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1
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Addassi HA, Krga I, Villarreal F, LaComb JF, Frohman MA, Matsukuma K, Mackenzie GG. Inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice partly through a FAK-dependent mechanism. Carcinogenesis 2025; 46:bgae071. [PMID: 39487573 DOI: 10.1093/carcin/bgae071] [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: 06/22/2024] [Revised: 09/20/2024] [Accepted: 10/31/2024] [Indexed: 11/04/2024] Open
Abstract
Phospholipase D (PLD) plays a critical role in cancer progression. However, its role in pancreatic cancer remains unclear. Thus, we evaluated the role of PLD1, one of two classical isoforms of PLD, in pancreatic carcinogenesis in vivo. The role of PLD1 in tumor growth was evaluated by subcutaneously transplanting human MIA PaCa-2 cells expressing endogenous PLD1 levels (Ctr KD cells) or cells in which PLD1 was knocked down (Pld1 KD cells) into immunodeficient mice. Twenty days post-implantation, tumors that arose from Pld1-KD cells were significantly smaller, compared to controls (Ctr KD). Then, we assessed the role of PLD1 in the tumor microenvironment, by subcutaneously implanting mouse LSL-KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) cells into wild-type or PLD1 knockout (Pld1-/-) mice. Compared to wild type, tumor growth was attenuated in Pld1-/- mice by 39%, whereas treatment of Pld1-/- mice with gemcitabine reduced tumor growth by 79%. When PLD1 was ablated in LSL-KrasG12D;Ptf1Cre/+ (KC) mice, no reduction in acinar cell loss was observed, compared to KC mice. Finally, treatment of KC mice with a small molecule inhibitor of PLD1 and PLD2 (FIPI) significantly reduced acinar cell loss and cell proliferation, compared to vehicle-treated mice. Mechanistically, the effect of PLD on tumor growth is mediated, partly, by the focal adhesion kinase pathway. In conclusion, while PLD1 is a critical regulator of pancreatic xenograft and allograft growth, playing an important role at the tumor and at the microenvironment levels, the inhibition of PLD1 and PLD2 is necessary to reduce pancreatic carcinogenesis in KC mice and might represent a novel therapeutic target.
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Affiliation(s)
- Hala A Addassi
- Department of Nutrition, University of California, Davis, One Shields Ave., Davis, CA 95616, United States
- UC Davis Comprehensive Cancer Center, University of California, Davis Medical Center, 45th St., Sacramento, CA 95817, United States
| | - Irena Krga
- Department of Nutrition, University of California, Davis, One Shields Ave., Davis, CA 95616, United States
| | - Fernando Villarreal
- Department of Nutrition, University of California, Davis, One Shields Ave., Davis, CA 95616, United States
| | - Joseph F LaComb
- Department of Family, Population and Preventive Medicine, Stony Brook University, Nicolls Road, Stony Brook, NY 11794, United States
| | - Michael A Frohman
- Department of Pharmacological Sciences, Stony Brook University, Nicolls Road, Stony Brook, NY 11794, United States
| | - Karen Matsukuma
- UC Davis Comprehensive Cancer Center, University of California, Davis Medical Center, 45th St., Sacramento, CA 95817, United States
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, V St., Sacramento, CA 95817, United States
| | - Gerardo G Mackenzie
- Department of Nutrition, University of California, Davis, One Shields Ave., Davis, CA 95616, United States
- UC Davis Comprehensive Cancer Center, University of California, Davis Medical Center, 45th St., Sacramento, CA 95817, United States
- Department of Family, Population and Preventive Medicine, Stony Brook University, Nicolls Road, Stony Brook, NY 11794, United States
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2
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Tarr J, Salovich JM, Aichinger M, Jeon K, Veerasamy N, Sensintaffar JL, Arnhof H, Samwer M, Christov PP, Kim K, Wunberg T, Schweifer N, Trapani F, Arnold A, Martin F, Zhao B, Miriyala N, Sgubin D, Fogarty S, Moore WJ, Stott GM, Olejniczak ET, Engelhardt H, Rudolph D, Lee T, McConnell DB, Fesik SW. Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors. J Med Chem 2024; 67:14370-14393. [PMID: 39102508 PMCID: PMC11345828 DOI: 10.1021/acs.jmedchem.4c01188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/10/2024] [Accepted: 07/15/2024] [Indexed: 08/07/2024]
Abstract
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.
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Affiliation(s)
- James
C. Tarr
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - James M. Salovich
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Martin Aichinger
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - KyuOk Jeon
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Nagarathanam Veerasamy
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - John L. Sensintaffar
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Heribert Arnhof
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Matthias Samwer
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Plamen P. Christov
- Molecular
Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37323-0146, United States
| | - Kwangho Kim
- Molecular
Design and Synthesis Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37323-0146, United States
| | - Tobias Wunberg
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Norbert Schweifer
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Francesca Trapani
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Allison Arnold
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Florian Martin
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Bin Zhao
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Nagaraju Miriyala
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Danielle Sgubin
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Stuart Fogarty
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - William J. Moore
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21701-4907, United States
| | - Gordon M. Stott
- Leidos
Biomedical Research, Frederick National
Laboratory for Cancer Research, Frederick, Maryland 21701-4907, United States
| | - Edward T. Olejniczak
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Harald Engelhardt
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Dorothea Rudolph
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Taekyu Lee
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Darryl B. McConnell
- Discovery
Research, Boehringer Ingelheim Regional
Center Vienna GmbH & Co KG, 1120 Vienna, Austria
| | - Stephen W. Fesik
- Department
of Biochemistry, Vanderbilt University School
of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
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3
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Abd El-Hameed RH, Mohamed MS, Awad SM, Hassan BB, Khodair MAEF, Mansour YE. Novel benzo chromene derivatives: design, synthesis, molecular docking, cell cycle arrest, and apoptosis induction in human acute myeloid leukemia HL-60 cells. J Enzyme Inhib Med Chem 2023; 38:405-422. [DOI: 10.1080/14756366.2022.2151592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Affiliation(s)
- Rania H. Abd El-Hameed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Mosaad S. Mohamed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Samir M. Awad
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Bardes B. Hassan
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | | | - Yara E. Mansour
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
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4
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Thummuri D, Khan S, Underwood PW, Zhang P, Wiegand J, Zhang X, Budamagunta V, Sobh A, Tagmount A, Loguinov A, Riner AN, Akki AS, Williamson E, Hromas R, Vulpe CD, Zheng G, Trevino JG, Zhou D. Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-X L-Specific Degrader DT2216. Mol Cancer Ther 2022; 21:184-192. [PMID: 34667112 PMCID: PMC8742767 DOI: 10.1158/1535-7163.mct-21-0474] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/16/2021] [Accepted: 10/14/2021] [Indexed: 01/09/2023]
Abstract
Pancreatic cancer is the third most common cause of cancer-related deaths in the United States. Although gemcitabine is the standard of care for most patients with pancreatic cancer, its efficacy is limited by the development of resistance. This resistance may be attributable to the evasion of apoptosis caused by the overexpression of BCL-2 family antiapoptotic proteins. In this study, we investigated the role of BCL-XL in gemcitabine resistance to identify a combination therapy to more effectively treat pancreatic cancer. We used CRISPR-Cas9 screening to identify the key genes involved in gemcitabine resistance in pancreatic cancer. Pancreatic cancer cell dependencies on different BCL-2 family proteins and the efficacy of the combination of gemcitabine and DT2216 (a BCL-XL proteolysis targeting chimera or PROTAC) were determined by MTS, Annexin-V/PI, colony formation, and 3D tumor spheroid assays. The therapeutic efficacy of the combination was investigated in several patient-derived xenograft (PDX) mouse models of pancreatic cancer. We identified BCL-XL as a key mediator of gemcitabine resistance. The combination of gemcitabine and DT2216 synergistically induced cell death in multiple pancreatic cancer cell lines in vitro In vivo, the combination significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice compared with the individual agents in pancreatic cancer PDX models. Their synergistic antitumor activity is attributable to DT2216-induced degradation of BCL-XL and concomitant suppression of MCL-1 by gemcitabine. Our results suggest that DT2216-mediated BCL-XL degradation augments the antitumor activity of gemcitabine and their combination could be more effective for pancreatic cancer treatment.
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Affiliation(s)
- Dinesh Thummuri
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Sajid Khan
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Patrick W Underwood
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida
| | - Peiyi Zhang
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Janet Wiegand
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Xuan Zhang
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Vivekananda Budamagunta
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Amin Sobh
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Abderrahmane Tagmount
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Alexander Loguinov
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Andrea N Riner
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida
| | - Ashwin S Akki
- Department of Pathology, College of Medicine, University of Florida, Gainesville, Florida
| | - Elizabeth Williamson
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Robert Hromas
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Christopher D Vulpe
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Guangrong Zheng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida
| | - Jose G Trevino
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida
- Division of Surgical Oncology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Daohong Zhou
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida.
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5
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Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy. Cells 2021; 10:cells10123348. [PMID: 34943856 PMCID: PMC8699513 DOI: 10.3390/cells10123348] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduce expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This can lead to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.
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6
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Chen X, Zeh HJ, Kang R, Kroemer G, Tang D. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol 2021; 18:804-823. [PMID: 34331036 DOI: 10.1038/s41575-021-00486-6] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.
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Affiliation(s)
- Xin Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.,Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Herbert J Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. .,Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China. .,Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Daolin Tang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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7
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Lamie PF, Philoppes JN. Design, synthesis, stereochemical determination, molecular docking study, in silico pre-ADMET prediction and anti-proliferative activities of indole-pyrimidine derivatives as Mcl-1 inhibitors. Bioorg Chem 2021; 116:105335. [PMID: 34509795 DOI: 10.1016/j.bioorg.2021.105335] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/13/2021] [Accepted: 09/03/2021] [Indexed: 10/20/2022]
Abstract
In this study, fourteen novel indole-pyrimidine hybrids were designed and synthesized. Their chemical structures were confirmed using different spectroscopic techniques (1H NMR, 13C NMR, IR and mass). Their (E) stereochemical configuration was determined theoretically (MM2 property) and experimentally using 2D NMR technique (NOESY experiment). The prepared compounds were subjected to preliminary biological studies as Mcl-1 inhibitors. Most of the compounds exhibited good abilities for targeting Mcl-1 protein, especially, 7d, 7e, 7i and 7k (Ki = 11.19-15.21 nM). These derivatives were further evaluated against Bcl-XL and Bcl-2 proteins. Some compounds were found to have dual Mcl-1/Bcl-XL such as 7i, or Bcl-XL/Bcl-2 inhibitory activity as 7d. The most potent derivatives as Mcl-1 inhibitors were chosen as representative examples for determination of in-vitro anti-proliferative activity against PC-3, K-562 and MDA-MB-231 cell lines. They possessed excellent to good anti-proliferative activities. All of the synthesized compounds were docked into Mcl-1 active site. Drug-likeness properties and in silico pre-ADMET characters were also predicted.
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Affiliation(s)
- Phoebe F Lamie
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
| | - John N Philoppes
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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8
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Al-Odat O, von Suskil M, Chitren R, Elbezanti W, Srivastava S, Budak-Alpddogan T, Jonnalagadda S, Aggarwal B, Pandey M. Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma. Front Pharmacol 2021; 12:699629. [PMID: 34349655 PMCID: PMC8327170 DOI: 10.3389/fphar.2021.699629] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/24/2021] [Indexed: 01/29/2023] Open
Abstract
Multiple myeloma (MM) is a plasma cells neoplasm. The overexpression of Bcl-2 family proteins, particularly myeloid cell leukemia 1 (Mcl-1), plays a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis of MM. Thus, inhibition of the Mcl-1 protein considered as a therapeutic strategy to kill the myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. This review presents the critical role of Mcl-1 in the progression of MM, the most prominent BH3 mimetic and semi-BH3 mimetic that selectively inhibit Mcl-1, and could be used as single agent or combined with existing therapies.
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Affiliation(s)
- Omar Al-Odat
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States.,Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, United States
| | - Max von Suskil
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States.,Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, United States
| | - Robert Chitren
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States.,Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, United States
| | - Weam Elbezanti
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States.,Department of Hematology, Cooper Health University, Camden, NJ, United States
| | | | | | - Subash Jonnalagadda
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, United States
| | | | - Manoj Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
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9
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Marques-Piubelli ML, Schlette EJ, Khoury JD, Furqan F, Vega F, Soto LMS, Wistuba II, Wierda WG, Konopleva M, Ferrajoli A, Strati P. Expression of BCL2 alternative proteins and association with outcome in CLL patients treated with venetoclax. Leuk Lymphoma 2021; 62:1129-1135. [PMID: 33327833 DOI: 10.1080/10428194.2020.1861278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/29/2020] [Indexed: 12/21/2022]
Abstract
Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ (p = .60, p = .46), BCL-2A1+ (p = .60, p = .29), and either BCL-W + or BCL-2A1+ (p = .33, p = .20), though not statistically significant. Pretreatment IHC expression of BCL-2 alternative proteins does not predict response to venetoclax in CLL, but may be a surrogate for an indolent biology. Sensitive techniques are needed to explore anti-apoptotic pathways.
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Affiliation(s)
- Mario L Marques-Piubelli
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ellen J Schlette
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph D Khoury
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fateeha Furqan
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Francisco Vega
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luisa M Solis Soto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William G Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alessandra Ferrajoli
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paolo Strati
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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10
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Kashyap D, Garg VK, Goel N. Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 125:73-120. [PMID: 33931145 DOI: 10.1016/bs.apcsb.2021.01.003] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Apoptosis, also named programmed cell death, is a fundament process required for morphogenetic homeostasis during early development and in pathophysiological conditions. It is come into existence in 1972 by work of Kerr, Wyllie and Currie and later on investigated during the research on development of the C. elegans. Trigger by several stimuli, apoptosis is necessary during the embryonic development and aging as homeostatic mechanism to control the cell population and also play a key role as defense mechanism against the immune responses and elimination of damaged cells. Cancer, a genetic disease, is a growing burden on the health and economy of both developing and developed countries. Every year there is tremendously increasing in the number of new cancer cases and mortality rate. Although, there is a significant improvement have been made in biotechnological and bioinformatic fields however, the therapeutic advantages and cancer etiology is still under explored. Several studies determined the deregulation of different apoptotic components during the cancer development and progression. Apoptosis relies on activation of distinct signaling pathways that are often deregulated in cancer. Thus, exploring the single or more than one apoptotic component underlying their expression in carcinogenesis could help to track the disease progression. Current book chapter will provide the several evidences supporting the use of different apoptotic components as prognosis and prediction markers in various human cancer types.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduation Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Neelam Goel
- Department of Information Technology, UIET, Panjab University, Chandigarh, India.
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11
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Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology. Bioorg Med Chem Lett 2021; 32:127717. [DOI: 10.1016/j.bmcl.2020.127717] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/20/2020] [Accepted: 11/21/2020] [Indexed: 01/19/2023]
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12
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Chetry S, Sharma P, Frontera A, Dutta D, Verma AK, Bhattacharyya MK. Unconventional formation of a 1D-chain of H-bonded water molecules in bipyridine-based supramolecular hexameric hosts of isostructural coordination compounds of Co(II) and Zn(II): Antiproliferative evaluation and theoretical studies. Polyhedron 2020. [DOI: 10.1016/j.poly.2020.114809] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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13
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Morimoto Y, Takada K, Takeuchi O, Watanabe K, Hirohara M, Hamamoto T, Masuda Y. Bcl-2/Bcl-xL inhibitor navitoclax increases the antitumor effect of Chk1 inhibitor prexasertib by inducing apoptosis in pancreatic cancer cells via inhibition of Bcl-xL but not Bcl-2. Mol Cell Biochem 2020; 472:187-198. [PMID: 32567031 DOI: 10.1007/s11010-020-03796-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/13/2020] [Indexed: 12/21/2022]
Abstract
In our previous study, we showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, enhances the effects of standard drugs for pancreatic cancer, including gemcitabine (GEM), S-1, and the combination of GEM and S-1 (GS). The combination of prexasertib and GS has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating anti-apoptotic protein Bcl-2. In the present study, we investigated the combined effect of GEM, S-1, and prexasertib with a selective Bcl-2 inhibitor (venetoclax) and a non-selective Bcl-2 inhibitor (navitoclax) in SUIT-2 pancreatic cancer cells. An MTT assay revealed that the combination of prexasertib with navitoclax showed a synergistic effect but the combination with venetoclax did not. Investigation of the pancreatic cancer cell lines SUIT-2, MIA PaCa-2, and BxPC-3 revealed that BxPC-3 also showed a high synergistic effect when combined with prexasertib and navitoclax but not venetoclax. Mechanistic analysis of the combined effect showed that apoptosis was induced. Bcl-2 knockdown with siRNA and prexasertib treatment did not induce apoptosis, whereas Bcl-xL knockdown with siRNA and prexasertib treatment resulted in strong induction of apoptosis. In addition, among the three cell lines, the combined effect of prexasertib and navitoclax resulted in increased apoptotic cell death because the protein expression levels of Bcl-xL and Chk1 were higher. Our results demonstrate that the combination of prexasertib and navitoclax has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating Bcl-xL. Simultaneous inhibition of Chk1 and Bcl-xL could be a new strategy for treating pancreatic cancer.
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Affiliation(s)
- Yoshihito Morimoto
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan.
| | - Kimihiko Takada
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Osamu Takeuchi
- BioMedical Laboratory, Department of Research, Kitasato Institute Hospital, Tokyo, 108-8642, Japan
| | - Kazuhiro Watanabe
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Masayoshi Hirohara
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Tomoyuki Hamamoto
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Yutaka Masuda
- Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
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14
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Yin Z, Yang D, Wang J, Jiang Y. Structure-based Drug Design Strategies in the Development of Small Molecule Inhibitors Targeting Bcl-2 Family Proteins. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180817666200213114759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Proteins of B-cell lymphoma (Bcl-2) family are key regulators of apoptosis and are involved
in the pathogenesis of various cancers. Disrupting the interactions between the antiapoptotic
and proapoptotic Bcl-2 members is an attractive strategy to reactivate the apoptosis of cancer cells.
Structure-based drug design (SBDD) has been successfully applied to the discovery of small molecule
inhibitors targeting Bcl-2 proteins in past decades. Up to now, many Bcl-2 inhibitors with different
paralogue selectivity profiles have been developed and some were used in clinical trials. This
review focused on the recent applications of SBDD strategies in the development of small molecule
inhibitors targeting Bcl-2 family proteins.
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Affiliation(s)
- Zhe Yin
- Thoracic Surgery Department, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Donglin Yang
- International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Jun Wang
- International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, China
| | - Yuequan Jiang
- Thoracic Surgery Department, Chongqing University Cancer Hospital, Chongqing 400030, China
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Abstract
![]()
Accurate determination
of the binding affinity of the ligand to
the receptor remains a difficult problem in computer-aided drug design.
Here, we study and compare the efficiency of Jarzynski’s equality
(JE) combined with steered molecular dynamics and the linear interaction
energy (LIE) method by assessing the binding affinity of 23 small
compounds to six receptors, including β-lactamase, thrombin,
factor Xa, HIV-1 protease (HIV), myeloid cell leukemia-1, and cyclin-dependent
kinase 2 proteins. It was shown that Jarzynski’s nonequilibrium
binding free energy ΔGneqJar correlates with the available
experimental data with the correlation levels R =
0.89, 0.86, 0.83, 0.80, 0.83, and 0.81 for six data sets, while for
the binding free energy ΔGLIE obtained
by the LIE method, we have R = 0.73, 0.80, 0.42,
0.23, 0.85, and 0.01. Therefore, JE is recommended to be used for
ranking binding affinities as it provides accurate and robust results.
In contrast, LIE is not as reliable as JE, and it should be used with
caution, especially when it comes to new systems.
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Affiliation(s)
- Kiet Ho
- Institute for Computational Sciences and Technology, Quang Trung Software City, SBI Building, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam
| | - Duc Toan Truong
- Institute for Computational Sciences and Technology, Quang Trung Software City, SBI Building, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.,Department of Theoretical Physics, Faculty of Physics and Engineering Physics, Ho Chi Minh University of Science, Ho Chi Minh City, Vietnam
| | - Mai Suan Li
- Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland
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16
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Anwar M, Malhotra P, Kochhar R, Bhatia A, Mahmood A, Singh R, Mahmood S. TCF 4 tumor suppressor: a molecular target in the prognosis of sporadic colorectal cancer in humans. Cell Mol Biol Lett 2020; 25:24. [PMID: 32265994 PMCID: PMC7110825 DOI: 10.1186/s11658-020-00217-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 03/11/2020] [Indexed: 12/11/2022] Open
Abstract
Background A huge array of function is played by the Wnt/β-catenin signaling pathway in development by balancing gene expression through the modulation of cell-specific DNA binding downstream effectors such as T-cell factor/lymphoid enhancer factor (TCF/LEF). The β-catenin/TCF-4 complex is a central regulatory switch for differentiation and proliferation of intestinal cells (both normal and malignant). Thus, in the present study we evaluated each of 60 cases of sporadic adenocarcinoma, alongside adjoining and normal mucosa specimens of colorectum in humans, for mutation and expression analysis of the gene coding for TCF-4 protein. Methods DNA sequencing following PCR amplification and SSCP analysis (single strand conformation polymorphism) was employed to detect TCF-4 gene mutations in the case of exon 1. Quantitative real-time (qRT) PCR, immunohistochemistry (IHC), confocal microscopy and western blot analysis were used to detect TCF-4 gene/protein expression. Results Sequencing analysis confirmed 5/60 patients with a point mutation in exon 1 of the TCF-4 gene in tumor samples. mRNA expression using qRT-PCR showed approximately 83% decreased TCF-4 mRNA expression in tumor tissue and adjoining mucosa compared to normal mucosa. Similarly, a significant decrease in protein expression using IHC showed decreased TCF-4 protein expression in tumor tissue and adjoining mucosa compared to normal mucosa, which also corresponds to some important clinicopathological factors, including disease metastasis and tumor grade. Mutational alterations and downregulation of TCF-4 mRNA and hence decreased expression of TCF-4 protein in tumors suggest its involvement in the pathogenesis of CRC. Conclusions A remarkable decrease in TCF-4 mRNA and protein expression was detected in tumorous and adjoining tissues compared to normal mucosa. Hence the alterations in genomic architecture along with downregulation of TCF-4 mRNA and decreased expression of TCF-4 protein in tumors, which is in accordance with clinical features, suggest its involvement in the pathogenesis of CRC. Thus, deregulation and collaboration of TCF-4 with CRC could be a concrete and distinctive feature in the prognosis of the disease at an early stage of development.
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Affiliation(s)
- Mumtaz Anwar
- 1Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, 160012 India.,2Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.,3Department of Pharmacology, University of Illinois at Chicago, Chicago, 60612 USA
| | - Pooja Malhotra
- 2Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India.,4Department of Medicine, University of Illinois at Chicago, Chicago, 60612 USA
| | - Rakesh Kochhar
- 2Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Alka Bhatia
- 1Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, 160012 India
| | - Akhtar Mahmood
- 5Department of Biochemistry, Panjab University, Chandigarh, 160014 India
| | - Rajinder Singh
- 6Department of Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012 India
| | - Safrun Mahmood
- 1Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, 160012 India
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17
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Castillo L, Young AIJ, Mawson A, Schafranek P, Steinmann AM, Nessem D, Parkin A, Johns A, Chou A, Law AMK, Lucas MC, Murphy KJ, Deng N, Gallego-Ortega D, Caldon CE, Timpson P, Pajic M, Ormandy CJ, Oakes SR. MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma. Oncogene 2020; 39:1821-1829. [PMID: 31735913 PMCID: PMC7033042 DOI: 10.1038/s41388-019-1091-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 10/22/2019] [Accepted: 10/28/2019] [Indexed: 11/23/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC.
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Affiliation(s)
- Lesley Castillo
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Adelaide I J Young
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Amanda Mawson
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Pia Schafranek
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Angela M Steinmann
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Danielle Nessem
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Ashleigh Parkin
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Amber Johns
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Angela Chou
- University of Sydney, Camperdown, NSW, 2006, Australia
| | - Andrew M K Law
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Morghan C Lucas
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Kendelle J Murphy
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
| | - Niantao Deng
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - David Gallego-Ortega
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Catherine E Caldon
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Paul Timpson
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Marina Pajic
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Christopher J Ormandy
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia
| | - Samantha R Oakes
- Cancer Research Division, Garvan Institute of Medical Research and the Kinghorn Cancer Centre, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
- St. Vincent's Clinical School, UNSW Medicine, 384 Victoria Street, Kensington, NSW, 2052, Australia.
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18
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Akula SM, Candido S, Abrams SL, Steelman LS, Lertpiriyapong K, Cocco L, Ramazzotti G, Ratti S, Follo MY, Martelli AM, Murata RM, Rosalen PL, Bueno-Silva B, Matias de Alencar S, Falasca M, Montalto G, Cervello M, Notarbartolo M, Gizak A, Rakus D, Libra M, McCubrey JA. Abilities of β-Estradiol to interact with chemotherapeutic drugs, signal transduction inhibitors and nutraceuticals and alter the proliferation of pancreatic cancer cells. Adv Biol Regul 2020; 75:100672. [PMID: 31685431 DOI: 10.1016/j.jbior.2019.100672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/12/2019] [Accepted: 10/15/2019] [Indexed: 06/10/2023]
Abstract
Improving the effects of chemotherapy and reducing the side effects are important goals in cancer research. Various approaches have been examined to enhance the effectiveness of chemotherapy. For example, signal transduction inhibitors or hormonal based approaches have been included with chemo- or radio-therapy. MIA-PaCa-2 and BxPC-3 pancreatic ductal adenocarcinoma (PDAC) cells both express the estrogen receptor (ER). The effects of β-estradiol on the growth of PDAC cells has not been examined yet the ER is expressed in PDAC cells. We have examined the effects of combining β-estradiol with chemotherapeutic drugs, signal transcription inhibitors, natural products and nutraceuticals on PDAC. In most cases, inclusion of β-estradiol with chemotherapeutic drugs increased chemosensitivity. These results indicate some approaches involving β-estradiol which may be used to increase the effectiveness of chemotherapeutic and other drugs on the growth of PDAC.
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Affiliation(s)
- Shaw M Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy; Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania, Italy
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA
| | - Kvin Lertpiriyapong
- Center of Comparative Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine and the Hospital for Special Surgery, New York City, New York, USA
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Giulia Ramazzotti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Matilde Y Follo
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Ramiro M Murata
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA; Department of Foundational Sciences, School of Dental Medicine, East Carolina University, USA
| | - Pedro L Rosalen
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Bruno Bueno-Silva
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil; Dental Research Division, Guarulhos University, Guarulhos, Brazil
| | | | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia, 6102, Australia
| | - Giuseppe Montalto
- Dipartimento di Promozione Della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy; Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Monica Notarbartolo
- Department of Biological, Chemical and Pharmaceutical Science and Technology (STEBICEF), University of Palermo, Palermo, Italy
| | - Agnieszka Gizak
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Dariusz Rakus
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy; Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA.
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Tang Y, Yang P, Zhu Y, Su Y. LncRNA TUG1 contributes to ESCC progression via regulating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro. Thorac Cancer 2019; 11:82-94. [PMID: 31742924 PMCID: PMC6938768 DOI: 10.1111/1759-7714.13236] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/18/2019] [Accepted: 10/18/2019] [Indexed: 12/20/2022] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Latest studies report that long noncoding RNAs (LncRNAs) play an essential role in diversified pathological processes of ESCC, although the mechanism by which they do so remains unknown. This study aimed to explore the parts of lncRNA taurine upregulated gene 1 (TUG1) in ESCC tissues and cells, its biofunctional effect and its underlying regulatory mechanism in ESCC. Methods The levels of TUG1 and miR‐148a‐3p were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR) in ESCC cells and tissues. The biofunctional effects were examined by MTT, flow cytometry, and transwell assay. The protein expression levels of epithelial‐mesenchymal transition (EMT)‐related proteins and MCL‐1 were determined by western blot analysis. The binding sites between miR‐148a‐3p and TUG1 or MCL‐1 were predicted by online software starBase and confirmed by dual luciferase reporter assay. Results The mRNA expression of TUG1 was significantly upregulated in ESCC tissues or cells, and was negatively correlated to miR‐148a‐3p expression in tissues. Knockdown of TUG1 inhibited the proliferation, migration, and invasion, promoted apoptosis, and relieved the EMT progression in EC9706 and OE19 cells. Besides, knockdown of miR‐148a‐3p inverted positive effects from TUG1 deletion on ESCC cells. Besides, MCL‐1 reversed the inhibitive effects from TUG1 deletion on expression of EMT‐associated proteins (Wnt1, C‐myc, CyclinD1, and β‐catenin) above subsequently. Conclusion TUG1 regulated the biofunction and EMT progression of ESCC by mediating miR‐148a‐3p/MCL‐1/Wnt/β‐catenin axis in vitro.
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Affiliation(s)
- Yin Tang
- Department of Laboratory, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, China
| | - Ping Yang
- Department of Laboratory, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, China
| | - Yunfeng Zhu
- Department of Laboratory, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, China
| | - Yong Su
- Department of Stomatology, Zhangjiagang Hospital of Traditional Chinese Medicine, Zhangjiagang, China
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20
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Denis C, Sopková-de Oliveira Santos J, Bureau R, Voisin-Chiret AS. Hot-Spots of Mcl-1 Protein. J Med Chem 2019; 63:928-943. [DOI: 10.1021/acs.jmedchem.9b00983] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Camille Denis
- Normandie Univiversité, UNICAEN, CERMN, 14000 Caen, France
| | | | - Ronan Bureau
- Normandie Univiversité, UNICAEN, CERMN, 14000 Caen, France
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21
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Kour S, Rana S, Contreras JI, King HM, Robb CM, Sonawane YA, Bendjennat M, Crawford AJ, Barger CJ, Kizhake S, Luo X, Hollingsworth MA, Natarajan A. CDK5 Inhibitor Downregulates Mcl-1 and Sensitizes Pancreatic Cancer Cell Lines to Navitoclax. Mol Pharmacol 2019; 96:419-429. [PMID: 31467029 PMCID: PMC6726458 DOI: 10.1124/mol.119.116855] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/23/2019] [Indexed: 12/17/2022] Open
Abstract
Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,1'-biphenyl]-4-yl)-N-(5-cyclobutyl-1H-pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8H)-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-[(4-{[(2R)-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 protein inhibitors. SIGNIFICANCE STATEMENT: Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax.
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Affiliation(s)
- Smit Kour
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Sandeep Rana
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Jacob I Contreras
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Hannah M King
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Caroline M Robb
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Yogesh A Sonawane
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Mourad Bendjennat
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Ayrianne J Crawford
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Carter J Barger
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Smitha Kizhake
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer and Allied Diseases (S.Ko., S.R., J.I.C., H.M.K., C.M.R., Y.A.S., M.B., A.J.C., C.J.B., S.Ki., X.L., M.A.H., A.N.), Departments of Pharmaceutical Sciences (A.N.) and Genetics Cell Biology and Anatomy (A.N.), and Fred & Pamela Buffett Cancer Center (X.L., M.A.H., A.N.), University of Nebraska Medical Center, Omaha, Nebraska
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Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, Jeon KO, Mills JJ, Bian Z, Sensintaffar JL, Arnold AL, Fogarty SA, Perry E, Ramsey HE, Cook RS, Hollingshead M, Davis Millin M, Lee KM, Koss B, Budhraja A, Opferman JT, Kim K, Arteaga CL, Moore WJ, Olejniczak ET, Savona MR, Fesik SW. Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer. J Med Chem 2019; 62:3971-3988. [DOI: 10.1021/acs.jmedchem.8b01991] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Taekyu Lee
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Plamen P. Christov
- Chemical Synthesis Core, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Subrata Shaw
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - James C. Tarr
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Bin Zhao
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Nagarathanam Veerasamy
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Kyu Ok Jeon
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Jonathan J. Mills
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Zhiguo Bian
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - John L. Sensintaffar
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Allison L. Arnold
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Stuart A. Fogarty
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Evan Perry
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Haley E. Ramsey
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States
| | - Rebecca S. Cook
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | | | | | - Kyung-min Lee
- Department of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Brian Koss
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
| | - Amit Budhraja
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
| | - Joseph T. Opferman
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, United States
| | - Kwangho Kim
- Chemical Synthesis Core, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Carlos L. Arteaga
- Department of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - William J. Moore
- Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, United States
| | - Edward T. Olejniczak
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
| | - Michael R. Savona
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States
| | - Stephen W. Fesik
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States
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23
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Tamtaji OR, Mirhosseini N, Reiter RJ, Behnamfar M, Asemi Z. Melatonin and pancreatic cancer: Current knowledge and future perspectives. J Cell Physiol 2018; 234:5372-5378. [PMID: 30229898 DOI: 10.1002/jcp.27372] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has a high mortality rate due to the absence of early symptoms and subsequent late diagnosis; additionally, pancreatic cancer has a high resistance to radio- and chemotherapy. Multiple inflammatory pathways are involved in the pathophysiology of pancreatic cancer. Melatonin an indoleamine produced in the pineal gland mediated and receptor-independent action is the pancreas and other where has both receptors. Melatonin is a potent antioxidant and tissue protector against inflammation and oxidative stress. In vivo and in vitro studies have shown that melatonin supplementation is an appropriate therapeutic approach for pancreatic cancer. Melatonin may be an effective apoptosis inducer in cancer cells through regulation of a large number of molecular pathways including oxidative stress, heat shock proteins, and vascular endothelial growth factor. Limited clinical studies, however, have evaluated the role of melatonin in pancreatic cancer. This review summarizes what is known regarding the effects of melatonin on pancreatic cancer and the mechanisms involved.
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Affiliation(s)
- Omid Reza Tamtaji
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science, Center, San Antonio, Texas
| | - Morteza Behnamfar
- Student Research Committee, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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24
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Shaw S, Bian Z, Zhao B, Tarr JC, Veerasamy N, Jeon KO, Belmar J, Arnold AL, Fogarty SA, Perry E, Sensintaffar JL, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW. Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design. J Med Chem 2018; 61:2410-2421. [PMID: 29323899 DOI: 10.1021/acs.jmedchem.7b01155] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.
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Affiliation(s)
- Subrata Shaw
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Zhiguo Bian
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Bin Zhao
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - James C Tarr
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Nagarathanam Veerasamy
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Kyu Ok Jeon
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Johannes Belmar
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Allison L Arnold
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Stuart A Fogarty
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Evan Perry
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - John L Sensintaffar
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - DeMarco V Camper
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Olivia W Rossanese
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Taekyu Lee
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Edward T Olejniczak
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
| | - Stephen W Fesik
- Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States
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25
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Roeten MSF, Cloos J, Jansen G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother Pharmacol 2018; 81:227-243. [PMID: 29184971 PMCID: PMC5778165 DOI: 10.1007/s00280-017-3489-0] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/19/2017] [Indexed: 12/13/2022]
Abstract
Targeting of the protein degradation pathway, in particular, the ubiquitin-proteasome system, has emerged as an attractive novel cancer chemotherapeutic modality. Although proteasome inhibitors have been most successfully applied in the treatment of hematological malignancies, they also received continuing interest for the treatment of solid tumors. In this review, we summarize the current positioning of proteasome inhibitors in the treatment of common solid malignancies (e.g., lung, colon, pancreas, breast, and head and neck cancer), addressing topics of their mechanism(s) of action, predictive factors and molecular mechanisms of resistance.
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Affiliation(s)
- Margot S F Roeten
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
| | - Jacqueline Cloos
- Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
- Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Location VUmc, VU University Medical Center, Amsterdam, The Netherlands
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26
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Liu T, Gao Y, Zhang X, Wan Y, Du L, Fang H, Li M. Discovery of a Turn-On Fluorescent Probe for Myeloid Cell Leukemia-1 Protein. Anal Chem 2017; 89:11173-11177. [DOI: 10.1021/acs.analchem.7b01148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Tingting Liu
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Yuqi Gao
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Xiaomeng Zhang
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Yichao Wan
- Key
Laboratory of Theoretical Organic Chemistry and Functional Molecule
(MOE), College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
| | - Lupei Du
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Hao Fang
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
| | - Minyong Li
- Department
of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE),
School of Pharmacy, Shandong University, Jinan, Shandong 250012, China
- State
Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, China
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27
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Yu X, Li W, Xia Z, Xie L, Ma X, Liang Q, Liu L, Wang J, Zhou X, Yang Y, Liu H. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis. BMC Cancer 2017; 17:449. [PMID: 28659182 PMCID: PMC5490225 DOI: 10.1186/s12885-017-3442-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 06/22/2017] [Indexed: 01/10/2023] Open
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed. Methods We used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin. Results The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage. Conclusions The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.
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Affiliation(s)
- Xinfang Yu
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China.,Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, Hunan, 410013, China
| | - Wei Li
- Department of Radiology, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Changsha, Hunan, 410013, China
| | - Zhenkun Xia
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Li Xie
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Xiaolong Ma
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Qi Liang
- Department of Radiology, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Changsha, Hunan, 410013, China
| | - Lijun Liu
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China.,Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Jian Wang
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China.,Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Xinmin Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Yifeng Yang
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China.,Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China
| | - Haidan Liu
- Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China. .,Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, 139 Renmin Road, Changsha, Hunan, 410011, China.
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28
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Glantz-Gashai Y, Meirson T, Reuveni E, Samson AO. Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:1803-1813. [PMID: 28684899 PMCID: PMC5484510 DOI: 10.2147/dddt.s133127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Myeloid cell leukemia-1 (Mcl-1) is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA)-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB) ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA), molecular dynamics (MD), and nuclear magnetic resonance (NMR), respectively. The evaluated potential Mcl-1 ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to treat cancer, thus partially validating our virtual screen. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in the treatment of cancer. The normal mode-, MD-, and NMR-based conformation greatly expand the conformational sampling used herein for in silico identification of potential Mcl-1 inhibitors.
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Affiliation(s)
| | - Tomer Meirson
- Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel
| | - Eli Reuveni
- Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel
| | - Abraham O Samson
- Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel
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Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis. Cell Mol Gastroenterol Hepatol 2017; 4:185-200.e1. [PMID: 28948203 PMCID: PMC5604117 DOI: 10.1016/j.jcmgh.2017.02.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 02/09/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Bcl-xL, an anti-apoptotic Bcl-2 family protein, is overexpressed in 90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, Bcl-xL expression in pancreatic intraepithelial neoplasias (PanINs) and its significance in PDAC carcinogenesis remain unclear. The aim of this study was to elucidate the significance of Bcl-xL expression in PanINs. METHODS We investigated the expression levels of Bcl-xL in pancreas-specific KrasG12D (P-KrasG12D) mice and human PanINs and PDAC. We examined the impact of Bcl-xL expression on Kras-mutated pancreatic neoplasia using Bcl-xL-overexpressing P-KrasG12D mice and Bcl-xL-knockout P-KrasG12D mice. RESULTS In P-KrasG12D mice, the number of PanINs increased and their grades progressed with age. In total, 55.6% of these mice developed PDAC at 12-14 months. According to the immunohistochemistry of mouse pancreas and human resected specimens, Bcl-xL expression was increased significantly in PanIN-1 compared with that in normal pancreatic ducts, and augmented further with the progression of pancreatic neoplasia in PanIN-2/3 and PDAC. Oncogene-induced senescence was observed frequently in PanIN-1, but rarely was detected in PanIN-2/3 and PDAC. Bcl-xL overexpression significantly accelerated the progression to high-grade PanINs and PDAC and reduced the survival of P-KrasG12D mice. Bcl-xL overexpression in P-KrasG12D mice suppressed oncogene-induced senescence in PanIN-1 and inhibited apoptosis in PanIN-3. Bcl-xL deficiency in P-KrasG12D mice induced cellular senescence in PanIN-2/3. CONCLUSIONS Bcl-xL expression increases with the progression from PanIN-1 to PDAC, whereas oncogene-induced senescence decreases. Bcl-xL overexpression increases PDAC incidence rates by inhibiting oncogene-induced senescence and apoptosis in PanINs. Conversely, Bcl-xL deficiency induced senescence in PanINs. Anti-Bcl-xL treatments may have the potency to suppress the progression from PanINs to PDAC.
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Modi V, Sankararamakrishnan R. Binding affinity of pro-apoptotic BH3 peptides for the anti-apoptotic Mcl-1 and A1 proteins: Molecular dynamics simulations of Mcl-1 and A1 in complex with six different BH3 peptides. J Mol Graph Model 2017; 73:115-128. [PMID: 28279820 DOI: 10.1016/j.jmgm.2016.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/29/2016] [Accepted: 12/08/2016] [Indexed: 02/07/2023]
Abstract
The anti-apoptotic members of Bcl-2 family of proteins bind to their pro-apoptotic counterparts to induce or prevent cell death.Based on the distinct binding profiles for specific pro-apoptotic BH3 peptides, the anti-apoptotic Bcl-2 proteins can be divided into at least two subclasses. The subclass that includes Bcl-XL binds strongly to Bad BH3 peptide while it has weak binding affinity for the second subclass of Bcl-2 proteins such as Mcl-1 and A1. Anti-apoptotic Bcl-2 proteins are considered to be attractive drug targets for anti-cancer drugs. BH3-mimetic inhibitors such as ABT-737 have been shown to be specific to Bcl-XL subclass while Mcl-1 and A1 show resistance to the same drug. An efficacious inhibitor should target all the anti-apoptotic Bcl-2 proteins. Hence, development of inhibitors selective to Mcl-1 and A1 is of prime importance for targeted cancer therapeutics. The first step to achieve this goal is to understand the molecular basis of high binding affinities of specific pro-apoptotic BH3 peptides for Mcl-1 and A1. To understand the interactions between the BH3 peptides and Mcl-1/A1, we performed multi-nanosecond molecular dynamics (MD) simulations of six complex structures of Mcl-1 and A1. With the exception of Bad, all complex structures were experimentally determined. Bad complex structures were modeled. Our simulation studies identified specific pattern of polar interactions between Mcl-1/A1 and high-affinity binding BH3 peptides. The lack of such polar interactions in Bad peptide complex is attributed to specific basic residues present before and after the highly conserved Leu residue. The close approach of basic residues in Bad and Mcl-1/A1 is hypothesized to be the cause of weak binding affinity. To test this hypothesis, we generated in silico mutants of these basic residues in Bad peptide and Mcl-1/A1 proteins. MD simulations of the mutant systems established the pattern of stable polar interactions observed in high-affinity binding BH3 peptides. We have thus identified specific residue positions in Bad and Mcl-1/A1 responsible for the weak binding affinity. Results from these simulation studies will aid in the development of inhibitors specific to Mcl-1 and A1 proteins.
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Affiliation(s)
- Vivek Modi
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, 208016, India
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Deng J. How to unleash mitochondrial apoptotic blockades to kill cancers? Acta Pharm Sin B 2017; 7:18-26. [PMID: 28119805 PMCID: PMC5237704 DOI: 10.1016/j.apsb.2016.08.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 06/27/2016] [Indexed: 01/28/2023] Open
Abstract
Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.
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Key Words
- ASH, American Society of Hematology
- ATAP, amphipathic tail-anchoring peptide
- Apoptosis
- BAD, BCL-2-associated death promoter protein
- BAK, BCL-2 homologous antagonist killer
- BAX, BCL-2-associated X protein
- BCL-2 family
- BCL-2, B-cell lymphoma 2
- BCL-w (BCL2L2), BCL-2-like protein 2
- BCL-xL, B-cell lymphoma X long
- BCR, B-cell receptor
- BFL-1 (BCL2A1), BCL-2-related protein A1
- BH3 profiling
- BH3, BCL-2 homology 3
- BID, BH3 interacting domain death agonist
- BIK, BCL-2-interacting killer
- BIM, BCL-2-interacting mediator of cell death
- BOK, BCL-2 related ovarian killer
- BTK, Bruton׳s tyrosine kinase
- CDK, cyclin-dependent kinase
- CHOP, cyclophosphamide, hydroxydaunorubicin, oncovin-vincristine and prednisone
- CLL, chronic lymphocytic leukemia
- CML, chronic myelogenous leukemia
- CR, complete response;EGFR, epidermal growth factor receptor
- Combination therapy
- ER, endoplasmic reticulum
- ERK, extracellular signal-regulated kinase
- FDA, U. S. Food and Drug Administration
- GSK-3, glycogen synthase kinase-3
- ITK, interleukin-2-inducible T-cell kinase
- MCL, myeloid cell leukemia
- MOMP, mitochondrial outer membrane permeabilization
- Mitochondrial priming
- NHL, non-Hodgkin lymphoma
- NIH, National Institutes of Health
- NSCLC, non-small cell lung cancer
- PI3K, phosphatidylinositol-3-kinase
- PUMA, p53 up-regulated modulator of apoptosis
- SLL, small lymphocytic lymphoma
- T-ALL, T-acute lymphocytic leukemia
- Targeted therapy
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Lu Z, Su J, Li Z, Zhan Y, Ye D. Hyaluronic acid-coated, prodrug-based nanostructured lipid carriers for enhanced pancreatic cancer therapy. Drug Dev Ind Pharm 2016; 43:160-170. [PMID: 27553814 DOI: 10.1080/03639045.2016.1226337] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
CONTEXT Gemcitabine (GEM) and Baicalein (BCL) are reported to have anti-tumor effects including pancreatic cancer. Hyaluronic acid (HA) can bind to over-expressed receptors in various kinds of cancer cells. OBJECTIVE The aim of this study is to develop prodrugs containing HA, BCL and GEM, and construct nanomedicine incorporate GEM and BCL in the core and HA on the surface. This system could target the cancer cells and co-deliver the drugs. METHODS GEM-stearic acid lipid prodrug (GEM-SA) and hyaluronic acid-amino acid-baicalein prodrug (HA-AA-BCL) were synthesized. Then, GEM and BCL prodrug-based targeted nanostructured lipid carriers (HA-GEM-BCL NLCs) were prepared by the nanoprecipitation technique. The in vitro cytotoxicity studies of the NLCs were evaluated on AsPC1 pancreatic cancer cell line. In vivo anti-tumor effects were observed on the murine-bearing pancreatic cancer model. RESULTS HA-GEM-BCL NLCs were effective in entering pancreatic cancer cells over-expressing HA receptors, and showed cytotoxicity of tumor cells in vitro. In vivo study revealed significant tumor growth inhibition ability of HA-GEM-BCL NLCs in murine pancreatic cancer model. CONCLUSION It could be concluded that HA-GEM-BCL NLCs could be featured as promising co-delivery, tumor-targeted nanomedicine for the treatment of cancers.
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Affiliation(s)
- Zhihe Lu
- a Department of Pharmacy , Linyi People's Hospital , Linyi , Shandong , China
| | - Jingrong Su
- b Department of Science and Education , Linyi People's Hospital , Linyi , Shandong , China
| | - Zhengrong Li
- a Department of Pharmacy , Linyi People's Hospital , Linyi , Shandong , China
| | - Yuzhu Zhan
- c Department of Pediatric Nephrologist , Linyi People's Hospital , Linyi , Shandong , China
| | - Decai Ye
- d Department of Neurology , Linyi People's Hospital , Linyi , Shandong , China
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Drennen B, Scheenstra JA, Yap JL, Chen L, Lanning ME, Roth BM, Wilder PT, Fletcher S. Structural Re-engineering of the α-Helix Mimetic JY-1-106 into Small Molecules: Disruption of the Mcl-1-Bak-BH3 Protein-Protein Interaction with 2,6-Di-Substituted Nicotinates. ChemMedChem 2016; 11:827-33. [PMID: 26844930 DOI: 10.1002/cmdc.201500461] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 11/23/2015] [Indexed: 01/19/2023]
Abstract
The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical Bcl-2 homology-3 (BH3) domains of its pro-apoptotic counterparts, such as Bak. Herein, we describe the discovery of small-molecule inhibitors of the Mcl-1 oncoprotein based on a novel chemotype. Particularly, re-engineering of our α-helix mimetic JY-1-106 into 2,6-di-substituted nicotinates afforded inhibitors of comparable potencies but with significantly decreased molecular weights. The most potent inhibitor 2-(benzyloxy)-6-(4-chloro-3,5-dimethylphenoxy)nicotinic acid (1 r: Ki =2.90 μm) likely binds in the p2 pocket of Mcl-1 and engages R263 in a salt bridge through its carboxylic acid, as supported by 2D (1) H-(15) N HSQC NMR data. Significantly, inhibitors were easily accessed in just four steps, which will facilitate future optimization efforts.
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Affiliation(s)
- Brandon Drennen
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Jacob A Scheenstra
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Jeremy L Yap
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Lijia Chen
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Maryanna E Lanning
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA
| | - Braden M Roth
- Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Paul T Wilder
- Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.,University of Maryland, Greenebaum Cancer Center, Baltimore, MD, 21201, USA
| | - Steven Fletcher
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA. .,University of Maryland, Greenebaum Cancer Center, Baltimore, MD, 21201, USA.
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Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein. Eur J Med Chem 2016; 113:273-92. [PMID: 26985630 DOI: 10.1016/j.ejmech.2016.02.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 02/02/2016] [Accepted: 02/03/2016] [Indexed: 12/21/2022]
Abstract
Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia.
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35
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Chen L, Wilder PT, Drennen B, Tran J, Roth BM, Chesko K, Shapiro P, Fletcher S. Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1). Org Biomol Chem 2016; 14:5505-10. [DOI: 10.1039/c5ob02063h] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A novel Mcl-1 inhibitor chemotype based on a tetrahydroquinoline carboxylic acid was developed utilizing structure-based design, which was subsequently validated by a fluorescence polarization competition assay and HSQC NMR analysis.
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Affiliation(s)
- L. Chen
- Department of Pharmaceutical Sciences
- University of Maryland School of Pharmacy
- Baltimore
- USA
| | - P. T. Wilder
- Department of Biochemistry and Molecular Biology
- University of Maryland School of Medicine
- Baltimore
- USA
- University of Maryland Greenebaum Cancer Center
| | - B. Drennen
- Department of Pharmaceutical Sciences
- University of Maryland School of Pharmacy
- Baltimore
- USA
| | - J. Tran
- PharmD Program
- University of Maryland School of Pharmacy
- Baltimore
- USA
| | - B. M. Roth
- Department of Biochemistry and Molecular Biology
- University of Maryland School of Medicine
- Baltimore
- USA
- University of Maryland Greenebaum Cancer Center
| | - K. Chesko
- Department of Pharmaceutical Sciences
- University of Maryland School of Pharmacy
- Baltimore
- USA
| | - P. Shapiro
- Department of Pharmaceutical Sciences
- University of Maryland School of Pharmacy
- Baltimore
- USA
- University of Maryland Greenebaum Cancer Center
| | - S. Fletcher
- Department of Pharmaceutical Sciences
- University of Maryland School of Pharmacy
- Baltimore
- USA
- University of Maryland Greenebaum Cancer Center
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Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors. Bioorg Med Chem 2015; 23:7685-93. [PMID: 26620718 DOI: 10.1016/j.bmc.2015.11.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 11/09/2015] [Accepted: 11/13/2015] [Indexed: 01/07/2023]
Abstract
Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
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37
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Anwar M, Kochhar R, Singh R, Bhatia A, Vaiphei K, Mahmood A, Mahmood S. Frequent activation of the β-catenin gene in sporadic colorectal carcinomas: A mutational & expression analysis. Mol Carcinog 2015; 55:1627-1638. [PMID: 26373808 DOI: 10.1002/mc.22414] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 08/02/2015] [Accepted: 08/31/2015] [Indexed: 01/11/2023]
Abstract
β-catenin (CTNNB1), an oncogene/onco-protein and an adhesion molecule is a key effector in colorectal cancer (CRC). Its activation, and subsequent up-regulation of Wnt-signaling, is an important event in the development of certain human cancers including CRC. Mutations in the β-catenin gene in the region of serine-threonine glycogen kinase (GSK)-3β phosphorylation target sites have been identified in colorectal cancer in humans. In the current study, we investigated 60 sporadic colorectal adenocarcinomas along with adjoining and normal mucosa cases in humans for β-catenin mutations. Thirteen of sixty colorectal tumors from humans had point mutations with a frequency of 21.66% at codons 24, 26, 27, 32, 34, 35, 41, 42,43, 46, 49, 54, 55, or 67 sites which are mutated in colorectal cancer and some of these sites in other cancers. Thus, there appears to be a key involvement of β-catenin activation in human colorectal carcinogenesis. mRNA expression analysis using q-Real Time PCR showed 21.5-fold up-regulation of β-catenin mRNA in tumor tissue compared to normal and adjoining mucosa. Protein expression analysis using immunohistochemistry, confocal microscopy, and Western blot confirmed aberrant accumulation of β-catenin protein along the nucleus and cytoplasm following mutation. The observed mutations and up-regulation of mRNA in tumors, and the increased expression of β-catenin protein in CRC suggest that these alterations are early and prognostic events in sporadic colorectal carcinogenesis in humans. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Mumtaz Anwar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.,Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Rakesh Kochhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Rajinder Singh
- Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Kim Vaiphei
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Akhtar Mahmood
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Safrun Mahmood
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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Quinn BA, Dash R, Sarkar S, Azab B, Bhoopathi P, Das SK, Emdad L, Wei J, Pellecchia M, Sarkar D, Fisher PB. Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline. Cancer Res 2015; 75:2305-15. [PMID: 26032425 DOI: 10.1158/0008-5472.can-14-3013] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo.
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Affiliation(s)
- Bridget A Quinn
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Rupesh Dash
- Institute of Life Sciences, Bhubaneswar, Orissa, India
| | - Siddik Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Belal Azab
- The University of Jordan, Department of Biological Sciences, Amman, Jordan
| | - Praveen Bhoopathi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Jun Wei
- Sanford-Burnham Medical Research Institute, La Jolla, California
| | | | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
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Burke JP, Bian Z, Shaw S, Zhao B, Goodwin CM, Belmar J, Browning CF, Vigil D, Friberg A, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J Med Chem 2015; 58:3794-805. [PMID: 25844895 PMCID: PMC5565203 DOI: 10.1021/jm501984f] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.
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Affiliation(s)
| | - Zhiguo Bian
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Subrata Shaw
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Bin Zhao
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Craig M. Goodwin
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Johannes Belmar
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Carrie F. Browning
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | | | | | - DeMarco V. Camper
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Olivia W. Rossanese
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Taekyu Lee
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Edward T. Olejniczak
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
| | - Stephen W. Fesik
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, USA
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Hata AN, Engelman JA, Faber AC. The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics. Cancer Discov 2015; 5:475-87. [PMID: 25895919 DOI: 10.1158/2159-8290.cd-15-0011] [Citation(s) in RCA: 453] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 03/27/2015] [Indexed: 12/23/2022]
Abstract
UNLABELLED The ability of cancer cells to suppress apoptosis is critical for carcinogenesis. The BCL2 family proteins comprise the sentinel network that regulates the mitochondrial or intrinsic apoptotic response. Recent advances in our understanding of apoptotic signaling pathways have enabled methods to identify cancers that are "primed" to undergo apoptosis, and have revealed potential biomarkers that may predict which cancers will undergo apoptosis in response to specific therapies. Complementary efforts have focused on developing novel drugs that directly target antiapoptotic BCL2 family proteins. In this review, we summarize the current knowledge of the role of BCL2 family members in cancer development and response to therapy, focusing on targeted therapeutics, recent progress in the development of apoptotic biomarkers, and therapeutic strategies designed to overcome deficiencies in apoptosis. SIGNIFICANCE Apoptosis, long known to be important for response to conventional cytotoxic chemotherapy, has more recently been shown to be essential for the efficacy of targeted therapies. Approaches that increase the likelihood of a cancer to undergo apoptosis following therapy may help improve targeted treatment strategies. Cancer Discov; 5(5); 475-87. ©2015 AACR.
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Affiliation(s)
- Aaron N Hata
- Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jeffrey A Engelman
- Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
| | - Anthony C Faber
- Virginia Commonwealth University Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Richmond, Virginia.
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WANG GUAN, CHEN SHAOHUA, EDWARDS HOLLY, CUI XINMING, CUI LI, GE YUBIN. Combination of chloroquine and GX15-070 (obatoclax) results in synergistic cytotoxicity against pancreatic cancer cells. Oncol Rep 2014; 32:2789-94. [DOI: 10.3892/or.2014.3525] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 08/18/2014] [Indexed: 11/06/2022] Open
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Belmar J, Fesik SW. Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther 2014; 145:76-84. [PMID: 25172548 DOI: 10.1016/j.pharmthera.2014.08.003] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 08/14/2014] [Indexed: 11/28/2022]
Abstract
The Bcl-2 family of proteins serves as primary regulators of apoptosis. Myeloid cell leukemia 1 (Mcl-1), a pro-survival member of the Bcl-2 family of proteins, is overexpressed and the Mcl-1 gene is amplified in many tumor types. Moreover, the overexpression of Mcl-1 is the cause of resistance to several chemotherapeutic agents. Thus, Mcl-1 is a promising cancer target. This review highlights the current progress on the discovery of small molecule Mcl-1 inhibitors.
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Affiliation(s)
- Johannes Belmar
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, United States
| | - Stephen W Fesik
- Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, TN 37232-0146, United States.
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Mao K, Zhang J, He C, Xu K, Liu J, Sun J, Wu G, Tan C, Zeng Y, Wang J, Xiao Z. Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett 2014; 352:245-52. [PMID: 25034398 DOI: 10.1016/j.canlet.2014.07.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 06/29/2014] [Accepted: 07/03/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV-associated HCC to sorafenib. METHODS Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3'-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining. RESULT The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3'-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis. CONCLUSIONS Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC.
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Affiliation(s)
- Kai Mao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jianlong Zhang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chuanchao He
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Kang Xu
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jieqiong Liu
- Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian Sun
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Gang Wu
- Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Cui Tan
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yunjie Zeng
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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Abulwerdi F, Liao C, Mady AS, Gavin J, Shen C, Cierpicki T, Stuckey J, Showalter HDH, Nikolovska-Coleska Z. 3-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR, and biological evaluation. J Med Chem 2014; 57:4111-33. [PMID: 24749893 PMCID: PMC4033665 DOI: 10.1021/jm500010b] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Indexed: 02/02/2023]
Abstract
Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, is a validated and attractive target for cancer therapy. Overexpression of Mcl-1 in many cancers results in disease progression and resistance to current chemotherapeutics. Utilizing high-throughput screening, compound 1 was identified as a selective Mcl-1 inhibitor and its binding to the BH3 binding groove of Mcl-1 was confirmed by several different, but complementary, biochemical and biophysical assays. Guided by structure-based drug design and supported by NMR experiments, comprehensive SAR studies were undertaken and a potent and selective inhibitor, compound 21, was designed which binds to Mcl-1 with a Ki of 180 nM. Biological characterization of 21 showed that it disrupts the interaction of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell death through a Bak/Bax-dependent mechanism, and selectively sensitizes Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell lines with compound 21 resulted in cell death through activation of caspase-3 and induction of apoptosis.
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Affiliation(s)
- Fardokht
A. Abulwerdi
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Interdepartmental
Program in Medicinal Chemistry, College of Pharmacy, Life Sciences Institute, and Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Chenzhong Liao
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Ahmed S. Mady
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Interdepartmental
Program in Medicinal Chemistry, College of Pharmacy, Life Sciences Institute, and Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Jordan Gavin
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Chenxi Shen
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Tomasz Cierpicki
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
| | - Jeanne
A. Stuckey
- Interdepartmental
Program in Medicinal Chemistry, College of Pharmacy, Life Sciences Institute, and Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - H. D. Hollis Showalter
- Interdepartmental
Program in Medicinal Chemistry, College of Pharmacy, Life Sciences Institute, and Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Zaneta Nikolovska-Coleska
- Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, United States
- Interdepartmental
Program in Medicinal Chemistry, College of Pharmacy, Life Sciences Institute, and Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States
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Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady ASA, Gulappa T, Cierpicki T, Owens S, Zhang T, Sun D, Stuckey JA, Mohammad RM, Nikolovska-Coleska Z. A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 2014; 13:565-75. [PMID: 24019208 PMCID: PMC4174574 DOI: 10.1158/1535-7163.mct-12-0767] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Using a high-throughput screening (HTS) approach, we have identified and validated several small-molecule Mcl-1 inhibitors (SMI). Here, we describe a novel selective Mcl-1 SMI inhibitor, 2 (UMI-77), developed by structure-based chemical modifications of the lead compound 1 (UMI-59). We have characterized the binding of UMI-77 to Mcl-1 by using complementary biochemical, biophysical, and computational methods and determined its antitumor activity against a panel of pancreatic cancer cells and an in vivo xenograft model. UMI-77 binds to the BH3-binding groove of Mcl-1 with Ki of 490 nmol/L, showing selectivity over other members of the antiapoptotic Bcl-2 family. UMI-77 inhibits cell growth and induces apoptosis in pancreatic cancer cells in a time- and dose-dependent manner, accompanied by cytochrome c release and caspase-3 activation. Coimmunoprecipitation experiments revealed that UMI-77 blocks the heterodimerization of Mcl-1/Bax and Mcl-1/Bak in cells, thus antagonizing the Mcl-1 function. The Bax/Bak-dependent induction of apoptosis was further confirmed using murine embryonic fibroblasts that are Bax- and Bak-deficient. In an in vivo BxPC-3 xenograft model, UMI-77 effectively inhibited tumor growth. Western blot analysis in tumor remnants revealed enhancement of proapoptotic markers and significant decrease of survivin. Collectively, these promising findings show the therapeutic potential of Mcl-1 inhibitors against pancreatic cancer and warrant further preclinical investigations.
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Affiliation(s)
- Fardokht Abulwerdi
- Corresponding Author: Zaneta Nikolovska-Coleska, 4510E MSRB I, 1150 West Medical Center Drive, Ann Arbor, MI 48109.
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Liu H, Yang J, Yuan Y, Xia Z, Chen M, Xie L, Ma X, Wang J, Ouyang S, Wu Q, Yu F, Zhou X, Yang Y, Cao Y, Hu J, Yin B. Regulation of Mcl-1 by constitutive activation of NF-κB contributes to cell viability in human esophageal squamous cell carcinoma cells. BMC Cancer 2014; 14:98. [PMID: 24529193 PMCID: PMC3930545 DOI: 10.1186/1471-2407-14-98] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 02/11/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with a 5-year survival rate less than 15%. Understanding of the molecular mechanisms involved in the pathogenesis of ESCC becomes critical to develop more effective treatments. METHODS Mcl-1 expression was measured by reverse transcription (RT)-PCR and Western blotting. Human Mcl-1 promoter activity was evaluated by reporter gene assay. The interactions between DNA and transcription factors were confirmed by electrophoretic mobility shift assay (EMSA) in vitro and by chromatin immunoprecipitation (ChIP) assay in cells. RESULTS Four human ESCC cell lines, TE-1, Eca109, KYSE150 and KYSE510, are revealed increased levels of Mcl-1 mRNA and protein compare with HaCaT, an immortal non-tumorigenic cell line. Results of reporter gene assays demonstrate that human Mcl-1 promoter activity is decreased by mutation of kappaB binding site, specific NF-kappaB inhibitor Bay11-7082 or dominant inhibitory molecule DNMIkappaBalpha in TE-1 and KYSE150 cell lines. Mcl-1 protein level is also attenuated by Bay11-7082 treatment or co-transfection of DNMIkappaBalpha in TE-1 and KYSE150 cells. EMSA results indicate that NF-kappaB subunits p50 and p65 bind to human Mcl-1-kappaB probe in vitro. ChIP assay further confirm p50 and p65 directly bind to human Mcl-1 promoter in intact cells, by which regulates Mcl-1 expression and contributes to the viability of TE-1 cells. CONCLUSIONS Our data provided evidence that one of the mechanisms of Mcl-1 expression in human ESCC is regulated by the activation of NF-kappaB signaling. The newly identified mechanism might provide a scientific basis for developing effective approaches to treatment human ESCC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Jianguo Hu
- Department of Cardiothoracic Surgery, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, Hunan 410011, China.
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Chen S, Wang G, Niu X, Zhao J, Tan W, Wang H, Zhao L, Ge Y. Combination of AZD2281 (Olaparib) and GX15-070 (Obatoclax) results in synergistic antitumor activities in preclinical models of pancreatic cancer. Cancer Lett 2014; 348:20-8. [PMID: 24534203 DOI: 10.1016/j.canlet.2014.02.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/21/2014] [Accepted: 02/10/2014] [Indexed: 01/21/2023]
Abstract
In this study, we explored the antitumor activities of the PARP inhibitor AZD2281 (Olaparib) and the pan-Bcl-2 inhibitor GX15-070 (Obatoclax) in six pancreatic cancer cell lines. While both agents were able to cause growth arrest and limited apoptosis, the combination of the two was able to synergistically cause growth arrest and non-apoptotic cell death. Furthermore, in an in vivo xenograft model, the combination caused substantially increased tumor necrosis compared to either treatment alone. Our results support further investigation of the combination of Bcl-2 and PARP inhibitors for the treatment of pancreatic cancer.
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Affiliation(s)
- Shaohua Chen
- The State Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China
| | - Guan Wang
- The State Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China
| | - Xiaojia Niu
- The State Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China
| | - Jianyun Zhao
- The State Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China
| | - Wenxi Tan
- Department of Pathophysiology College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Hebin Wang
- Department of Pathophysiology College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Lijing Zhao
- Department of Pathophysiology College of Basic Medical Sciences, Jilin University, Changchun, China.
| | - Yubin Ge
- The State Engineering Laboratory of AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, China; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
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Ziemba B, Franiak-Pietryga I, Pion M, Appelhans D, Muñoz-Fernández MÁ, Voit B, Bryszewska M, Klajnert-Maculewicz B. Toxicity and proapoptotic activity of poly(propylene imine) glycodendrimers in vitro: Considering their contrary potential as biocompatible entity and drug molecule in cancer. Int J Pharm 2014; 461:391-402. [DOI: 10.1016/j.ijpharm.2013.12.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 12/09/2013] [Indexed: 01/09/2023]
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Stan SD, Singh SV, Whitcomb DC, Brand RE. Phenethyl isothiocyanate inhibits proliferation and induces apoptosis in pancreatic cancer cells in vitro and in a MIAPaca2 xenograft animal model. Nutr Cancer 2013; 66:747-55. [PMID: 24195616 PMCID: PMC4008639 DOI: 10.1080/01635581.2013.795979] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Pancreatic cancer is often diagnosed at an advanced stage and it has a poor prognosis that points to an increased need to develop effective chemoprevention strategies for this disease. We examined the ability of phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate found in cruciferous vegetables, to inhibit the growth of pancreatic cancer cells in vitro and in a MIAPaca2 xenograft animal model. Exposure to PEITC inhibited pancreatic cancer cell growth in a dose-dependent manner, with an IC50 of approximately 7 μmol/L. PEITC treatment induced G2/M phase cell cycle arrest, downregulated the antiapoptotic proteins Bcl-2 and Bcl-XL, upregulated the proapoptotic protein Bak, and suppressed Notch 1 and 2 levels. In addition, treatment with PEITC induced cleavage of poly-(ADP-ribose) polymerase and led to increased cytoplasmic histone-associated DNA fragmentation and subdiploid (apoptotic) fraction in pancreatic cancer cells. Oral administration of PEITC suppressed the growth of pancreatic cancer cells in a MIAPaca2 xenograft animal model. Our data show that PEITC exerts its inhibitory effect on pancreatic cancer cells through several mechanisms, including G2/M phase cell cycle arrest and induction of apoptosis, and supports further investigation of PEITC as a chemopreventive agent for pancreatic cancer.
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Affiliation(s)
- Silvia D. Stan
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana
| | - Shivendra V. Singh
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - David C. Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Randall E. Brand
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Chen Z, Sangwan V, Banerjee S, Mackenzie T, Dudeja V, Li X, Wang H, Vickers SM, Saluja AK. miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death. Mol Cancer 2013; 12:105. [PMID: 24025188 PMCID: PMC3848798 DOI: 10.1186/1476-4598-12-105] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 08/20/2013] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, mainly due to lack of effective available therapies. Cancer cell survival is dependent upon up-regulation of the pro-survival response, mediated by anti-apoptotic proteins such as Mcl-1. RESULTS Here we show that over-expression of Mcl-1 in pancreatic patient tumor samples is linked to advancement of the disease. We have previously shown that triptolide, a diterpene triepoxide, is effective both in vitro and in vivo, in killing pancreatic cancer cells. Decrease of Mcl-1 levels, either by siRNA or by treatment with triptolide results in cell death. Using pancreatic cancer cell lines, we have shown that miR-204, a putative regulator of Mcl-1, is repressed in cancer cell lines compared to normal cells. Over-expression of miR-204, either by a miR-204 mimic, or by triptolide treatment results in a decrease in Mcl-1 levels, and a subsequent decrease in cell viability. Using luciferase reporter assays, we confirmed the ability of miR-204 to down-regulate Mcl-1 by directly binding to the Mcl-1 3' UTR. Using human xenograft samples treated with Minnelide, a water soluble variant of triptolide, we have shown that miR-204 is up-regulated and Mcl-1 is down-regulated in treated vs. control tumors. CONCLUSION Triptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.
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Affiliation(s)
- Zhiyu Chen
- Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
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