity of (−)-saframycin A analogues. Eur J Med Chem 2012; 49:239-44. [DOI: 10.1016/j.ejmech.2012.01.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Revised: 01/09/2012] [Accepted: 01/09/2012] [Indexed: 11/25/2022]
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44
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Feuerhahn S, Giraudon C, Martínez-Díez M, Bueren-Calabuig JA, Galmarini CM, Gago F, Egly JM. XPF-dependent DNA breaks and RNA polymerase II arrest induced by antitumor DNA interstrand crosslinking-mimetic alkaloids. ACTA ACUST UNITED AC 2011; 18:988-99. [PMID: 21867914 DOI: 10.1016/j.chembiol.2011.06.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Revised: 06/03/2011] [Accepted: 06/17/2011] [Indexed: 11/27/2022]
Abstract
Trabectedin and Zalypsis are two potent anticancer tetrahydroisoquinoline alkaloids that can form a covalent bond with the amino group of a guanine in selected triplets of DNA duplexes and eventually give rise to double-strand breaks. Using well-defined in vitro and in vivo assays, we show that the resulting DNA adducts stimulate, in a concentration-dependent manner, cleavage by the XPF/ERCC1 nuclease on the strand opposite to that bonded by the drug. They also inhibit RNA synthesis by: (1) preventing binding of transcription factors like Sp1 to DNA, and (2) arresting elongating RNA polymerase II at the same nucleotide position regardless of the strand they are located on. Structural models provide a rationale for these findings and highlight the similarity between this type of DNA modification and an interstrand crosslink.
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Affiliation(s)
- Sascha Feuerhahn
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS, BP 163, 67404 Illkirch Cedex, CU Strasbourg, France
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45
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Shukla S, Ohnuma S, Ambudkar SV. Improving cancer chemotherapy with modulators of ABC drug transporters. Curr Drug Targets 2011; 12:621-30. [PMID: 21039338 DOI: 10.2174/138945011795378540] [Citation(s) in RCA: 171] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Accepted: 03/18/2010] [Indexed: 02/07/2023]
Abstract
ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1) and ABCG2, are membrane proteins that couple the energy derived from ATP hydrolysis to efflux many chemically diverse compounds across the plasma membrane, thereby playing a critical and important physiological role in protecting cells from xenobiotics. These transporters are also implicated in the development of multidrug resistance (MDR) in cancer cells that have been treated with chemotherapeutics. One approach to blocking the efflux capability of an ABC transporter in a cell or tissue is inhibiting the activity of the transporters with a modulator. Since ABC transporter modulators can be used in combination with chemotherapeutics to increase the effective intracellular concentration of anticancer drugs, the possible impact of modulators of ABC drug transporters is of great clinical interest. Another possible clinical use of modulators that has recently attracted attention is their ability to increase oral bioavailability or increase tissue penetration of drugs transported by the transporters. Several preclinical and clinical studies have been performed to evaluate the feasibility and the safety of this approach. The primary focus of this review is to discuss progress made in recent years in the identification and applicability of compounds that may serve as ABC transporter modulators and the possible role of these compounds in altering the pharmacokinetics and pharmacodynamics of therapeutic drugs used in the clinic.
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Affiliation(s)
- S Shukla
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
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46
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A journey under the sea: the quest for marine anti-cancer alkaloids. Molecules 2011; 16:9665-96. [PMID: 22113577 PMCID: PMC6264372 DOI: 10.3390/molecules16119665] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Accepted: 11/09/2011] [Indexed: 01/31/2023] Open
Abstract
The alarming increase in the global cancer death toll has fueled the quest for new effective anti-tumor drugs thorough biological screening of both terrestrial and marine organisms. Several plant-derived alkaloids are leading drugs in the treatment of different types of cancer and many are now being tested in various phases of clinical trials. Recently, marine-derived alkaloids, isolated from aquatic fungi, cyanobacteria, sponges, algae, and tunicates, have been found to also exhibit various anti-cancer activities including anti-angiogenic, anti-proliferative, inhibition of topoisomerase activities and tubulin polymerization, and induction of apoptosis and cytotoxicity. Two tunicate-derived alkaloids, aplidin and trabectedin, offer promising drug profiles, and are currently in phase II clinical trials against several solid and hematologic tumors. This review sheds light on the rich array of anti-cancer alkaloids in the marine ecosystem and introduces the most investigated compounds and their mechanisms of action.
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47
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Dolfini D, Gatta R, Mantovani R. NF-Y and the transcriptional activation of CCAAT promoters. Crit Rev Biochem Mol Biol 2011; 47:29-49. [PMID: 22050321 DOI: 10.3109/10409238.2011.628970] [Citation(s) in RCA: 189] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The CCAAT box promoter element and NF-Y, the transcription factor (TF) that binds to it, were among the first cis-elements and trans-acting factors identified; their interplay is required for transcriptional activation of a sizeable number of eukaryotic genes. NF-Y consists of three evolutionarily conserved subunits: a dimer of NF-YB and NF-YC which closely resembles a histone, and the "innovative" NF-YA. In this review, we will provide an update on the functional and biological features that make NF-Y a fundamental link between chromatin and transcription. The last 25 years have witnessed a spectacular increase in our knowledge of how genes are regulated: from the identification of cis-acting sequences in promoters and enhancers, and the biochemical characterization of the corresponding TFs, to the merging of chromatin studies with the investigation of enzymatic machines that regulate epigenetic states. Originally identified and studied in yeast and mammals, NF-Y - also termed CBF and CP1 - is composed of three subunits, NF-YA, NF-YB and NF-YC. The complex recognizes the CCAAT pentanucleotide and specific flanking nucleotides with high specificity (Dorn et al., 1997; Hatamochi et al., 1988; Hooft van Huijsduijnen et al, 1987; Kim & Sheffery, 1990). A compelling set of bioinformatics studies clarified that the NF-Y preferred binding site is one of the most frequent promoter elements (Suzuki et al., 2001, 2004; Elkon et al., 2003; Mariño-Ramírez et al., 2004; FitzGerald et al., 2004; Linhart et al., 2005; Zhu et al., 2005; Lee et al., 2007; Abnizova et al., 2007; Grskovic et al., 2007; Halperin et al., 2009; Häkkinen et al., 2011). The same consensus, as determined by mutagenesis and SELEX studies (Bi et al., 1997), was also retrieved in ChIP-on-chip analysis (Testa et al., 2005; Ceribelli et al., 2006; Ceribelli et al., 2008; Reed et al., 2008). Additional structural features of the CCAAT box - position, orientation, presence of multiple Transcriptional Start Sites - were previously reviewed (Dolfini et al., 2009) and will not be considered in detail here.
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Affiliation(s)
- Diletta Dolfini
- Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Milan, Italy
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48
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Uboldi S, Bernasconi S, Romano M, Marchini S, Fuso Nerini I, Damia G, Ganzinelli M, Marangon E, Sala F, Clivio L, Chiorino G, Di Giandomenico S, Rocchi M, Capozzi O, Margison GP, Watson AJ, Caccuri AM, Pastore A, Fossati A, Mantovani R, Grosso F, Tercero JC, Erba E, D'Incalci M. Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents. Int J Cancer 2011; 131:59-69. [PMID: 21805478 DOI: 10.1002/ijc.26340] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 07/21/2011] [Indexed: 02/05/2023]
Abstract
Myxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and β, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.
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Affiliation(s)
- S Uboldi
- Department of Oncology, Mario Negri Institute, Via La Masa 19, 20156 Milan, Italy
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49
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Educational paper. The development of new therapies for pediatric oncology. Eur J Pediatr 2011; 170:555-9. [PMID: 21190039 DOI: 10.1007/s00431-010-1374-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 11/25/2010] [Indexed: 11/27/2022]
Abstract
Although cure rates for children with cancer are approximately 70%, improvements in cure rates have slowed in the past decade, likely due to our inability to further improve outcome using currently available drugs. Novel drug approaches are needed for children with difficult-to-treat malignancies, such as stage IV neuroblastoma, sarcomas, brain tumors, and relapsed leukemia. Several novel agents show promise for improving outcome in patients with either high risk or recurrent disease. For leukemia, inhibitors of cell cycle progression, such as clofarabine and nelarabine, have shown great promise in their ability to increase treatment efficacy in high-risk disease. Targeted agents such as tyrosine kinase inhibitors, DNA binding compounds (trabectedin), and monoclonal antibodies (GD2 inhibitors for neuroblastoma and anti-CD22 antibodies for pre-B acute lymphocytic leukemia (ALL)) also show promise for future treatment. Extensive reviews of each of these agents are presented elsewhere; this article provides an overview of molecular agents at different stages of FDA/EMA approval; those that are currently approved for use in children, currently approved for use in adults, as well as those that show promise in early clinical trial testing, or are supported by strong preclinical data.
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50
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Escape from stress granule sequestration: another way to drug resistance? Biochem Soc Trans 2010; 38:1537-42. [DOI: 10.1042/bst0381537] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Overexpression of P-glycoprotein, encoded by the MDR1 (multidrug resistance 1) gene, is often responsible for multidrug resistance and chemotherapy failure in cancer. We have demonstrated that, in leukaemic cells, P-glycoprotein expression is regulated at the translational level. More recently, we have shown that in cells overexpressing P-glycoprotein, MDR1 mRNA does not aggregate into translationally silent stress granules. Importantly, this is not unique for MDR1, since other transcripts encoding transmembrane proteins, and which are thus translated at the endoplasmic reticulum, follow the same pattern. By using a series of chimaeric transcripts, we have demonstrated that transcript localization at the endoplasmic reticulum bypasses the signals dictating stress granule sequestration. Polysome profile analyses and protein synthesis experiments indicate that, upon stress withdrawal, endoplasmic-reticulum-bound transcripts resume translation faster than those at the cytosol, which have been sequestered into stress granules. This may represent a novel mechanism by which drug-resistant cells respond quickly to stress, helping them to survive the cytotoxic effect of chemotherapeutic drugs.
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