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Al-Hamaly MA, Winter E, Blackburn JS. The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia. Cancer Biol Ther 2025; 26:2460252. [PMID: 39905687 PMCID: PMC11801350 DOI: 10.1080/15384047.2025.2460252] [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: 05/21/2024] [Revised: 12/22/2024] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
Acute lymphocytic leukemia (ALL) is the most common leukemia in children, with the T-cell subtype (T-ALL) accounting for 15% of those cases. Despite advancements in the treatment of T-ALL, patients still face a dismal prognosis following their first relapse. Relapse can be attributed to the inability of chemotherapy agents to eradicate leukemia stem cells (LSC), which possess self-renewal capabilities and are responsible for the long-term maintenance of the disease. Mitochondria have been recognized as a therapeutic vulnerability for cancer stem cells, including LSCs. Mitocans have shown promise in T-ALL both in vitro and in vivo, with some currently in early-phase clinical trials. However, due to challenges in studying LSCs in T-ALL, our understanding of how mitochondrial function influences self-renewal remains limited. This review highlights the emerging literature on targeting mitochondria in diverse T-ALL models, emphasizing specific mitochondrial vulnerabilities linked to LSC self-renewal and their potential to significantly improve T-ALL treatment.
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Affiliation(s)
- Majd A. Al-Hamaly
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Evelyn Winter
- Department of Agriculture, Biodiversity and Forestry, Federal University of Santa Catarina, Curitibanos, Brazil
| | - Jessica S. Blackburn
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
- Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
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Luskin MR, Shimony S, Keating J, Winer ES, Garcia JS, Stone RM, Jabbour E, Flamand Y, Stevenson K, Ryan J, Zeng Z, Letai A, Konopleva M, Jain N, DeAngelo DJ. Venetoclax plus low-intensity chemotherapy for adults with acute lymphoblastic leukemia. Blood Adv 2025; 9:617-626. [PMID: 39546748 PMCID: PMC11847096 DOI: 10.1182/bloodadvances.2024014405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/08/2024] [Accepted: 10/25/2024] [Indexed: 11/17/2024] Open
Abstract
ABSTRACT In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions. This phase 1b study of venetoclax plus attenuated chemotherapy enrolled 19 patients with ALL either newly diagnosed (aged ≥60 years, n = 11 [B-cell, n = 8; T-cell, n = 3]) or relapsed/refractory (R/R; aged ≥18 years, n = 8 [B-cell, n = 3; T-cell, n = 5]). Venetoclax was given for 21 days with each cycle of mini-hyper-CVD (mini-HCVD; cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). There were no dose-limiting toxicities at dose level 1 (DL1; n = 3, 400 mg/d) or DL2 (n = 6, 600 mg/d); DL2 was the recommended phase 2 dose and explored further (n = 10). The most common nonhematologic adverse events were grade ≥3 infections. There were no deaths within 60 days. There was no tumor lysis syndrome, hepatotoxicity, prolonged cytopenias, or early discontinuation for toxicity. Among patients with newly diagnosed ALL, 10 of 11 (90.9%) achieved a measurable residual disease-negative (<0.01% sensitivity) complete remission (CR) including 6 patients with hypodiploid TP53-mutated ALL. All patients in CR bridged to hematopoietic stem cell transplant (n = 9) or completed protocol (n = 1). With a median follow-up of 60 months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6 months (95% confidence interval [CI], 35.5 to not available), with a 2-year DFS rate of 90% (95% CI, 71-100). Among patients with R/R ALL, 3 of 8 (37.5%) achieved CR. In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well tolerated with promising efficacy. This trial was registered at www.clinicaltrials.gov as #NCT03319901.
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Affiliation(s)
- Marlise R. Luskin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Shai Shimony
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Julia Keating
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
| | - Eric S. Winer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | - Richard M. Stone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Elias Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yael Flamand
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
| | - Kristen Stevenson
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
| | - Jeremy Ryan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Zhihong Zeng
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Hematology and Oncology, Montefiore Einstein Comprehensive Cancer Center and Albert Einstein College of Medicine, New York, NY
| | - Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daniel J. DeAngelo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Calvo J, Naguibneva I, Kypraios A, Gilain F, Uzan B, Gaillard B, Bellenger L, Renou L, Antoniewski C, Lapillonne H, Petit A, Ballerini P, Mancini SJ, Marchand T, Peyron JF, Pflumio F. High CD44 expression and enhanced E-selectin binding identified as biomarkers of chemoresistant leukemic cells in human T-ALL. Leukemia 2025; 39:323-336. [PMID: 39580584 PMCID: PMC11794132 DOI: 10.1038/s41375-024-02473-7] [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: 04/12/2024] [Revised: 11/07/2024] [Accepted: 11/11/2024] [Indexed: 11/25/2024]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by increased proliferation and incomplete maturation of T-cell progenitors, for which relapse is often of poor prognosis. To improve patient outcomes, it is critical to understand the chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment. Single-cell RNA sequencing of human T-ALL cells from adipocyte-rich and adipocyte-poor BM revealed a distinct leukemic cell population defined by quiescence and high CD44 expression (Ki67neg/lowCD44high). During in vivo treatment, these cells evaded chemotherapy, and were further called Chemotherapy-resistant Leukemic Cells (CLCs). Patient sample analysis revealed Ki67neg/lowCD44high CLCs at diagnosis and during relapse, with each displaying a specific transcriptomic signature. Interestingly, CD44high expression in T-ALL Ki67neg/low CLCs was associated with E-selectin binding. Analysis of 39 human T-ALL samples revealed significantly enhanced E-selectin binding activity in relapse/refractory samples compared with drug-sensitive samples. These characteristics of chemoresistant T-ALL CLCs provide key insights for prognostic stratification and novel therapeutic options.
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Affiliation(s)
- Julien Calvo
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France.
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France.
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France.
- OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France.
| | - Irina Naguibneva
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
| | - Anthony Kypraios
- Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), INSERM U1065, 06204, Nice, France
| | - Florian Gilain
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
- OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France
| | - Benjamin Uzan
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
| | - Baptiste Gaillard
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
| | - Lea Bellenger
- ARTbio Bioinformatics Analysis Facility, IBPS, CNRS, Sorbonne Université, Institut Français de Bioinformatique, 75005, Paris, France
| | - Laurent Renou
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
- OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France
| | - Christophe Antoniewski
- ARTbio Bioinformatics Analysis Facility, IBPS, CNRS, Sorbonne Université, Institut Français de Bioinformatique, 75005, Paris, France
| | - Helene Lapillonne
- Sorbonne University, AP-HP, Laboratory of Hematology, Armand-Trousseau Hospital, 75012, Paris, France
- Sorbonne Université, Centre de Recherche Saint-Antoine UMR_S938, Pediatric Hematology Oncology Unit, AP-HP, Armand-Trousseau Hospital, 75012, Paris, France
| | - Arnaud Petit
- Sorbonne University, AP-HP, Laboratory of Hematology, Armand-Trousseau Hospital, 75012, Paris, France
- Sorbonne Université, Centre de Recherche Saint-Antoine UMR_S938, Pediatric Hematology Oncology Unit, AP-HP, Armand-Trousseau Hospital, 75012, Paris, France
| | - Paola Ballerini
- Sorbonne University, AP-HP, Laboratory of Hematology, Armand-Trousseau Hospital, 75012, Paris, France
- Sorbonne Université, Centre de Recherche Saint-Antoine UMR_S938, Pediatric Hematology Oncology Unit, AP-HP, Armand-Trousseau Hospital, 75012, Paris, France
| | | | - Tony Marchand
- Université Rennes, EFS, Inserm, MOBIDIC-UMR_S 1236, F-35000, Rennes, France
- Service d'hématologie Clinique, Centre Hospitalier Universitaire de Rennes, 35003, Rennes, France
| | - Jean-François Peyron
- Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), INSERM U1065, 06204, Nice, France
| | - Françoise Pflumio
- Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations, iRCM/SGCSR/Laboratoire des cellules Souches Hématopoïétiques et des Leucémies (LSHL), F-92260, Fontenay-aux-Roses, France
- Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l'Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, Unité Mixte de Recherche (UMR) 1274-E008, Inserm, CEA, 92265, Fontenay-aux Roses, France
- OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Paris, France
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Sergio I, Varricchio C, Squillante F, Cantale Aeo NM, Campese AF, Felli MP. Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia. Int J Mol Sci 2024; 25:12839. [PMID: 39684550 DOI: 10.3390/ijms252312839] [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: 10/18/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed to T-cell lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% of adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis and therapy resistance. Notch inhibition is a promising therapeutic target for personalized medicine, and a variety of strategies to prevent Notch activation, including γ-secretase (GS) inhibitors (GSIs) and antibodies neutralizing Notch receptors or ligands, have been developed. Disruption of apoptosis is pivotal in cancer development and progression. Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use.
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Affiliation(s)
- Ilaria Sergio
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Claudia Varricchio
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Squillante
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | | | | | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
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Xiong J, Dong L, Lv Q, Yin Y, Zhao J, Ke Y, Wang S, Zhang W, Wu M. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes. Clin Transl Med 2024; 14:e1772. [PMID: 39270064 PMCID: PMC11398298 DOI: 10.1002/ctm2.1772] [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: 03/21/2024] [Revised: 06/17/2024] [Accepted: 07/08/2024] [Indexed: 09/15/2024] Open
Abstract
Tumour cell senescence can be induced by various factors, including DNA damage, inflammatory signals, genetic toxins, ionising radiation and nutrient metabolism. The senescence-associated secretory phenotype (SASP), secreted by senescent tumour cells, possesses the capacity to modulate various immune cells, including macrophages, T cells, natural killer cells and myeloid-derived suppressor cells, as well as vascular endothelial cells and fibroblasts within the tumour microenvironment (TME), and this modulation can result in either the promotion or suppression of tumorigenesis and progression. Exploring the impact of SASP on the TME could identify potential therapeutic targets, yet limited studies have dissected its functions. In this review, we delve into the causes and mechanisms of tumour cell senescence. We then concentrate on the influence of SASP on the tumour immune microenvironment, angiogenesis, extracellular matrix and the reprogramming of cancer stem cells, along with their associated tumour outcomes. Last, we present a comprehensive overview of the diverse array of senotherapeutics, highlighting their prospective advantages and challenge for the treatment of cancer patients. KEY POINTS: Senescence-associated secretory phenotype (SASP) secretion from senescent tumour cells significantly impacts cancer progression and biology. SASP is involved in regulating the remodelling of the tumour microenvironment, including immune microenvironment, vascular, extracellular matrix and cancer stem cells. Senotherapeutics, such as senolytic, senomorphic, nanotherapy and senolytic vaccines, hold promise for enhancing cancer treatment efficacy.
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Affiliation(s)
- Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lu Dong
- The Second Clinical College of Wuhan University, Wuhan, China
| | - Qiongying Lv
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yutong Yin
- The First Clinical College of Wuhan University, Wuhan, China
| | - Jiahui Zhao
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Youning Ke
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shimony S, Luskin MR. SOHO State of the Art Updates and Next Questions | Approach to Older Adults With Phildadelphia-Chromosome Negative Acute Lymphoblastic Leukemia. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:133-140. [PMID: 38102012 DOI: 10.1016/j.clml.2023.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 12/17/2023]
Abstract
Philadelphia-chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL) has historically been associated with poor outcomes in older patients due to adverse disease biology, as well as inferior tolerance of conventional chemotherapy. Fortunately, novel therapies, including inotuzumab ozogamicin, blinatumomab, and venetoclax, are now being incorporated into first-line therapy to improve efficacy and decrease toxicity of initial therapy. Inotuzumab ozogamicin, alone or in combination with low intensity chemotherapy, appears to be best suited for the induction phase of treatment due to efficacy in the setting of high tumor burden. In contrast, blinatumomab may be best suited for consolidation due to superior efficacy in setting of morphologic remission, with or without measurable residual disease (MRD). Venetoclax is being investigated in combination with chemotherapy and can be used for treatment of older adults with both B-cell and T-cell ALL. Ongoing trials incorporating inotuzumab, blinatumomab, and venetoclax demonstrate high rates of MRD-negative complete remissions with low early mortality. Long-term outcomes have been less favorable so far, with several trials reporting nonrelapse mortality during subsequent treatment. Unanswered questions remain regarding the optimal treatment of older adults with Ph-neg ALL, including central nervous system (CNS) prophylaxis, the most appropriate consolidation to minimize toxicity without compromising efficacy, and the role of transplant and cellular therapy. T-cell ALL remains an area of unmet need and effort is required to ensure that therapeutic advances benefit all populations equitably. In this manuscript, we review current data and ongoing trials regarding the treatment of older adults with Ph-neg ALL and define topics for further research.
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Affiliation(s)
- Shai Shimony
- Dana-Farber Cancer Institute, Boston, MA; Rabin Medical Center and Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
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Wei SJ, Yang IH, Mohiuddin IS, Kshirsagar GJ, Nguyen TH, Trasti S, Maurer BJ, Kang MH. DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194939. [PMID: 37116859 DOI: 10.1016/j.bbagrm.2023.194939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 04/30/2023]
Abstract
Small cell lung cancer (SCLC) is a neuroendocrine tumor noted for the rapid development of both metastases and resistance to chemotherapy. High mutation burden, ubiquitous loss of TP53 and RB1, and a mutually exclusive amplification of MYC gene family members contribute to genomic instability and make the development of new targeted agents a challenge. Previously, we reported a novel OCT4-induced MYC transcriptional activation pathway involving c-MYC, pOCT4S111, and MAPKAPK2 in progressive neuroblastoma, also a neuroendocrine tumor. Using tumor microarray analysis of clinical samples and preclinical models, we now report a correlation in expression between these proteins in SCLC. In correlating c-MYC protein expression with genomic amplification, we determined that some SCLC cell lines exhibited high c-MYC without genomic amplification, implying amplification-independent MYC activation. We then confirmed direct interaction between OCT4 and DNA-PKcs and identified specific OCT4 and DNA-PKcs binding sites. Knock-down of both POU5F1 (encoding OCT4) and PRKDC (encoding DNA-PKcs) resulted in decreased c-MYC expression. Further, we confirmed binding of OCT4 to the promoter/enhancer region of MYC. Together, these data establish the presence of a DNA-PKcs/OCT4/c-MYC pathway in SCLCs. We then disruptively targeted this pathway and demonstrated anticancer activity in SCLC cell lines and xenografts using both DNA-PKcs inhibitors and a protein-protein interaction inhibitor of DNA-PKcs and OCT4. In conclusion, we demonstrate here that DNA-PKcs can mediate high c-MYC expression in SCLCs, and that this pathway may represent a new therapeutic target for SCLCs with high c-MYC expression.
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Affiliation(s)
- Sung-Jen Wei
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - In-Hyoung Yang
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ismail S Mohiuddin
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ganesh J Kshirsagar
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Thinh H Nguyen
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Scott Trasti
- Laboratory Animal Resources Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Barry J Maurer
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Min H Kang
- Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Goursaud L, Berthon C, Quesnel B. Successful bridging to cell therapy for relapsed/refractory acute lymphoblastic leukaemia with a combination of venetoclax and PEG-asparaginase. Br J Haematol 2023; 200:e37-e39. [PMID: 36470305 DOI: 10.1111/bjh.18595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/18/2022] [Accepted: 11/27/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Laure Goursaud
- CHU Lille, Service des Maladies du Sang, Lille, France.,CNRS, Inserm, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Celine Berthon
- CHU Lille, Service des Maladies du Sang, Lille, France.,CNRS, Inserm, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France
| | - Bruno Quesnel
- CHU Lille, Service des Maladies du Sang, Lille, France.,CNRS, Inserm, UMR9020 - UMR-S 1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.,Univ. Lille, Lille, France
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9
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The Emerging Role of Venetoclax-Based Treatments in Acute Lymphoblastic Leukemia. Int J Mol Sci 2022; 23:ijms231810957. [PMID: 36142863 PMCID: PMC9504828 DOI: 10.3390/ijms231810957] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/17/2022] Open
Abstract
Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations.
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10
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Baran N, Lodi A, Dhungana Y, Herbrich S, Collins M, Sweeney S, Pandey R, Skwarska A, Patel S, Tremblay M, Kuruvilla VM, Cavazos A, Kaplan M, Warmoes MO, Veiga DT, Furudate K, Rojas-Sutterin S, Haman A, Gareau Y, Marinier A, Ma H, Harutyunyan K, Daher M, Garcia LM, Al-Atrash G, Piya S, Ruvolo V, Yang W, Shanmugavelandy SS, Feng N, Gay J, Du D, Yang JJ, Hoff FW, Kaminski M, Tomczak K, Eric Davis R, Herranz D, Ferrando A, Jabbour EJ, Emilia Di Francesco M, Teachey DT, Horton TM, Kornblau S, Rezvani K, Sauvageau G, Gagea M, Andreeff M, Takahashi K, Marszalek JR, Lorenzi PL, Yu J, Tiziani S, Hoang T, Konopleva M. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia. Nat Commun 2022; 13:2801. [PMID: 35589701 PMCID: PMC9120040 DOI: 10.1038/s41467-022-30396-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/25/2022] [Indexed: 01/05/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
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Affiliation(s)
- Natalia Baran
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Alessia Lodi
- grid.89336.370000 0004 1936 9924Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX USA
| | - Yogesh Dhungana
- grid.240871.80000 0001 0224 711XSt. Jude Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Shelley Herbrich
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Meghan Collins
- grid.89336.370000 0004 1936 9924Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX USA
| | - Shannon Sweeney
- grid.89336.370000 0004 1936 9924Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX USA
| | - Renu Pandey
- grid.89336.370000 0004 1936 9924Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX USA
| | - Anna Skwarska
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Shraddha Patel
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Mathieu Tremblay
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Vinitha Mary Kuruvilla
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Antonio Cavazos
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Mecit Kaplan
- grid.240145.60000 0001 2291 4776Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Marc O. Warmoes
- grid.240145.60000 0001 2291 4776Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Diogo Troggian Veiga
- grid.249880.f0000 0004 0374 0039The Jackson Laboratory for Genomic Medicine, Farmington, CT USA
| | - Ken Furudate
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA ,grid.257016.70000 0001 0673 6172Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori Japan
| | - Shanti Rojas-Sutterin
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Andre Haman
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Yves Gareau
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Anne Marinier
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Helen Ma
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Karine Harutyunyan
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - May Daher
- grid.240145.60000 0001 2291 4776Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Luciana Melo Garcia
- grid.240145.60000 0001 2291 4776Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Gheath Al-Atrash
- grid.240145.60000 0001 2291 4776Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Sujan Piya
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Vivian Ruvolo
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Wentao Yang
- grid.240871.80000 0001 0224 711XDepartment of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Sriram Saravanan Shanmugavelandy
- grid.240145.60000 0001 2291 4776Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Ningping Feng
- grid.240145.60000 0001 2291 4776TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA
| | - Jason Gay
- grid.240145.60000 0001 2291 4776TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA
| | - Di Du
- grid.240145.60000 0001 2291 4776Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Jun J. Yang
- grid.240871.80000 0001 0224 711XDepartment of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Fieke W. Hoff
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Marcin Kaminski
- grid.240871.80000 0001 0224 711XDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Katarzyna Tomczak
- grid.240145.60000 0001 2291 4776Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - R. Eric Davis
- grid.240145.60000 0001 2291 4776Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Daniel Herranz
- grid.430387.b0000 0004 1936 8796Rutgers Robert Wood Johnson Medical School, Cancer Institute of New Jersey, New Brunswick, NJ USA
| | - Adolfo Ferrando
- grid.21729.3f0000000419368729Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY USA
| | - Elias J. Jabbour
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - M. Emilia Di Francesco
- grid.240145.60000 0001 2291 4776Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - David T. Teachey
- grid.25879.310000 0004 1936 8972Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA USA
| | - Terzah M. Horton
- grid.39382.330000 0001 2160 926XTexas Children’s Cancer Center, Baylor College of Medicine, Houston, TX USA
| | - Steven Kornblau
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Katayoun Rezvani
- grid.240145.60000 0001 2291 4776Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Guy Sauvageau
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada
| | - Mihai Gagea
- grid.240145.60000 0001 2291 4776Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Michael Andreeff
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Koichi Takahashi
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Joseph R. Marszalek
- grid.240145.60000 0001 2291 4776TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA
| | - Philip L. Lorenzi
- grid.240145.60000 0001 2291 4776Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Jiyang Yu
- grid.240871.80000 0001 0224 711XDepartment of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - Stefano Tiziani
- grid.89336.370000 0004 1936 9924Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX USA
| | - Trang Hoang
- grid.14848.310000 0001 2292 3357Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC Canada ,grid.14848.310000 0001 2292 3357Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC Canada
| | - Marina Konopleva
- grid.240145.60000 0001 2291 4776Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
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11
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Shirazi-Tehrani E, Vafadar A, Keshavarzi M, Firouzabadi N. Anticancer properties of vincristine is modulated by microRNAs in acute lymphoblastic leukemia Nalm6 cell line. Anticancer Drugs 2022; 33:e680-e685. [PMID: 34459460 DOI: 10.1097/cad.0000000000001234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Precursor B-cell acute lymphoblastic leukemia (B-ALL), a highly diverse disease, is the most widespread pediatric malignancy characterized by cytogenetic and molecular abnormalities such as altered microRNA (miR) expression signatures. MiRs are a class of short noncoding RNAs. Dysregulation in the expression of miRs plays a crucial role in different types of cancers. Vincristine is an antineoplastic drug with a broad spectrum of activity against different hematologic malignancies and is the first-line treatment for B-ALL. Previous studies have proposed miR-17 and miR-181/b as oncomirs and miR-34/a as a tumor suppressor in Nalm6 cells, thus in the current study, we investigated the effects of vincristine treatment on the expression of miR-17, miR-34/a and miR-181/b expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was conducted to estimate the optimal concentration of vincristine in the Nalm-6 cell line. Expression of miRs was calculated using real-time PCR. Our results showed significant downregulation of miR-17 (FC = 0.226; P < 0.0004) in Nalm6 cells after vincristine treatment. Conversely, miR-34/a (FC = 4.823; P < 0.0001) was significantly upregulated. Also, the expression of miR-181/b (FC = 0.156; P < 0.3465) was not significantly different between the vincristine treated group and the control group. In conclusion, it is proposed that one of the mechanisms by which vincristine improves B-ALL is by modulating the expression of specific miRs. These specific miRs will serve as good diagnostic and prognostic biomarkers.
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Affiliation(s)
- Elham Shirazi-Tehrani
- Department of Pharmacology & Toxicology, School of Pharmacy
- Pharmaceutical Sciences Research Center
| | - Asma Vafadar
- Diagnostic Laboratory Sciences and Technology Research Center
- Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy
- Pharmaceutical Sciences Research Center
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12
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Turati VA, Guerra-Assunção JA, Potter NE, Gupta R, Ecker S, Daneviciute A, Tarabichi M, Webster AP, Ding C, May G, James C, Brown J, Conde L, Russell LJ, Ancliff P, Inglott S, Cazzaniga G, Biondi A, Hall GW, Lynch M, Hubank M, Macaulay I, Beck S, Van Loo P, Jacobsen SE, Greaves M, Herrero J, Enver T. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia. NATURE CANCER 2021; 2:835-852. [PMID: 34734190 PMCID: PMC7611923 DOI: 10.1038/s43018-021-00219-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 05/11/2021] [Indexed: 05/01/2023]
Abstract
Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.
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Affiliation(s)
| | | | | | - Rajeev Gupta
- UCL Cancer Institute, University College London, United Kingdom
| | - Simone Ecker
- UCL Cancer Institute, University College London, United Kingdom
| | | | | | - Amy P. Webster
- UCL Cancer Institute, University College London, United Kingdom
| | - Chuling Ding
- UCL Cancer Institute, University College London, United Kingdom
| | - Gillian May
- UCL Cancer Institute, University College London, United Kingdom
| | - Chela James
- UCL Cancer Institute, University College London, United Kingdom
| | - John Brown
- UCL Cancer Institute, University College London, United Kingdom
| | - Lucia Conde
- UCL Cancer Institute, University College London, United Kingdom
| | - Lisa J. Russell
- Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, UK
| | - Phil Ancliff
- Great Ormond Street Hospital, London, United Kingdom
| | - Sarah Inglott
- Great Ormond Street Hospital, London, United Kingdom
| | - Giovanni Cazzaniga
- Centro Ricerca M. Tettamanti, University of Milano Bicocca, Monza, Italy
| | - Andrea Biondi
- University of Milano-Bicocca, Department of Pediatrics, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy
| | | | - Mark Lynch
- Fluidigm Corporation, San Francisco, CA, USA
| | - Mike Hubank
- Institute of Cancer Research, Sutton, United Kingdom
- Royal Marsden Hospital, Sutton, United Kingdom
| | | | - Stephan Beck
- UCL Cancer Institute, University College London, United Kingdom
| | | | - Sten E. Jacobsen
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
- Center for Hematology and Regenerative Medicine, Department of Medicine and Department of Cell and Molecular Biology, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Mel Greaves
- Institute of Cancer Research, Sutton, United Kingdom
| | - Javier Herrero
- UCL Cancer Institute, University College London, United Kingdom
| | - Tariq Enver
- UCL Cancer Institute, University College London, United Kingdom
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13
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Larkin KTM, Byrd JC. Inhibiting the Inhibitors of Apoptosis: When Two Targets Are Better Than One. Cancer Discov 2021; 11:1324-1326. [PMID: 34078661 DOI: 10.1158/2159-8290.cd-21-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this issue of Cancer Discovery, Pullarkat and colleagues present the results from a phase I clinical trial that is the first to combine small-molecule inhibitors for multiple antiapoptotic proteins, BCL2 as well as BCL-XL, with a traditional chemotherapy backbone for patients with relapsed/refractory acute lymphoblastic leukemia. This trial has demonstrated impressive response rates with acceptable toxicity while providing proof of concept that dual targeting-hitting BCL2 hard and BCL-XL soft-is both effective and tolerable in a heterogeneous patient population with prior existing cytopenias.See related article by Pullarkat et al., p. 1440.
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Affiliation(s)
| | - John C Byrd
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
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14
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Butler M, van der Meer LT, van Leeuwen FN. Amino Acid Depletion Therapies: Starving Cancer Cells to Death. Trends Endocrinol Metab 2021; 32:367-381. [PMID: 33795176 DOI: 10.1016/j.tem.2021.03.003] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/25/2021] [Accepted: 03/09/2021] [Indexed: 01/01/2023]
Abstract
Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.
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Affiliation(s)
- Miriam Butler
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
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15
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Mohiuddin IS, Wei SJ, Yang IH, Martinez GM, Yang S, Cho EJ, Dalby KN, Kang MH. Development of cell-based high throughput luminescence assay for drug discovery in inhibiting OCT4/DNA-PKcs and OCT4-MK2 interactions. Biotechnol Bioeng 2021; 118:1987-2000. [PMID: 33565603 DOI: 10.1002/bit.27712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/19/2021] [Accepted: 02/06/2021] [Indexed: 12/13/2022]
Abstract
Amplification-independent c-MYC overexpression is suggested in multiple cancers. Targeting c-MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c-MYC activity in cancer, we identified two kinases, MAPKAPK2 (MK2) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which phosphorylate the Ser111 and the Ser93 residues of OCT4, respectively, to transcriptionally activate c-MYC. Using these observations, we present here a novel cell-based luminescence assay to identify compounds that inhibit the interaction between these kinases and OCT4. After screening approximately 80,000 compounds, we identified 56 compounds ("hits") that inhibited the luminescence reaction between DNA-PKcs and OCT4, and 65 hits inhibiting the MK2-OCT4 interaction. Using custom antibodies specific for pOCT4S93 and pOCT4S111 , the "hits" were validated for their effect on OCT4 phosphorylation and activation. Using a two-step method for validation, we identified two candidate compounds from the DNA-PKcs assay and three from the MK2 assay. All five compounds demonstrate a significant ability to kill cancer cells in the nanomolar range. In conclusion, we developed a cell-based luminescence assay to identify novel inhibitors targeting c-MYC transcriptional activation, and have found five compounds that may function as lead compounds for further development.
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Affiliation(s)
- Ismail S Mohiuddin
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Sung-Jen Wei
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - In-Hyoung Yang
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Gloria M Martinez
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Shengping Yang
- Department of Biostatistics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Eun J Cho
- Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Kevin N Dalby
- Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Min H Kang
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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16
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Pullarkat VA, Lacayo NJ, Jabbour E, Rubnitz JE, Bajel A, Laetsch TW, Leonard J, Colace SI, Khaw SL, Fleming SA, Mattison RJ, Norris R, Opferman JT, Roberts KG, Zhao Y, Qu C, Badawi M, Schmidt M, Tong B, Pesko JC, Sun Y, Ross JA, Vishwamitra D, Rosenwinkel L, Kim SY, Jacobson A, Mullighan CG, Alexander TB, Stock W. Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancer Discov 2021; 11:1440-1453. [PMID: 33593877 DOI: 10.1158/2159-8290.cd-20-1465] [Citation(s) in RCA: 180] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/25/2021] [Accepted: 02/11/2021] [Indexed: 11/16/2022]
Abstract
Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-XL without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant.See related commentary by Larkin and Byrd, p. 1324.This article is highlighted in the In This Issue feature, p. 1307.
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Affiliation(s)
- Vinod A Pullarkat
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
| | - Norman J Lacayo
- Department of Pediatrics - Hematology/Oncology, Stanford University, Palo Alto, California
| | - Elias Jabbour
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey E Rubnitz
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.,Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, Tennessee
| | - Ashish Bajel
- Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Theodore W Laetsch
- Department of Pediatrics, The University of Texas Southwestern Medical Center/Children's Health, Dallas, Texas.,Division of Oncology, Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jessica Leonard
- Department of Hematology/Medical Oncology, Oregon Health Sciences University, Portland, Oregon
| | - Susan I Colace
- Pediatrics - Hematology and Oncology, Nationwide Children's Hospital, Columbus, Ohio
| | | | - Shaun A Fleming
- Department of Hematology, The Alfred Hospital and Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
| | - Ryan J Mattison
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
| | - Robin Norris
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Kathryn G Roberts
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Yaqi Zhao
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Chunxu Qu
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | | | | | - Bo Tong
- AbbVie Inc., North Chicago, Illinois
| | | | - Yan Sun
- AbbVie Inc., North Chicago, Illinois
| | | | | | | | | | | | - Charles G Mullighan
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Thomas B Alexander
- Department of Pediatrics, The University of North Carolina, Chapel Hill, North Carolina
| | - Wendy Stock
- The University of Chicago Medicine, Chicago, Illinois
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17
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Métayer LE, Brown RD, Carlebur S, Burke GAA, Brown GC. Mechanisms of cell death induced by arginase and asparaginase in precursor B-cell lymphoblasts. Apoptosis 2020; 24:145-156. [PMID: 30578463 PMCID: PMC6373273 DOI: 10.1007/s10495-018-1506-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Arginase has therapeutic potential as a cytotoxic agent in some cancers, but this is unclear for precursor B acute lymphoblastic leukaemia (pre-B ALL), the commonest form of childhood leukaemia. We compared arginase cytotoxicity with asparaginase, currently used in pre-B ALL treatment, and characterised the forms of cell death induced in a pre-B ALL cell line 697. Arginase and asparaginase both efficiently killed 697 cells and mature B lymphoma cell line Ramos, but neither enzyme killed normal lymphocytes. Arginase depleted cellular arginine, and arginase-treated media induced cell death, blocked by addition of arginine or arginine-precursor citrulline. Asparaginase depleted both asparagine and glutamine, and asparaginase-treated media induced cell death, blocked by asparagine, but not glutamine. Both enzymes induced caspase cleavage and activation, chromatin condensation and phosphatidylserine exposure, indicating apoptosis. Both arginase- and asparaginase-induced death were blocked by caspase inhibitors, but with different sensitivities. BCL-2 overexpression inhibited arginase- and asparaginase-induced cell death, but did not prevent arginase-induced cytostasis, indicating a different mechanism of growth arrest. An autophagy inhibitor, chloroquine, had no effect on the cell death induced by arginase, but doubled the cell death induced by asparaginase. In conclusion, arginase causes death of lymphoblasts by arginine-depletion induced apoptosis, via mechanism distinct from asparaginase. Therapeutic implications for childhood ALL include: arginase might be used as treatment (but antagonised by dietary arginine and citrulline), chloroquine may enhance efficacy of asparaginase treatment, and partial resistance to arginase and asparaginase may develop by BCL-2 expression. Arginase or asparaginase might potentially be used to treat Burkitt lymphoma.
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Affiliation(s)
- Lucy E Métayer
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
| | - Richard D Brown
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
| | - Saskia Carlebur
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK
| | - G A Amos Burke
- Department of Paediatrics, University of Cambridge, Cambridge, CB2 OQQ, UK
| | - Guy C Brown
- Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
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18
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Abstract
Significance: Mitochondria undergo constant morphological changes through fusion, fission, and mitophagy. As the key organelle in cells, mitochondria are responsible for numerous essential cellular functions such as metabolism, regulation of calcium (Ca2+), generation of reactive oxygen species, and initiation of apoptosis. Unsurprisingly, mitochondrial dysfunctions underlie many pathologies including cancer. Recent Advances: Currently, the gold standard for cancer treatment is chemotherapy, radiation, and surgery. However, the efficacy of these treatments varies across different cancer cells. It has been suggested that mitochondria may be at the center of these diverse responses. In the past decade, significant advances have been made in understanding distinct types of mitochondrial dysfunctions in cancer. Through investigations of underlying mechanisms, more effective treatment options are developed. Critical Issues: We summarize various mitochondria dysfunctions in cancer progression that have led to the development of therapeutic options. Current mitochondrial-targeted therapies and challenges are discussed. Future Directions: To address the "root" of cancer, utilization of mitochondrial-targeted therapy to target cancer stem cells may be valuable. Investigation of other areas such as mitochondrial trafficking may offer new insights into cancer therapy. Moreover, common antibiotics could be explored as mitocans, and synthetic lethality screens can be utilized to overcome the plasticity of cancer cells.
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Affiliation(s)
- Hsin Yao Chiu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Emmy Xue Yun Tay
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Derrick Sek Tong Ong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reshma Taneja
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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19
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Straszkowski L, Jovic T, Castillo-Tandazo W, Ritchie DS, Purton LE. Effects of chemotherapy agents used to treat pediatric acute lymphoblastic leukemia patients on bone parameters and longitudinal growth of juvenile mice. Exp Hematol 2020; 82:1-7. [PMID: 32006607 DOI: 10.1016/j.exphem.2020.01.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 12/28/2022]
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Therapies for pediatric ALL have improved such that more than 80% of patients survive to 5 years post-therapy, and most survive to adulthood. These ALL patients experience long-term side effects that permanently affect their quality of life, with bone loss and reduced longitudinal growth being the most common skeletal complications. To determine the effects of the chemotherapeutic agents used in ALL induction therapy on bone density and longitudinal growth in mice, we treated juvenile mice with doxorubicin, dexamethasone, vincristine, l-asparaginase, or combination therapy. At adulthood, mice were culled and bones collected and scanned by micro-computed tomography (micro-CT). Mice that received doxorubicin and combination therapy exhibited reduced longitudinal growth and significant reductions in trabecular bone volume, trabecular thickness, and trabecular number, with increased trabecular separation. Mean cortical thickness, cortical area, marrow area, endocortical perimeter, and polar moment of inertia were significantly reduced by doxorubicin and combination therapy. Vincristine treatment significantly decreased trabecular bone volume, trabecular number, and increased trabecular separation but had no effects on cortical bone. Dexamethasone treatment increased trabecular bone separation, cortical marrow area, and cortical bone periosteal perimeter. Mice treated with l-asparaginase did not have any bone phenotypes. In conclusion, these data indicate that the majority of the chemotherapy agents used in induction therapy for pediatric ALL have long-term effects on bone in mice. A single dose of doxorubicin in juvenile mice was sufficient to cause the majority of the bone phenotypes, with combination therapy intensifying these effects.
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Affiliation(s)
| | - Tanja Jovic
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Wilson Castillo-Tandazo
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia
| | - David S Ritchie
- Department of Medicine, University of Melbourne, Parkville, VIC, Australia; Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia; Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Louise E Purton
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
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20
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Hu P, Li H, Yu X, Liu X, Wang X, Qing Y, Wang Z, Wang H, Zhu M, Xu J, Tan R, Guo Q, Hui H. GL-V9 exerts anti-T cell malignancies effects via promoting lysosome-dependent AKT1 degradation and activating AKT1/FOXO3A/BIM axis. Free Radic Biol Med 2019; 145:237-249. [PMID: 31560953 DOI: 10.1016/j.freeradbiomed.2019.09.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/22/2019] [Accepted: 09/23/2019] [Indexed: 02/06/2023]
Abstract
T-cell malignancies are characterized by the excessive proliferation of hematopoietic precursor cells of T-cell lineage lymphocytes in the bone marrow. Previous studies suggest that T-cell malignancies are usually accompanied by highly activated PI3K/AKT signaling which confers the ability of cancer cells to proliferate and survive. Here, we found that GL-V9, a newly synthesized flavonoid compound, had a potent to inhibit the activation of AKT1 and induce the cell apoptosis in T-cell malignancies including cell lines and primary lymphoblastic leukemia. Results showed that GL-V9-induced degradation of AKT1 blocked PI3K/AKT1 signaling and the degradation of AKT1 could be reversed by NH4Cl, an inhibitor of lysosomal function. Inhibiting AKT1 promoted dephosphorylation of FOXO3A and its nuclear translocation. We further demonstrated that GL-V9-induced apoptosis effects were dependent on the binding of FOXO3A to the BIM promoter, resulting in the production of BH3-only protein BIM. Moreover, GL-V9 showed a more persistent and stronger apoptosis induction effects than pharmacologic PI3K inhibitor. The in vivo studies also verified that GL-V9 possessed the anti-tumor effects by reducing the leukemic burden in T-ALL-bearing BALB/c nude mice. In conclusion, our study provides a new insight into the mechanism of GL-V9-induced apoptosis, suggesting the potency of GL-V9 to be a promising agent against T-cell malignancies.
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Affiliation(s)
- Po Hu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Hui Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Xiaoxuan Yu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Xiao Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Xiangyuan Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Yingjie Qing
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Zhanyu Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Hongzheng Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Mengyuan Zhu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China
| | - Jingyan Xu
- Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Renxiang Tan
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
| | - Hui Hui
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
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21
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Choo Z, Loh AHP, Chen ZX. Destined to Die: Apoptosis and Pediatric Cancers. Cancers (Basel) 2019; 11:cancers11111623. [PMID: 31652776 PMCID: PMC6893512 DOI: 10.3390/cancers11111623] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 01/10/2023] Open
Abstract
Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding these pathways not only unraveled key molecules that may serve as potential targets for drug discovery, but also molecular nodes that integrate with other signaling networks involved in processes such as development. This review presents current knowledge of the complex regulatory system that governs apoptosis with respect to other processes in pediatric cancers, so that fresh insights may be derived regarding treatment resistance or for more effective treatment options.
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Affiliation(s)
- Zhang'e Choo
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
| | - Amos Hong Pheng Loh
- VIVA-KKH Pediatric Brain and Solid Tumor Program, KK Women's and Children's Hospital, Singapore 229899, Singapore.
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore 229899, Singapore.
| | - Zhi Xiong Chen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
- VIVA-KKH Pediatric Brain and Solid Tumor Program, KK Women's and Children's Hospital, Singapore 229899, Singapore.
- National University Cancer Institute, Singapore, Singapore 119074, Singapore.
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22
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Leung KT, Zhang C, Chan KYY, Li K, Cheung JTK, Ng MHL, Zhang XB, Sit T, Lee WYW, Kang W, To KF, Yu JWS, Man TKF, Wang H, Tsang KS, Cheng FWT, Lam GKS, Chow TW, Leung AWK, Leung TF, Yuen PMP, Ng PC, Li CK. CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity. Leukemia 2019; 34:709-720. [DOI: 10.1038/s41375-019-0593-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022]
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23
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Avgeris M, Stamati L, Kontos CK, Piatopoulou D, Marmarinos A, Xagorari M, Baka M, Doganis D, Anastasiou T, Kosmidis H, Gourgiotis D, Scorilas A. BCL2L12 improves risk stratification and prediction of BFM-chemotherapy response in childhood acute lymphoblastic leukemia. Clin Chem Lab Med 2019; 56:2104-2118. [PMID: 30016275 DOI: 10.1515/cclm-2018-0507] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 06/07/2018] [Indexed: 01/31/2023]
Abstract
Background Risk-adjusted treatment has led to outstanding improvements of the remission and survival rates of childhood acute lymphoblastic leukemia (ALL). Nevertheless, overtreatment-related toxicity and resistance to therapy have not been fully prevented. In the present study, we evaluated for the first time the clinical impact of the apoptosis-related BCL2L12 gene in prognosis and risk stratification of BFM-treated childhood ALL. Methods Bone marrow specimens were obtained from childhood ALL patients upon disease diagnosis and the end-of-induction (EoI; day 33) of the BFM protocol, as well as from control children. Following total RNA extraction and reverse transcription, BCL2L12 expression levels were determined by qPCR. Patients' cytogenetics, immunophenotyping and minimal residual disease (MRD) evaluation were performed according to the international guidelines. Results BCL2L12 expression was significantly increased in childhood ALL and correlated with higher BCL2/BAX expression ratio and favorable disease markers. More importantly, BCL2L12 expression was associated with disease remission, while the reduced BCL2L12 expression was able to predict patients' poor response to BFM therapy, in terms of M2-M3 response and MRD≥0.1% on day 15. The survival analysis confirmed the significantly higher risk of the BFM-treated patients underexpressing BCL2L12 at disease diagnosis for early relapse and worse survival. Lastly, evaluation of BCL2L12 expression clearly strengthened the prognostic value of the established disease prognostic markers, leading to superior prediction of patients' outcome and improved specificity of BFM risk stratification. Conclusions The expression levels of the apoptosis-related BCL2L12 predict response to treatment and survival outcome of childhood ALL patients receiving BFM chemotherapy.
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Affiliation(s)
- Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Lamprini Stamati
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, National and Kapodistrian University of Athens, Medical School, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Christos K Kontos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Despina Piatopoulou
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, National and Kapodistrian University of Athens, Medical School, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Antonios Marmarinos
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, National and Kapodistrian University of Athens, Medical School, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Marieta Xagorari
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, National and Kapodistrian University of Athens, Medical School, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Margarita Baka
- Department of Pediatric Oncology, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Dimitrios Doganis
- Department of Pediatric Oncology, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Theodora Anastasiou
- Laboratory of Hematology, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Helen Kosmidis
- Department of Pediatric Oncology, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Dimitrios Gourgiotis
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, National and Kapodistrian University of Athens, Medical School, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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24
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Santana-Bejarano UF, Bobadilla-Morales L, Mendoza-Maldonado L, Torres-Anguiano E, Brukman-Jiménez SA, Barba-Barba CC, Corona-Rivera JR, Corona-Rivera A. In vitro effect of curcumin in combination with chemotherapy drugs in Ph + acute lymphoblastic leukemia cells. Oncol Lett 2019; 17:5224-5240. [PMID: 31186739 DOI: 10.3892/ol.2019.10204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 12/29/2018] [Indexed: 12/19/2022] Open
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), is characterized by the t(9;22)(q34q11) that generates the BCR-ABL protein with uncontrolled tyrosine kinase activity. Recently, a connection between BCR-ABL signaling with NF-κB activation mediated by CK2 has been hypothesized. Approximately 95% of patients with Ph+ ALL have the BCR-ABLp190 isoform, which causes aggressive leukemia with a high rate of chemotherapy resistance. Therefore, the use of compounds that could improve the efficacy of chemotherapy drugs is of particular interest. Curcumin is an active chemical in turmeric with antineoplastic potential; it regulates protein-kinases by modulating downstream molecular pathways. The present study evaluated the effect of curcumin in combination with the chemotherapeutic drugs vincristine, imatinib and daunorubicin in the human OP-1 cell line. Several doses of the chemotherapy drugs were examined, and the effects were evaluated following 12, 24 and 48 h of exposure. The interaction between the chemotherapy drugs and curcumin was determined by the dose-effect curve, which generated a combination index (CI); these data were represented in isobolograms. In addition, the individual effect of each drug was compared with its effect in combination with curcumin on cell viability, apoptosis degree, NF-κB activation and gene expression changes. The present study observed that curcumin potentiates the efficacy of vincristine and imatinib, generating an additive/synergistic effect in a dose- and time-dependent manner. These combinations significantly increased the apoptosis degree, decreased the activation of NF-κB and the expression of its regulated genes. Conversely treatment with daunorubicin + curcumin combination produced an antagonistic/additive effect in a dose-dependent manner, and this combination significantly increased the apoptosis degree. However, this effect seems not to be associated with NF-κB activity, as no significant changes were observed in its activation or in the expression of the genes that it regulates. The results of the present study demonstrate that curcumin may be used as an adjuvant agent for chemotherapy in patients with Ph+ ALL.
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Affiliation(s)
- Uriel Francisco Santana-Bejarano
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Lucina Bobadilla-Morales
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Dr. Juan I. Menchaca Civil Hospital of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Lucero Mendoza-Maldonado
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Elizabeth Torres-Anguiano
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Sinhue Alejandro Brukman-Jiménez
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Cesar Cenobio Barba-Barba
- Cytogenetics Unit, Dr. Juan I. Menchaca Civil Hospital of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Jorge Román Corona-Rivera
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México
| | - Alfredo Corona-Rivera
- Cytogenetics and Genomics Laboratory, Human Genetics Institute 'Dr. Enrique Corona Rivera', Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,PhD Program in Molecular Biology and Human Genetics, Health Sciences University Center, University of Guadalajara, Guadalajara, Jalisco 44340, México.,Cytogenetics Unit, Dr. Juan I. Menchaca Civil Hospital of Guadalajara, Guadalajara, Jalisco 44340, México
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25
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McBride A, Houtmann S, Wilde L, Vigil C, Eischen CM, Kasner M, Palmisiano N. The Role of Inhibition of Apoptosis in Acute Leukemias and Myelodysplastic Syndrome. Front Oncol 2019; 9:192. [PMID: 30972300 PMCID: PMC6445951 DOI: 10.3389/fonc.2019.00192] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/06/2019] [Indexed: 12/24/2022] Open
Abstract
Avoidance of apoptosis is a key mechanism that malignancies, including acute leukemias and MDS, utilize in order to proliferate and resist chemotherapy. Recently, venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, has been approved for the treatment of upfront AML in an unfit, elderly population. This paper reviews the pre-clinical and clinical data for apoptosis inhibitors currently in development for the treatment of AML, ALL, and MDS.
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Affiliation(s)
- Amanda McBride
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sarah Houtmann
- Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Lindsay Wilde
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Carlos Vigil
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, United States
| | - Christine M Eischen
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Margaret Kasner
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Neil Palmisiano
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
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26
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Olivas-Aguirre M, Pottosin I, Dobrovinskaya O. Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia. J Leukoc Biol 2019; 105:935-946. [PMID: 30698851 DOI: 10.1002/jlb.5vmr0818-330rr] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/11/2019] [Accepted: 01/12/2019] [Indexed: 12/29/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T-cell subtype of ALL (T-ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T-ALL represents a high-risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction. Accordingly, a new class of anticancer compounds named mitocans has been developed, which target mitochondria at distinct crucial points to promote their dysfunction and subsequent cell death. The present review analyses the role of mitochondria in malignant reprogramming and emerging therapeutic strategies targeting mitochondria as an "Achilles' heel" in T-ALL, with an emphasis on BH3 mimetics, sequestering pro-survival BCL proteins and voltage-dependent anion channel (VDAC)1-directed drugs, which promote the suppression of aerobic glycolysis, VDAC1 closure, mitochondrial Ca2+ overload, stoppage of the oxidative phosphorylation, oxidative stress, and release of proapoptotic factors.
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Affiliation(s)
- Miguel Olivas-Aguirre
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima, Mexico
| | - Igor Pottosin
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima, Mexico
| | - Oxana Dobrovinskaya
- Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima, Mexico
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Pustylnikov S, Costabile F, Beghi S, Facciabene A. Targeting mitochondria in cancer: current concepts and immunotherapy approaches. Transl Res 2018; 202:35-51. [PMID: 30144423 PMCID: PMC6456045 DOI: 10.1016/j.trsl.2018.07.013] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce "metabolic anergy" of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system.
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Affiliation(s)
- Sergey Pustylnikov
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Francesca Costabile
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Silvia Beghi
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrea Facciabene
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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28
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Verlekar D, Wei SJ, Cho H, Yang S, Kang MH. Ceramide synthase-6 confers resistance to chemotherapy by binding to CD95/Fas in T-cell acute lymphoblastic leukemia. Cell Death Dis 2018; 9:925. [PMID: 30206207 PMCID: PMC6133972 DOI: 10.1038/s41419-018-0964-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 07/11/2018] [Accepted: 07/25/2018] [Indexed: 12/21/2022]
Abstract
Ceramide synthases (CERS) produce ceramides which are key intermediators in the biosynthesis of complex sphingolipids and play an important role in cell proliferation, differentiation, apoptosis and senescence. CERS6 is an isoform of ceramide synthases known to generate ceramides with C16 acyl chain (C16-Cer). CERS6 and C16-Cer levels were significantly higher in acute lymphoblastic leukemia (ALL) cells in comparison to peripheral blood mononuclear cells and T lymphocytes derived from healthy human volunteers. We investigated the role of CERS6 in chemo-resistance in T-ALL cell lines. Stable knockdown of CERS6 in CCRF-CEM and MOLT-4 cells resulted in increased sensitivity to ABT-737, a pan-BCL-2 inhibitor, while CCRF-CEM cells with exogenous CERS6 expression showed resistance to ABT-737 relative to the vector control. The cytotoxic activity of ABT-737 in CERS6 knockdown cells was significantly reduced by the addition of a caspase-8 inhibitor Z-IETD, suggesting that CERS6 alters the cytotoxicity via extrinsic pathway of apoptosis. By co-immunoprecipitation of CERS6 in CCRF-CEM cells, we identified CD95/Fas, a mediator of extrinsic apoptotic pathway, as a novel CERS6 binding partner. In Fas pull-down samples, FADD (Fas-associated protein with death domain) was detected at higher levels in cells with CERS6 knockdown compared with control cells when treated with ABT-737, and this was reversed by the overexpression of CERS6, demonstrating that CERS6 interferes with Fas–FADD DISC assembly. CERS6 may serve as a biomarker in determining the effectiveness of anticancer agents acting via the extrinsic pathway in T-ALL.
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Affiliation(s)
- Dattesh Verlekar
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.,Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Sung-Jen Wei
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Hwangeui Cho
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Shengping Yang
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.,Department of Pathology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Min H Kang
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA. .,Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA. .,Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
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29
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Cho HE, Kang MH. pH gradient-liquid chromatography tandem mass spectrometric assay for determination of underivatized polyamines in cancer cells. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1085:21-29. [DOI: 10.1016/j.jchromb.2018.03.043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 10/17/2022]
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30
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Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. Oncotarget 2016; 6:32089-103. [PMID: 26392332 PMCID: PMC4741661 DOI: 10.18632/oncotarget.5156] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 09/03/2015] [Indexed: 01/09/2023] Open
Abstract
Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.
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31
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Karpel-Massler G, Ramani D, Shu C, Halatsch ME, Westhoff MA, Bruce JN, Canoll P, Siegelin MD. Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo. Oncotarget 2016; 7:33512-28. [PMID: 27172899 PMCID: PMC5085099 DOI: 10.18632/oncotarget.9257] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 04/26/2016] [Indexed: 12/11/2022] Open
Abstract
Cancer cells display a variety of global metabolic changes, which aside from the glycolytic pathway largely involve amino acid metabolism. To ensure aggressive growth, tumor cells highly depend on amino acids, most notably due to their pivotal need of protein synthesis. In this study, we assessed the overall hypothesis that depletion of asparagine by E. coli-derived L-asparaginase might be a novel means for the therapy of one of the most recalcitrant neoplasms and for which no efficient treatment currently exists - glioblastoma (WHO grade IV). Our results suggest that certain glioma cell cultures are particularly susceptible to inhibition of proliferation by L-asparaginase, while others display a more resistant phenotype. In sensitive cells, L-asparaginase induces apoptosis with dissipation of mitochondrial membrane potential and activation of effector caspases. L-asparaginase-mediated apoptosis was accompanied by modulation of pro- and anti-apoptotic Bcl-2 family members, including Noxa, Mcl-1 and the deubiquitinase Usp9X. Given the impact of L-asparaginase on these molecules, we found that L-asparaginase potently overcomes resistance to both intrinsic apoptosis induced by the Bcl-2/Bcl-xL inhibitor, ABT263, and extrinsic apoptosis mediated by TRAIL even in glioma cells that are resistant towards L-asparaginase single treatment. RNA interference studies showed that Usp9X, Mcl-1, Noxa and Bax/Bak are involved in ABT263/L-asparaginase-mediated cell death. In vivo, combined treatment with ABT263 and L-asparaginase led to an enhanced reduction of tumor growth when compared to each reagent alone without induction of toxicity. These observations suggest that L-asparaginase might be useful for the treatment of malignant glial neoplasms.
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Affiliation(s)
- Georg Karpel-Massler
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
| | - Doruntina Ramani
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
| | - Chang Shu
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
| | | | - Mike-Andrew Westhoff
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Jeffrey N. Bruce
- Department of Neurological Surgery, Columbia University Medical Center, New York, New York, United States of America
| | - Peter Canoll
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
| | - Markus D. Siegelin
- Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York, United States of America
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32
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Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts. Biol Blood Marrow Transplant 2016; 22:815-24. [DOI: 10.1016/j.bbmt.2016.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 01/04/2016] [Indexed: 01/03/2023]
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33
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SARI , a novel target gene of glucocorticoid receptor, plays an important role in dexamethasone-mediated killing of B lymphoma cells. Cancer Lett 2016; 373:57-66. [DOI: 10.1016/j.canlet.2016.01.034] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 01/17/2016] [Accepted: 01/18/2016] [Indexed: 12/18/2022]
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34
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Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, Marzo I, Harutyunyan KG, Golfman L, North P, Kerry J, Ballabio E, Chonghaile TN, Gonzalo O, Qiu Y, Jeremias I, Debose L, O'Brien E, Ma H, Zhou P, Jacamo R, Park E, Coombes KR, Zhang N, Thomas DA, O'Brien S, Kantarjian HM, Leverson JD, Kornblau SM, Andreeff M, Müschen M, Zweidler-McKay PA, Mulloy JC, Letai A, Milne TA, Konopleva M. MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199. Cell Rep 2015; 13:2715-27. [PMID: 26711339 PMCID: PMC4700051 DOI: 10.1016/j.celrep.2015.12.003] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 10/21/2015] [Accepted: 11/19/2015] [Indexed: 12/25/2022] Open
Abstract
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias.
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Affiliation(s)
- Juliana M Benito
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Laura Godfrey
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
| | - Kensuke Kojima
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 840-8502, Japan
| | - Leah Hogdal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Mark Wunderlich
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Huimin Geng
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Isabel Marzo
- Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain
| | - Karine G Harutyunyan
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Leonard Golfman
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Phillip North
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
| | - Jon Kerry
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
| | - Erica Ballabio
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK
| | - Triona Ní Chonghaile
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, York House, Dublin 2, Ireland
| | - Oscar Gonzalo
- Department of Biochemistry, Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain
| | - Yihua Qiu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Irmela Jeremias
- German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - LaKiesha Debose
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eric O'Brien
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Helen Ma
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ping Zhou
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rodrigo Jacamo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eugene Park
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Kevin R Coombes
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nianxiang Zhang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Deborah A Thomas
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Susan O'Brien
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hagop M Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Joel D Leverson
- Department of Oncology Development, AbbVie Inc., North Chicago, IL 60064, USA
| | - Steven M Kornblau
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Markus Müschen
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Patrick A Zweidler-McKay
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - James C Mulloy
- Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Thomas A Milne
- Weatherall Institute of Molecular Medicine, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Headington, Oxford OX3 9DS, UK.
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Cang S, Iragavarapu C, Savooji J, Song Y, Liu D. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol 2015; 8:129. [PMID: 26589495 PMCID: PMC4654800 DOI: 10.1186/s13045-015-0224-3] [Citation(s) in RCA: 215] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/10/2015] [Indexed: 12/21/2022] Open
Abstract
With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.
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Affiliation(s)
- Shundong Cang
- Department of Oncology, The Henan Province People's Hospital, Zhengzhou, China
| | - Chaitanya Iragavarapu
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, New York, 10595, USA
| | - John Savooji
- Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, New York, 10595, USA
| | - Yongping Song
- Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Delong Liu
- Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
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Rao J, Li F, Zhang RY, Zhou HH, Chen GA. BH3 mimetic ABT-737 induces apoptosis in CD34 + acute myeloid leukemia cells and shows synergistic effect with conventional chemotherapeutic drugs. Asia Pac J Clin Oncol 2015; 13:e144-e152. [PMID: 26552712 DOI: 10.1111/ajco.12420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2015] [Indexed: 11/27/2022]
Abstract
AIMS Acute myeloid leukemia (AML) is an immunophenotypically heterogenous malignant disease. The early immature CD34+ AML cell subpopulation is frequently impervious to intensive chemotherapy, making them largely responsible for relapse of AML. CD34+ AML cells have higher level of Bcl-2 protein expression than the CD34- subpopulation. As such, development of drugs that specifically target the Bcl-2 may have the potential to eliminate immature CD34+ AML progenitor cells and provide therapeutic benefit. In this work, we made an attempt to investigate the cytotoxic effect of a novel Bcl-2 family inhibitor, ABT-737, on CD34+ AML cell lines (KG1a and Kasumi-1) as well as CD34+ primary AML cells. METHODS Primary human CD34+ cells were isolated from bone marrow mononuclear cells using CD34 MicroBead kit. The growth inhibitory effect was measured by cell counting kit-8. Apoptosis was analyzed by annexin V/PI assays. Protein expression was determined by Western blotting analysis. RESULTS Inhibition of Bcl-2 by ABT-737 effectively inhibited growth and induced apoptosis in CD34+ AML cell lines and CD34+ primary AML cells without affecting CD34+ normal hematopoietic cells. Furthermore, Western blot analysis showed that ABT-737 induced apoptosis associated with caspase-3 activation and poly ADP-ribose polymerase (PARP) degradation. Finally, ABT-737 synergistically enhanced the cytotoxic effect of cytarabine and daunorubicin in CD34+ AML cells. CONCLUSION Taken together, these findings indicate that ABT-737 may offer as a promising molecular targeting agent in CD34+ AML.
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Affiliation(s)
- Jia Rao
- Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China
| | - Fei Li
- Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China
| | - Rong-Yan Zhang
- Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China
| | - Huan-Huan Zhou
- Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China
| | - Guo-An Chen
- Department of Hematology, First Affiliated Hospital, NanChang University, Nanchang, China
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Stamati L, Avgeris M, Kosmidis H, Baka M, Anastasiou T, Piatopoulou D, Scorilas A, Gourgiotis D. Overexpression of BCL2 and BAX following BFM induction therapy predicts ch-ALL patients' poor response to treatment and short-term relapse. J Cancer Res Clin Oncol 2015; 141:2023-36. [PMID: 25982455 DOI: 10.1007/s00432-015-1982-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 04/27/2015] [Indexed: 12/11/2022]
Abstract
PURPOSE The identification of childhood acute lymphoblastic leukemia (ch-ALL) patients who are at a higher risk of chemotherapy resistance and relapse is essential for successful treatment decisions, despite the application of novel therapies. The aim of the study is the evaluation of BCL2 and BAX expression for the prognosis of ch-ALL patients treated with Berlin-Frankfurt-Münster (BFM) backbone protocol. METHODS Bone marrow specimens were obtained at the time of diagnosis and on day 33 following BFM treatment induction from 82 ch-ALL patients, as well as from 63 healthy children. Following extraction, total RNA was reverse transcribed and BCL2 and BAX expression levels were determined by qPCR. RESULTS BCL2 expression and BCL2/BAX ratio were strongly upregulated in ch-ALL compared to healthy children and were correlated with favorable prognostic disease features. Increased levels of BCL2 and BAX expression were associated with disease remission, as ch-ALL patients with lower expression ran a significantly higher risk of M2-M3 response, positive MRD and poor survival outcome. Moreover, the upregulation of BCL2 and BAX following BFM treatment induction was shown to represent an independent predictor of patients' short-term relapse, which was further confirmed in ch-ALL patients with favorable prognostic markers. CONCLUSIONS In conclusion, BCL2 and BAX could be effectively used for an enhanced prediction of BFM-treated patients' outcome.
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Affiliation(s)
- Lamprini Stamati
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, University of Athens Medical School, "P&A Kyriakou" Children's Hospital, Levadias 13 Str., 115 27, Athens, Greece
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 157 01, Athens, Greece
| | - Helen Kosmidis
- Department of Pediatric Oncology, "P&A Kyriakou" Children's Hospital, Thivon & Levadias Str., 115 27, Athens, Greece
| | - Margarita Baka
- Department of Pediatric Oncology, "P&A Kyriakou" Children's Hospital, Thivon & Levadias Str., 115 27, Athens, Greece
| | - Theodora Anastasiou
- Laboratory of Hematology, "P&A Kyriakou" Children's Hospital, Thivon & Levadias Str., 115 27, Athens, Greece
| | - Despina Piatopoulou
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, University of Athens Medical School, "P&A Kyriakou" Children's Hospital, Levadias 13 Str., 115 27, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 157 01, Athens, Greece
| | - Dimitrios Gourgiotis
- Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, University of Athens Medical School, "P&A Kyriakou" Children's Hospital, Levadias 13 Str., 115 27, Athens, Greece.
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Abstract
The alteration in expression of B cell lymphoma-2 (Bcl-2) family of protein members in cancer is involved mainly in the regulation of apoptosis. Bcl-2 family proteins are currently used as major targets in the development of methods to improve treatment outcomes for cancer patients that underwent clinical trials. Although many agents have been developed for targeting Bcl-2 in the past decade, some previous attempts to target Bcl-2 have not resulted in beneficial clinical outcome for reasons unknown. Here, we propose that this was due in part for not considering the cellular level of a different antiapoptotic protein, i.e., galectin-3 (Gal-3). Gal-3 is a member of the β-galactoside binding protein family and a multifunctional oncogenic protein which regulates cell growth, cell adhesion, cell proliferation, angiogenesis, and apoptosis. Gal-3 is the sole protein that contains the NWGR anti-death motif of the Bcl-2 family and inhibits cell apoptosis induced by chemotherapeutic agents through phosphorylation, translocation and regulation of survival signaling pathways. It is now established that Gal-3 is a candidate target protein to suppress antiapoptotic activity and anticancer drug resistance. In this review, we describe the role and relevance of Gal-3 and Bcl-2 protein family in the regulation of apoptosis and propose a novel combination therapy modality. Combination therapy that targets Gal-3 could be essential for improvement of the efficacy of Bcl-2 targeting therapy in cancers and should be studied in future clinical trials. Otherwise, not considering Gal-3 cellular level could lead to trial failure.
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ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 2014; 124:3738-47. [DOI: 10.1182/blood-2014-05-574566] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Key Points
High levels of the anti-apoptotic factor BCL-2 can be therapeutically exploited by the BH3 mimetic ABT-199 in human T-ALL.
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Sequential treatment with aurora B inhibitors enhances cisplatin-mediated apoptosis via c-Myc. J Mol Med (Berl) 2014; 93:427-38. [PMID: 25411027 DOI: 10.1007/s00109-014-1228-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 10/13/2014] [Accepted: 11/06/2014] [Indexed: 02/06/2023]
Abstract
UNLABELLED Platinum compound such as cisplatin is the first-line chemotherapy of choice in most patients with ovarian carcinoma. However, patients with inherent or acquired cisplatin resistance often experience relapse. Therefore, novel therapies are urgently required to treat drug-resistant ovarian carcinoma. Here, we showed that compared to the non-functional traditional simultaneous treatment, sequential combination of Aurora B inhibitors followed by cisplatin synergistically enhanced apoptotic response in cisplatin-resistant OVCAR-8 cells. This effect was accompanied by the induction of polyploidy in a c-Myc-dependent manner, as c-Myc knockdown reduced the efficacy of the combination by suppressing the expression of Aurora B and impairing cellular response to Aurora B inhibitor, as indicated by the decreased polyploidy and hyperphosphorylation of histone H1. In c-Myc-deficient SKOV3 cells, c-Myc overexpression restored Aurora B expression, induced polyploidy after inhibition of Aurora B, and sensitized cells to this combination therapy. Thus, our report reveals for the first time that sequential treatment of Aurora B inhibitors and cisplatin is essential to inhibit ovarian carcinoma by inducing polyploidy and downregulating c-Myc and that c-Myc is identified as a predictive biomarker to select cells responsive to chemotherapeutical combinations targeting Aurora B. Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer. KEY MESSAGE Pretreatment of Aurora B inhibitors augment apoptotic effects of cisplatin. The synergy of Aurora B inhibitor with cisplatin is dependent on c-Myc expression. c-Myc-dependent induction of polyploidy sensitizes cells to cisplatin.
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Zhao W, Wei L, Tan D, Su G, Zheng Y, He C, Mao ZJ, Singleton TP, Yin B. Cellular intrinsic mechanism affecting the outcome of AML treated with Ara-C in a syngeneic mouse model. PLoS One 2014; 9:e109198. [PMID: 25314317 PMCID: PMC4196759 DOI: 10.1371/journal.pone.0109198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 09/05/2014] [Indexed: 11/18/2022] Open
Abstract
The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.
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MESH Headings
- Animals
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Biphenyl Compounds/pharmacology
- Cell Line, Tumor
- Cytarabine/pharmacology
- Cytarabine/therapeutic use
- Disease Models, Animal
- Down-Regulation/drug effects
- Drug Resistance, Neoplasm
- Gene Expression Profiling
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/metabolism
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/pathology
- Mice
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Nitrophenols/pharmacology
- Piperazines/pharmacology
- Sulfonamides/pharmacology
- Survival Rate
- Transplantation, Homologous
- Up-Regulation/drug effects
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Affiliation(s)
- Wenjun Zhao
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Lirong Wei
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Dongming Tan
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Guangsong Su
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Yanwen Zheng
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Chao He
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Zhengwei J. Mao
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center-Fairview, Minneapolis, Minnesota, United States of America
| | - Timothy P. Singleton
- Department of Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Bin Yin
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, PR China
- Thrombosis and Hemostasis Key Lab of the Ministry of Health, Soochow University, Suzhou, Jiangsu Province, PR China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu Province, PR China
- * E-mail:
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Tagde A, Singh H, Kang MH, Reynolds CP. The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. Blood Cancer J 2014; 4:e229. [PMID: 25036800 PMCID: PMC4219442 DOI: 10.1038/bcj.2014.45] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 04/08/2014] [Accepted: 04/30/2014] [Indexed: 12/20/2022] Open
Abstract
Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.
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Affiliation(s)
- A Tagde
- 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA
| | - H Singh
- 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA
| | - M H Kang
- 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [3] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA
| | - C P Reynolds
- 1] Cancer Center, School of Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [2] Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [3] Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [4] Department of Pediatrics, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA [5] Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, USA
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43
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Suryani S, Carol H, Chonghaile TN, Frismantas V, Sarmah C, High L, Bornhauser B, Cowley MJ, Szymanska B, Evans K, Boehm I, Tonna E, Jones L, Manesh DM, Kurmasheva RT, Billups C, Kaplan W, Letai A, Bourquin JP, Houghton PJ, Smith MA, Lock RB. Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. Clin Cancer Res 2014; 20:4520-31. [PMID: 25013123 DOI: 10.1158/1078-0432.ccr-14-0259] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. EXPERIMENTAL DESIGN The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. RESULTS ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). CONCLUSION These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy.
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Affiliation(s)
- Santi Suryani
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Hernan Carol
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Triona Ni Chonghaile
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Viktoras Frismantas
- Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland
| | - Chintanu Sarmah
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Laura High
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Beat Bornhauser
- Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland
| | - Mark J Cowley
- Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Barbara Szymanska
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Kathryn Evans
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Ingrid Boehm
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Elise Tonna
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Luke Jones
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | - Donya Moradi Manesh
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia
| | | | - Catherine Billups
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Warren Kaplan
- Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia
| | - Anthony Letai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jean-Pierre Bourquin
- Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland
| | - Peter J Houghton
- Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio
| | | | - Richard B Lock
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
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Sjoquist KM, Chin VT, Chantrill LA, O’Connor C, Hemmings C, Chang DK, Chou A, Pajic M, Johns AL, Nagrial AM, Biankin AV, Yip D. Personalising pancreas cancer treatment: When tissue is the issue. World J Gastroenterol 2014; 20:7849-7863. [PMID: 24976722 PMCID: PMC4069313 DOI: 10.3748/wjg.v20.i24.7849] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/15/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
The treatment of advanced pancreatic cancer has not moved much beyond single agent gemcitabine until recently when protocols such as FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) and nab-paclitaxel-gemcitabine have demonstrated some improved outcomes. Advances in technology especially in massively parallel genome sequencing has progressed our understanding of the biology of pancreatic cancer especially the candidate signalling pathways that are involved in tumourogenesis and disease course. This has allowed identification of potentially actionable mutations that may be targeted by new biological agents. The heterogeneity of pancreatic cancer makes tumour tissue collection important with the aim of being able to personalise therapies for the individual as opposed to a one size fits all approach to treatment of the condition. This paper reviews the developments in this area of translational research and the ongoing clinical studies that will attempt to move this into the everyday oncology practice.
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45
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Chen Y, Wang Z, Xu M, Wang X, Liu R, Liu Q, Zhang Z, Xia T, Zhao J, Jiang G, Xu Y, Liu S. Nanosilver incurs an adaptive shunt of energy metabolism mode to glycolysis in tumor and nontumor cells. ACS NANO 2014; 8:5813-5825. [PMID: 24810997 DOI: 10.1021/nn500719m] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Due to its significant antimicrobial properties, nanosilver (nAg) has been substantially used in a wide spectrum of areas. This has raised the concerns on the detrimental effects on environment and human health. Although numerous studies have documented nAg-mediated toxicity to cells or organisms, little attempt has been made to study the biological impacts of nAg on cells at nontoxic concentrations, namely, the distinct biological effects that can be separated from direct cytotoxicity. Here, we studied nAg-mediated effects on energy metabolism in cells under sublethal exposure. Treatment of nAg at nontoxic concentrations resulted in a decline of ATP synthesis and attenuation of respiratory chain function in nontumor HEK293T cells and tumor cells with differential respiration rate, including HepG2, HeLa, A498, and PC3 cells. Cellular energy homeostasis was switched from oxidative phosphorylation-based aerobic metabolism to anaerobic glycolysis, which is an adaption process to satisfy the energy demand for cell survival. Nanospheres with smaller size showed greater capability to alter cellular energy metabolism than those with larger size or nanoplates. Mechanistic investigation manifested that inhibition of PGC-1α by nAg was, at least partially, accountable for the transition from oxidative phosphorylation to glycolysis. Additionally, altered expression of a few energy metabolism-related genes (such as PFKFB3 and PDHA1) was also involved in the transition process. We further showed nAg-induced depolarization of mitochondrial membrane potential and reduction of respiratory chain complex activity. Together, our combined results uncovered the mechanisms by which nAg induced energy metabolism reprogramming in both tumor and nontumor cells under sublethal dosage.
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Affiliation(s)
- Yue Chen
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China
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He D, Wu H, Ding L, Li Y. Combination of BCL11A siRNA with vincristine increases the apoptosis of SUDHL6 cells. Eur J Med Res 2014; 19:34. [PMID: 24961604 PMCID: PMC4086990 DOI: 10.1186/2047-783x-19-34] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/11/2014] [Indexed: 02/02/2023] Open
Abstract
Background B cell chronic lymphocytic leukemia/lymphoma 11 A (BCL11A) is associated with human B cell malignancy initiation. Our previous study has shown that downregulation of BCL11A mRNA by small interfering RNA (siRNA) is capable of inducing apoptosis in the SUDHL6 cell line. To further explore the effects of BCL11A siRNA on the enhanced cytotoxicity of a chemotherapeutic drug, we investigated the effects of BCL11A siRNA combined with vincristine (VCR) on SUDHL6 cell proliferation and apoptosis. Methods Chemically synthesized BCL11A siRNA was transfected into SUDHL6 cells using the HiPerFect Transfection Reagent in combination with VCR. Cell proliferation was measured by the CCK8 assay. The morphology of apoptotic cells was observed with Hoechst 33258 staining. The rate of cell apoptosis was determined by annexin V-fluorescein isothiocyanate/propidium iodide double staining using fluorescence-activated cell sorting (FACS) analysis. Results After BCL11A siRNA plus VCR treatment, cell proliferation was significantly decreased in comparison with VCR or BCL11A siRNA treatment alone and negative control siRNA plus VCR treatment (P <0.05). The apoptotic rate of BCL11A siRNA plus VCR treated cells was significantly increased compared with BCL11A siRNA and VCR treatment alone and negative control siRNA plus VCR treatment (P <0.05). Conclusions The combination of BCL11A siRNA and VCR increases apoptosis in SUDHL6 cells. Our study implies that BCL11A siRNA in combination with VCR may be a useful approach for improving effective treatment for B cell lymphoma.
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Affiliation(s)
- Dongmei He
- Institute of Hematology, Medical College, Jinan University, No, 601, West Huangpu Road, Guangzhou, Tianhe District 510632, PR China.
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Ryu Y, Hall CP, Reynolds CP, Kang MH. Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737-induced apoptosis in human acute lymphoblastic leukemia cell lines. Exp Biol Med (Maywood) 2014; 239:1390-402. [PMID: 24951472 DOI: 10.1177/1535370214538745] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
ABT-737 is a BH3-mimetic that has a wide spectrum of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. Previously, we reported that in response to ABT-737, ABT-737-resistant ALL cell lines showed an apparent increase in Mcl-1 (an anti-apoptotic Bcl-2 family protein that is not effectively inhibited by ABT-737) while ABT-737-sensitive ALL cell lines showed decreased Mcl-1 levels. Here we explored the mechanism of Mcl-1 cleavage by ABT-737 and the effect of adjacent phosphorylation sites on Mcl-1 cleavage and apoptosis induced by ABT-737 in a human B-lineage ALL cell line. Caspase cleavage sites in Mcl-1 and the effect of mutation in Mcl-1 phosphorylation sites were determined by transducing Mcl-1 variants tagged with the V5 epitope into human ALL cells. Cytotoxicity was by fluorescence-based DIMSCAN, and changes in protein by immunoblotting. ABT-737 induced a caspase-dependent cleavage of Mcl-1. Of the two Mcl-1 caspase cleavage sites (D127 and D157), D157 was the site of ABT-737-induced cleavage in ALL cells. Cells with exogenously expressed Mcl-1 Δ157 fragment showed greater caspase-3 and caspase-9 activation when they were treated with ABT-737 compared with cells expressing wild-type or D157A mutant Mcl-1. Cells with mutated phosphorylation sites on Mcl-1 (S159A and T163A) were less susceptible to Mcl-1 cleavage and apoptosis induced by ABT-737. Our data showed that Mcl-1 is post-translationally regulated in response to ABT-737 treatment, primarily via a caspase-dependent cleavage that generates a pro-apoptotic Mcl-1 fragment.
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Affiliation(s)
- YongKu Ryu
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Connor P Hall
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Neuroscience and Pharmacology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - C Patrick Reynolds
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Neuroscience and Pharmacology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Min H Kang
- Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Cell Biology & Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA Neuroscience and Pharmacology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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48
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Fais F, Tenca C, Ghiotto F, Bruno S. Targeting the Bcl-2 family in B-cell chronic lymphocytic leukemia. Int J Hematol Oncol 2013. [DOI: 10.2217/ijh.13.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in human adults of the western world and no definitive cure is yet available. One key factor in CLL pathogenesis and disease progression is misbalanced Bcl-2 cell death machinery that is shifted towards protection from apoptosis. Thus, strategies to counteract the antiapoptotic action of the Bcl-2 family in CLL cells are being explored. The Bcl-2 family is composed of a growing number of proteins related to Bcl-2 by sequence homology and their interactions regulate the cell’s decision to die. The features of one particular subclass, the BH3-only proteins, are being studied and exploited for the development of therapeutic anticancer approaches that specifically target antiapoptotic Bcl-2 proteins overexpressed in tumors, including CLL. Preclinical and clinical efficacy and toxicity of the most effective among these ‘BH3 mimetics’ are presented, together with a model that accounts for the differential sensitivity of CLL and normal cells to Bcl-2 neutralization.
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Affiliation(s)
- Franco Fais
- Department of Experimental Medicine (DIMES), University of Genoa, Human Anatomy Section, Via De Toni 14, Genoa 16132, Italy
| | - Claudya Tenca
- Department of Experimental Medicine (DIMES), University of Genoa, Human Anatomy Section, Via De Toni 14, Genoa 16132, Italy
| | - Fabio Ghiotto
- Department of Experimental Medicine (DIMES), University of Genoa, Human Anatomy Section, Via De Toni 14, Genoa 16132, Italy
| | - Silvia Bruno
- Department of Experimental Medicine (DIMES), University of Genoa, Human Anatomy Section, Via De Toni 14, Genoa 16132, Italy
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49
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Parrondo R, de Las Pozas A, Reiner T, Perez-Stable C. ABT-737, a small molecule Bcl-2/Bcl-xL antagonist, increases antimitotic-mediated apoptosis in human prostate cancer cells. PeerJ 2013; 1:e144. [PMID: 24058878 PMCID: PMC3775631 DOI: 10.7717/peerj.144] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/06/2013] [Indexed: 12/22/2022] Open
Abstract
Castration-resistant prostate cancer (CRPC) expresses high levels of the anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1, resulting in resistance to apoptosis and association with poor prognosis. Docetaxel, an antimitotic drug that is the first-line treatment strategy for CRPC, is known to provide a small survival benefit. However, docetaxel chemotherapy alone is not enough to counteract the high levels of Bcl-2/Bcl-xL/Mcl-1 present in CRPC. ABT-737 is a small molecule that binds to Bcl-2/Bcl-xL (but not Mcl-1) with high affinity and disrupts their interaction with pro-apoptotic Bax/Bak, thus enhancing apoptosis. Our results indicate that ABT-737 can sensitize androgen-dependent LNCaP and CRPC PC3 cells to docetaxel- and to the novel antimitotic ENMD-1198-mediated caspase-dependent apoptosis. CRPC DU145 cells, however, are more resistant to ABT-737 because they are Bax null and not because they express the highest levels of anti-apoptotic Mcl-1 (associated with ABT-737 resistance). Knockdown of Bax or Bak in LNCaP indicates that ABT-737-induced antimitotic enhancement of apoptosis is more dependent on the levels of Bax than Bak. Furthermore, we find that the ability of docetaxel to increase cyclin B1/Cdk1-mediated phosphorylation of Bcl-2/Bcl-xL and decrease Mcl-1 is required for ABT-737 to enhance apoptosis in PC3 cells, as determined by addition of Cdk1 inhibitor purvalanol A and expression of shRNA specific for cyclin B1. Overall, our data suggests that the high levels of anti-apoptotic proteins in Bax-expressing CRPC cells can be overcome by targeting Bcl-2/Bcl-xL with ABT-737 and Mcl-1 with antimitotics.
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Affiliation(s)
- Ricardo Parrondo
- Geriatric Research, Education, and Clinical Center and Research Service, Bruce W. Carter Veterans Affairs Medical Center , Miami, FL , USA
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Guihard S, Peyrouze P, Cheok MH. Pharmacogenomic considerations of xenograft mouse models of acute leukemia. Pharmacogenomics 2013; 13:1759-72. [PMID: 23171339 DOI: 10.2217/pgs.12.158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The use of combination chemotherapy to cure acute lymphoblastic leukemia in children and acute myeloid leukemia in adults emerged for acute myeloid leukemia in the 1960s and for acute lymphoblastic leukemia in the 1980s as a paradigm for curing any disseminated cancer. This article summarizes recent developments and considerations in the use of acute leukemia xenografts established in immunodeficient mice to elucidate the genetic and genomic basis of acute leukemia pathogenesis and treatment response.
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Affiliation(s)
- Soizic Guihard
- Jean-Pierre Aubert Research Center, INSERM U837, Institute for Cancer Research, 1 Place de Verdun, F-59045 Lille Cedex, France
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