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1
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Garimella SV, Gampa SC, Chaturvedi P. Mitochondria in Cancer Stem Cells: From an Innocent Bystander to a Central Player in Therapy Resistance. Stem Cells Cloning 2023; 16:19-41. [PMID: 37641714 PMCID: PMC10460581 DOI: 10.2147/sccaa.s417842] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
Cancer continues to rank among the world's leading causes of mortality despite advancements in treatment. Cancer stem cells, which can self-renew, are present in low abundance and contribute significantly to tumor recurrence, tumorigenicity, and drug resistance to various therapies. The drug resistance observed in cancer stem cells is attributed to several factors, such as cellular quiescence, dormancy, elevated aldehyde dehydrogenase activity, apoptosis evasion mechanisms, high expression of drug efflux pumps, protective vascular niche, enhanced DNA damage response, scavenging of reactive oxygen species, hypoxic stability, and stemness-related signaling pathways. Multiple studies have shown that mitochondria play a pivotal role in conferring drug resistance to cancer stem cells, through mitochondrial biogenesis, metabolism, and dynamics. A better understanding of how mitochondria contribute to tumorigenesis, heterogeneity, and drug resistance could lead to the development of innovative cancer treatments.
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Affiliation(s)
- Sireesha V Garimella
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India
| | - Siri Chandana Gampa
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India
| | - Pankaj Chaturvedi
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
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2
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Higgs EF, Bao R, Hatogai K, Gajewski TF. Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration. J Immunother Cancer 2022; 10:jitc-2022-004797. [PMID: 35705315 PMCID: PMC9204399 DOI: 10.1136/jitc-2022-004797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Background A T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade. Methods RNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+ T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy. Results Among the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2+ tumor cells and CD8+ T cells. Additionally, melanomas with high MSH2+ tumor cell numbers were largely non-responders to anti-PD-1 therapy. Conclusions Increased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.
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Affiliation(s)
- Emily F Higgs
- Pathology, University of Chicago Department of Medicine, Chicago, Illinois, USA
| | - Riyue Bao
- Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.,UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Ken Hatogai
- Pathology, University of Chicago Department of Medicine, Chicago, Illinois, USA
| | - Thomas F Gajewski
- Pathology, University of Chicago Department of Medicine, Chicago, Illinois, USA
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da Paixão VF, Sosa OJ, da Silva Pellegrina DV, Dazzani B, Corrêa TB, Risério Bertoldi E, da Cruz E Alves-de-Moraes LB, de Oliveira Pessoa D, de Paiva Oliveira V, Alberto Chiong Zevallos R, Russo LC, Forti FL, Eduardo Ferreira J, Carioca Freitas H, Jukemura J, Machado MCC, Dirlei Begnami M, Setubal JC, Bassères DS, Moraes Reis E. Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma. Cell Oncol (Dordr) 2022; 45:479-504. [PMID: 35567709 DOI: 10.1007/s13402-022-00678-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
PURPOSE Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.
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Affiliation(s)
- Vinicius Ferreira da Paixão
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Omar Julio Sosa
- Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Bianca Dazzani
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Thalita Bueno Corrêa
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Ester Risério Bertoldi
- Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Luís Bruno da Cruz E Alves-de-Moraes
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Diogo de Oliveira Pessoa
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Victoria de Paiva Oliveira
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Ricardo Alberto Chiong Zevallos
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Lilian Cristina Russo
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Fabio Luis Forti
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - João Eduardo Ferreira
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - José Jukemura
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Maria Dirlei Begnami
- Departamento de Anatomia Patológica - AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - João Carlos Setubal
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Daniela Sanchez Bassères
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Eduardo Moraes Reis
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil.
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El Naggar O, Doyle B, Mariner K, Gilmour SK. Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells. Med Sci (Basel) 2022; 10:medsci10020028. [PMID: 35736348 PMCID: PMC9230675 DOI: 10.3390/medsci10020028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 11/26/2022] Open
Abstract
Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) polymerase (PARP), another important component of DNA damage repair, are somewhat effective in BRCA1/2 mutant tumors. However, ovarian cancers often reacquire functional BRCA and develop resistance to PARP inhibitors. Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, α-difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines. In vitro viability assays show that DFMO and rucaparib cotreatment significantly enhances the cytotoxicity of the chemotherapeutic agent, cisplatin. These results suggest that DFMO may be a useful adjunct chemotherapeutic to improve the anti-tumor efficacy of PARP inhibitors in treating ovarian cancer.
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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Wilczyński JR. Cancer Stem Cells: An Ever-Hiding Foe. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:219-251. [PMID: 35165866 DOI: 10.1007/978-3-030-91311-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
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7
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Alausa A, Victor UC, Celestine UO, Eweje IA, Balogun TA, Adeyemi R, Olatinwo M, Ogunlana AT, Oladipo O, Olaleke B. Phytochemical based sestrin2 pharmacological modulators in the treatment of adenocarcinomas. PHYTOMEDICINE PLUS 2021; 1:100133. [DOI: 10.1016/j.phyplu.2021.100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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8
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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9
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Gaggianesi M, Di Franco S, Pantina VD, Porcelli G, D'Accardo C, Verona F, Veschi V, Colarossi L, Faldetta N, Pistone G, Bongiorno MR, Todaro M, Stassi G. Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment. Front Oncol 2021; 11:702642. [PMID: 34354950 PMCID: PMC8330815 DOI: 10.3389/fonc.2021.702642] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME.
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Affiliation(s)
- Miriam Gaggianesi
- Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Simone Di Franco
- Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Vincenzo Davide Pantina
- Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | - Gaetana Porcelli
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Caterina D'Accardo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Francesco Verona
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
| | | | - Naida Faldetta
- Department of Surgery, Villa Sofia-Cervello Hospital, Palermo, Italy
| | - Giuseppe Pistone
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Maria Rita Bongiorno
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy
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Muyinda IJ, Park JG, Jang EJ, Yoo BC. KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism. Int J Mol Sci 2021; 22:5070. [PMID: 34064761 PMCID: PMC8150642 DOI: 10.3390/ijms22105070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022] Open
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells.
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Affiliation(s)
- Isaac James Muyinda
- Department of Translational Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Korea; (I.J.M.); (E.-J.J.)
- Uganda Cancer Institute, Mulago-Kampala 3935, Uganda
| | - Jae-Gwang Park
- Department of Translational Science, Research Institute, National Cancer Center, Goyang-si 10408, Korea;
| | - Eun-Jung Jang
- Department of Translational Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Korea; (I.J.M.); (E.-J.J.)
| | - Byong-Chul Yoo
- Department of Translational Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si 10408, Korea; (I.J.M.); (E.-J.J.)
- Department of Translational Science, Research Institute, National Cancer Center, Goyang-si 10408, Korea;
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Abad E, Civit L, Potesil D, Zdrahal Z, Lyakhovich A. Enhanced DNA damage response through RAD50 in triple negative breast cancer resistant and cancer stem-like cells contributes to chemoresistance. FEBS J 2021; 288:2184-2202. [PMID: 33090711 DOI: 10.1111/febs.15588] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 08/10/2020] [Accepted: 10/06/2020] [Indexed: 12/23/2022]
Abstract
A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self-defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple-negative breast cancer (TNBC) cells and corresponding CSC-like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP-binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11-Rad50-NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs.
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Affiliation(s)
- Etna Abad
- Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Laia Civit
- Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - David Potesil
- Research Group Proteomics, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Zbynek Zdrahal
- Research Group Proteomics, CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Russia
| | - Alex Lyakhovich
- Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
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12
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Wang HC, Chan LP, Wu CC, Chang SJ, Moi SH, Luo CW, Pan MR. Silencing DNA Polymerase β Induces Aneuploidy as a Biomarker of Poor Prognosis in Oral Squamous Cell Cancer. Int J Mol Sci 2021; 22:ijms22052402. [PMID: 33673690 PMCID: PMC7957714 DOI: 10.3390/ijms22052402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022] Open
Abstract
Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-β (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells.
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Affiliation(s)
- Hui-Ching Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Internal Medicine, Division of Hematology and Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Leong-Perng Chan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Chun-Chieh Wu
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Shu-Jyuan Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Sin-Hua Moi
- Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, No.1, Sec. 1, Syuecheng Rd., Dashu District, Kaohsiung 84001, Taiwan;
| | - Chi-Wen Luo
- Department of Surgery, Division of Breast Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-3121101-5092-34; Fax: +886-7-3218309
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13
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Soltanian S, Sheikhbahaei M. Effect of Menadione and Combination of Gemcitabine and Cisplatin on Cancer Stem Cells in Human Non-small Cell Lung Cancer (NSCLC) Cell Line A549. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:105-117. [PMID: 34400945 PMCID: PMC8170754 DOI: 10.22037/ijpr.2020.112373.13715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Chemotherapy-induced adverse effects and resistance of NSCLC to conventional drugs reduce the efficacy of current therapies. Tumors contain a small population of cancer stem cells (CSCs) that play a critical role in tumor initiation, maintenance, and drug resistance that finally lead to cancer recurrence. Therefore, CSC-targeting therapies can offer the best hope for developing curative cancer therapies. Vitamins have a high potential for cancer prevention and treatment. Vitamins also ameliorate the side effects which occur in chemo-radio therapy. Menadione (2-methyl-1,4-naphthoquinone/vitamin-K3) is a synthetic form of vitamin K that indicated antitumor activities. The purpose of this study was to evaluate the anti-CSCs effect of menadione and combination of cisplatin and gemcitabine as a first-line treatment in patients with NSCLC on the NSCLC cell line A549. MTT results displayed decreased cell survival after treatment with cisplatin/gemcitabine for 48 h treatment (IC50 values 0.25 µM for cisplatin and 5 µM for gemcitabine). Menadione also inhibited the cell growth in A549 cells (IC50: 16 µM). Quantitative RT-PCR showed significant downregulation of CSC markers (Oct4, Nanog, Sox2, Aldh1, Abcb1, CD44, and CD133) and Snail, epithelial-mesenchymal transition marker, after treatment with menadione and cisplatin/gemcitabine. Flow cytometry showed CD44-positive cells that constitute a high percentage (70%) of A549 cells reduced significantly after treatment with cisplatin/gemcitabine or menadione. However, A549 cells did not show a significant population positive for CD133 and ABCB1 (less than 0.05%), and these fractions did not change after treatment with two agents.
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14
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Bridges AE, Ramachandran S, Pathania R, Parwal U, Lester A, Rajpurohit P, Morera DS, Patel N, Singh N, Korkaya H, Manicassamy S, Prasad PD, Lokeshwar VB, Lokeshwar BL, Ganapathy V, Thangaraju M. RAD51AP1 Deficiency Reduces Tumor Growth by Targeting Stem Cell Self-Renewal. Cancer Res 2020; 80:3855-3866. [PMID: 32665355 DOI: 10.1158/0008-5472.can-19-3713] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/31/2020] [Accepted: 07/09/2020] [Indexed: 11/16/2022]
Abstract
RAD51-associated protein 1 (RAD51AP1) plays an integral role in homologous recombination by activating RAD51 recombinase. Homologous recombination is essential for preserving genome integrity and RAD51AP1 is critical for D-loop formation, a key step in homologous recombination. Although RAD51AP1 is involved in maintaining genomic stability, recent studies have shown that RAD51AP1 expression is significantly upregulated in human cancers. However, the functional role of RAD51AP1 in tumor growth and the underlying molecular mechanism(s) by which RAD51AP1 regulates tumorigenesis have not been fully understood. Here, we use Rad51ap1-knockout mice in genetically engineered mouse models of breast cancer to unravel the role of RAD51AP1 in tumor growth and metastasis. RAD51AP1 gene transcript was increased in both luminal estrogen receptor-positive breast cancer and basal triple-negative breast cancer, which is associated with poor prognosis. Conversely, knockdown of RAD51AP1 (RADP51AP1 KD) in breast cancer cell lines reduced tumor growth. Rad51ap1-deficient mice were protected from oncogene-driven spontaneous mouse mammary tumor growth and associated lung metastasis. In vivo, limiting dilution studies provided evidence that Rad51ap1 plays a critical role in breast cancer stem cell (BCSC) self-renewal. RAD51AP1 KD improved chemotherapy and radiotherapy response by inhibiting BCSC self-renewal and associated pluripotency. Overall, our study provides genetic and biochemical evidences that RAD51AP1 is critical for tumor growth and metastasis by increasing BCSC self-renewal and may serve as a novel target for chemotherapy- and radiotherapy-resistant breast cancer. SIGNIFICANCE: This study provides in vivo evidence that RAD51AP1 plays a critical role in breast cancer growth and metastasis by regulating breast cancer stem cell self-renewal.
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Affiliation(s)
- Allison E Bridges
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia
| | - Sabarish Ramachandran
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Rajneesh Pathania
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Utkarsh Parwal
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia
| | - Adrienne Lester
- Depatment of Undergraduate Health Professions, College of Allied Health Sciences, Augusta University, Augusta, Georgia
| | - Pragya Rajpurohit
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia
| | - Daley S Morera
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia
| | - Nikhil Patel
- Department of Pathology, Augusta University, Augusta, Georgia
| | - Nagendra Singh
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Hasan Korkaya
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Santhakumar Manicassamy
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Puttur D Prasad
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Vinata B Lokeshwar
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Bal L Lokeshwar
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Vadivel Ganapathy
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia.,Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia. .,Georgia Cancer Center Medical College of Georgia, Augusta University, Augusta, Georgia
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15
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Taylor SJ, Arends MJ, Langdon SP. Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:26-52. [PMID: 36046263 PMCID: PMC9400734 DOI: 10.37349/etat.2020.00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/18/2019] [Indexed: 11/30/2022] Open
Abstract
The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach.
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Affiliation(s)
- Sarah J Taylor
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Mark J Arends
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
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16
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Role of Rad51 and DNA repair in cancer: A molecular perspective. Pharmacol Ther 2020; 208:107492. [PMID: 32001312 DOI: 10.1016/j.pharmthera.2020.107492] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/13/2020] [Accepted: 01/22/2020] [Indexed: 12/24/2022]
Abstract
The maintenance of genome integrity is essential for any organism survival and for the inheritance of traits to offspring. To the purpose, cells have developed a complex DNA repair system to defend the genetic information against both endogenous and exogenous sources of damage. Accordingly, multiple repair pathways can be aroused from the diverse forms of DNA lesions, which can be effective per se or via crosstalk with others to complete the whole DNA repair process. Deficiencies in DNA healing resulting in faulty repair and/or prolonged DNA damage can lead to genes mutations, chromosome rearrangements, genomic instability, and finally carcinogenesis and/or cancer progression. Although it might seem paradoxical, at the same time such defects in DNA repair pathways may have therapeutic implications for potential clinical practice. Here we provide an overview of the main DNA repair pathways, with special focus on the role played by homologous repair and the RAD51 recombinase protein in the cellular DNA damage response. We next discuss the recombinase structure and function per se and in combination with all its principal mediators and regulators. Finally, we conclude with an analysis of the manifold roles that RAD51 plays in carcinogenesis, cancer progression and anticancer drug resistance, and conclude this work with a survey of the most promising therapeutic strategies aimed at targeting RAD51 in experimental oncology.
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17
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Abad E, Graifer D, Lyakhovich A. DNA damage response and resistance of cancer stem cells. Cancer Lett 2020; 474:106-117. [PMID: 31968219 DOI: 10.1016/j.canlet.2020.01.008] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/20/2022]
Abstract
The cancer stem cell (CSC) model defines tumors as hierarchically organized entities, containing a small population of tumorigenic CSC, or tumour-initiating cells, placed at the apex of this hierarchy. These cells may share common qualities with chemo- and radio-resistant cancer cells and contribute to self-renewal activities resulting in tumour formation, maintenance, growth and metastasis. Yet, it remains obscure what self-defense mechanisms are utilized by these cells against the chemotherapeutic drugs or radiotherapy. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis. In line with this note, an increased DDR that prevents CSC and chemoresistant cells from genotoxic pressure of chemotherapeutic drugs or radiation may be responsible for cancer metastasis. In this review, we focus on the current knowledge concerning the role of DDR in CSC and resistant cancer cells and describe the existing opportunities of re-sensitizing such cells to modulate therapeutic treatment effects.
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Affiliation(s)
- Etna Abad
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | | | - Alex Lyakhovich
- Institute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Russia; Vall D'Hebron Institut de Recerca, 08035, Barcelona, Spain.
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18
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Yang Q, Chen K, Zhang L, Feng L, Fu G, Jiang S, Bi S, Lin C, Zhou Y, Zhao H, Chen XL, Fu G, Xu B. Synthetic lethality of combined AT-101 with idarubicin in acute myeloid leukemia via blockade of DNA repair and activation of intrinsic apoptotic pathway. Cancer Lett 2019; 461:31-43. [DOI: 10.1016/j.canlet.2019.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 06/28/2019] [Accepted: 07/05/2019] [Indexed: 12/27/2022]
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19
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Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol 2019; 14:141. [PMID: 31395068 PMCID: PMC6688256 DOI: 10.1186/s13014-019-1345-6] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/24/2019] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence. Late detection and a particularly aggressive biology are the major challenges which determine therapeutic failure. In this review, we present the current status and the recent advances in PDAC treatment together with the biological and immunological hallmarks of this cancer entity. On this basis, we discuss new concepts combining distinct treatment modalities in order to improve therapeutic efficacy and clinical outcome - with a specific focus on protocols involving radio(chemo)therapeutic approaches.
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20
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Bian Y, Teper Y, Mathews Griner LA, Aiken TJ, Shukla V, Guha R, Shinn P, Xin HW, Pflicke H, Powers AS, Li D, Jiang JK, Patel P, Rogers SA, Aubé J, Ferrer M, Thomas CJ, Rudloff U. Target Deconvolution of a Multikinase Inhibitor with Antimetastatic Properties Identifies TAOK3 as a Key Contributor to a Cancer Stem Cell-Like Phenotype. Mol Cancer Ther 2019; 18:2097-2110. [PMID: 31395684 DOI: 10.1158/1535-7163.mct-18-1011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 03/11/2019] [Accepted: 07/29/2019] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer remains an incurable condition. Its progression is driven, in part, by subsets of cancer cells that evade the cytotoxic effects of conventional chemotherapies. These cells are often low-cycling, multidrug resistant, and adopt a stem cell-like phenotype consistent with the concept of cancer stem cells (CSC). To identify drugs impacting on tumor-promoting CSCs, we performed a differential high-throughput drug screen in pancreatic cancer cells cultured in traditional (2D) monolayers versus three-dimensional (3D) spheroids which replicate key elements of the CSC model. Among the agents capable of killing cells cultured in both formats was a 1H-benzo[d]imidazol-2-amine-based inhibitor of IL2-inducible T-cell kinase (ITK; NCGC00188382, inhibitor #1) that effectively mediated growth inhibition and induction of apoptosis in vitro, and suppressed cancer progression and metastasis formation in vivo An examination of this agent's polypharmacology via in vitro and in situ phosphoproteomic profiling demonstrated an activity profile enriched for mediators involved in DNA damage repair. Included was a strong inhibitory potential versus the thousand-and-one amino acid kinase 3 (TAOK3), CDK7, and aurora B kinases. We found that cells grown under CSC-enriching spheroid conditions are selectively dependent on TAOK3 signaling. Loss of TAOK3 decreases colony formation, expression of stem cell markers, and sensitizes spheroids to the genotoxic effect of gemcitabine, whereas overexpression of TAOK3 increases stem cell traits including tumor initiation and metastasis formation. By inactivating multiple components of the cell-cycle machinery in concert with the downregulation of key CSC signatures, inhibitor #1 defines a distinctive strategy for targeting pancreatic cancer cell populations.
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Affiliation(s)
- Yansong Bian
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Yaroslav Teper
- Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Lesley A Mathews Griner
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Taylor J Aiken
- Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.,Department of Surgery, University of Wisconsin, Madison, Wisconsin
| | - Vivek Shukla
- Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Rajarshi Guha
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Paul Shinn
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Hong-Wu Xin
- Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Holger Pflicke
- Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Astin S Powers
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Dandan Li
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Jian-Kang Jiang
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Paresma Patel
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Steven A Rogers
- Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
| | - Jeffrey Aubé
- Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
| | - Marc Ferrer
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Craig J Thomas
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland.
| | - Udo Rudloff
- Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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21
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Schulz A, Meyer F, Dubrovska A, Borgmann K. Cancer Stem Cells and Radioresistance: DNA Repair and Beyond. Cancers (Basel) 2019; 11:cancers11060862. [PMID: 31234336 PMCID: PMC6627210 DOI: 10.3390/cancers11060862] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022] Open
Abstract
The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming.
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Affiliation(s)
- Alexander Schulz
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
| | - Felix Meyer
- Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, 01307 Dresden, Germany.
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Kerstin Borgmann
- Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
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22
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Gorodetska I, Kozeretska I, Dubrovska A. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer 2019; 10:2109-2127. [PMID: 31205572 PMCID: PMC6548160 DOI: 10.7150/jca.30410] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.
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Affiliation(s)
- Ielizaveta Gorodetska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Iryna Kozeretska
- Department of General and Medical Genetics, ESC "The Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Anna Dubrovska
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Dresden, Germany; German Cancer Consortium (DKTK), Partner site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
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23
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Dzobo K, Senthebane DA, Thomford NE, Rowe A, Dandara C, Parker MI. Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 22:17-34. [PMID: 29356626 DOI: 10.1089/omi.2017.0174] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Dimakatso Alice Senthebane
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Nicholas Ekow Thomford
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Arielle Rowe
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa
| | - Collet Dandara
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - M Iqbal Parker
- 2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
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An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:240. [PMID: 30285798 PMCID: PMC6169080 DOI: 10.1186/s13046-018-0899-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 01/05/2023]
Abstract
Background Pancreatic cancer is a deadly disease with a very low 5-year patient survival rate of 6–8%. The major challenges of eliminating pancreatic cancer are treatment resistance and stromal barriers to optimal drug access within the tumor. Therefore, effective molecular targeting drugs with high intra-tumor access and retention are urgently needed for managing this devastating disease in the clinic. Methods This study has used the following in vitro and in vivo techniques for the investigation of exceptional anticancer drug FL118’s efficacy in treatment of resistant pancreatic cancer: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs. Results Our studies found that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, using in vivo-imaging, we found that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. In PDX model, we demonstrated that FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118. These FL118 efficacy results are consistent with our molecular-targeting data showing that FL118 inhibited the expression of multiple antiapoptotic proteins (survivin, Mcl-1, XIAP, cIAP2) and ERCC6, a critical regulator of DNA repair, in treatment-resistant pancreatic stem-like cancer cells. Furthermore, FL118 toxicity studies in BALB/cj mice and beagle dogs indicated that FL118 exhibits favorable hematopoietic and biochemical toxicities. Conclusion Together, our studies suggest that FL118 is a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.
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Soltanian S, Riahirad H, Pabarja A, Jafari E, Khandani BK. Effect of Cinnamic acid and FOLFOX in diminishing side population and downregulating cancer stem cell markers in colon cancer cell line HT-29. Daru 2018; 26:10.1007/s40199-018-0210-8. [PMID: 30209760 PMCID: PMC6154487 DOI: 10.1007/s40199-018-0210-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/06/2018] [Indexed: 12/26/2022] Open
Abstract
PURPOSE There is a lot of evidence suggesting that a small subset of cancer cells resistant to conventional chemotherapy and radiotherapy and known as cancer stem cells (CSCs) is responsible for promoting metastasis and cancer relapse. Therefore, targeting and eliminating the CSCs could lead to higher survival rates and a better quality of life. In comparison with conventional chemical drugs that may not be effective against CSCs, phytochemicals are strong anti-CSCs agents. The current study examines the effect of 5-fluorouracil plus oxaliplatin (FOLFOX) as a common chemotherapy drug on colorectal cancer as well as the influence of Cinnamic acid (CINN) as a plant-derived phytochemical on colon cancer stem-like cells in HT-29 adenocarcinoma cell line. METHODS The anti-proliferative effect of FOLFOX and CINN was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Flow cytometry analysis was used for the identification of side population (SP), CD44, and CD133 positive cells. The expression of OCT4, NANOG, ABCB1, and ALDH1A was assessed by RT-PCR. RESULTS The FOLFOX and CINN decreased cell viability in certain drug concentrations: IC50 = 5,40 μM oxaliplatin +220 μM 5-fluorouracil, and 13,50 mM for CINN. The CSC-associated markers (OCT4, NANOG, ABCB1, and ALDH1A) and the proportion of cancer stem-like cells (SP cells, CD44, and CD133 positive cells) were downregulated following the treatment of HT-29 adenocarcinoma cell line with IC50 concentrations of FOLFOX and CINN. CONCLUSION Our data suggests that CINN, a naturally occurring component, could be more effective than FOLFOX treatment in reducing the cancer stem-like cells and expression of CSC markers from HT-29 colon cancer cells. Graphical abstract ᅟ.
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Affiliation(s)
- Sara Soltanian
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Helia Riahirad
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Athareh Pabarja
- Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Elham Jafari
- Pathology and Stem Cell Research Center, Kerman University of Medical Science, Kerman, Iran
| | - Behjat Kalantari Khandani
- Department of Internal Medicine, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Griner LM, Gampa K, Do T, Nguyen H, Farley D, Hogan CJ, Auld DS, Silver SJ. Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening. J Vis Exp 2018. [PMID: 30247463 DOI: 10.3791/57476] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Cancer cells have routinely been cultured in two dimensions (2D) on a plastic surface. This technique, however, lacks the true environment a tumor mass is exposed to in vivo. Solid tumors grow not as a sheet attached to plastic, but instead as a collection of clonal cells in a three-dimensional (3D) space interacting with their neighbors, and with distinct spatial properties such as the disruption of normal cellular polarity. These interactions cause 3D-cultured cells to acquire morphological and cellular characteristics which are more relevant to in vivo tumors. Additionally, a tumor mass is in direct contact with other cell types such as stromal and immune cells, as well as the extracellular matrix from all other cell types. The matrix deposited is comprised of macromolecules such as collagen and fibronectin. In an attempt to increase the translation of research findings in oncology from bench to bedside, many groups have started to investigate the use of 3D model systems in their drug development strategies. These systems are thought to be more physiologically relevant because they attempt to recapitulate the complex and heterogeneous environment of a tumor. These systems, however, can be quite complex, and, although amenable to growth in 96-well formats, and some now even in 384, they offer few choices for large-scale growth and screening. This observed gap has led to the development of the methods described here in detail to culture tumor spheroids in a high-throughput capacity in 1536-well plates. These methods represent a compromise to the highly complex matrix-based systems, which are difficult to screen, and conventional 2D assays. A variety of cancer cell lines harboring different genetic mutations are successfully screened, examining compound efficacy by using a curated library of compounds targeting the Mitogen-Activated Protein Kinase or MAPK pathway. The spheroid culture responses are then compared to the response of cells grown in 2D, and differential activities are reported. These methods provide a unique protocol for testing compound activity in a high-throughput 3D setting.
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Affiliation(s)
- Lesley Mathews Griner
- Oncology Drug Discovery: Molecular Pharmacology, Novartis Institutes for Biomedical Research;
| | - Kalyani Gampa
- Oncology Drug Discovery: Molecular Pharmacology, Novartis Institutes for Biomedical Research
| | - Toan Do
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
| | - Huyen Nguyen
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
| | - David Farley
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
| | - Christopher J Hogan
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
| | - Douglas S Auld
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
| | - Serena J Silver
- Oncology Drug Discovery: Molecular Pharmacology, Novartis Institutes for Biomedical Research
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Li D, Mullinax JE, Aiken T, Xin H, Wiegand G, Anderson A, Thorgeirsson S, Avital I, Rudloff U. Loss of PDPK1 abrogates resistance to gemcitabine in label-retaining pancreatic cancer cells. BMC Cancer 2018; 18:772. [PMID: 30064387 PMCID: PMC6069886 DOI: 10.1186/s12885-018-4690-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 07/23/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Label-retaining cancer cells (LRCC) have been proposed as a model of slowly cycling cancer stem cells (CSC) which mediate resistance to chemotherapy, tumor recurrence, and metastasis. The molecular mechanisms of chemoresistance in LRCC remain to-date incompletely understood. This study aims to identify molecular targets in LRCC that can be exploited to overcome resistance to gemcitabine, a standard chemotherapy agent for the treatment of pancreas cancer. METHODS LRCC were isolated following Cy5-dUTP staining by flow cytometry from pancreatic cancer cell lines. Gene expression profiles obtained from LRCC, non-LRCC (NLRCC), and bulk tumor cells were used to generate differentially regulated pathway networks. Loss of upregulated targets in LRCC on gemcitabine sensitivity was assessed via RNAi experiments and pharmacological inhibition. Expression patterns of PDPK1, one of the upregulated targets in LRCC, was studied in patients' tumor samples and correlated with pathological variables and clinical outcome. RESULTS LRCC are significantly more resistant to gemcitabine than the bulk tumor cell population. Non-canonical EGF (epidermal growth factor)-mediated signal transduction emerged as the top upregulated network in LRCC compared to non-LRCC, and knock down of EGF signaling effectors PDPK1 (3-phosphoinositide dependent protein kinase-1), BMX (BMX non-receptor tyrosine kinase), and NTRK2 (neurotrophic receptor tyrosine kinase 2) or treatment with PDPK1 inhibitors increased growth inhibition and induction of apoptosis in response to gemcitabine. Knockdown of PDPK1 preferentially increased growth inhibition and reduced resistance to induction of apoptosis upon gemcitabine treatment in the LRCC vs non-LRCC population. These findings are accompanied by lower expression levels of PDPK1 in tumors compared to matched uninvolved pancreas in surgical resection specimens and a negative association of membranous localization on IHC with high nuclear grade (p < 0.01). CONCLUSION Pancreatic cancer cell-derived LRCC are relatively resistant to gemcitabine and harbor a unique transcriptomic profile compared to bulk tumor cells. PDPK1, one of the members of an upregulated EGF-signaling network in LRCC, mediates resistance to gemcitabine, is found to be dysregulated in pancreas cancer specimens, and might be an attractive molecular target for combination therapy studies.
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Affiliation(s)
- Dandan Li
- Rare Tumor Initiative, Cancer for Cancer Research, National Cancer Institute, Building 10, Room 2B-38E, Bethesda, MD USA
| | | | - Taylor Aiken
- Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD USA
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI USA
| | - Hongwu Xin
- Laboratory of Oncology, Center for Molecular Medicine and Department of Molecular Biology and Biochemistry, School of Basic Medicine, Yangtze University, Jingzhou, Hubei China
| | - Gordon Wiegand
- Flow Cytometry Core, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC USA
| | | | - Snorri Thorgeirsson
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, USA
| | - Itzhak Avital
- St. Peter’s Hospital, Rutgers University, Robert Wood Johnson School of Medicine, New Brunswick, NJ USA
| | - Udo Rudloff
- Rare Tumor Initiative, Cancer for Cancer Research, National Cancer Institute, Building 10, Room 2B-38E, Bethesda, MD USA
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Frankowski KJ, Wang C, Patnaik S, Schoenen FJ, Southall N, Li D, Teper Y, Sun W, Kandela I, Hu D, Dextras C, Knotts Z, Bian Y, Norton J, Titus S, Lewandowska MA, Wen Y, Farley KI, Griner LM, Sultan J, Meng Z, Zhou M, Vilimas T, Powers AS, Kozlov S, Nagashima K, Quadri HS, Fang M, Long C, Khanolkar O, Chen W, Kang J, Huang H, Chow E, Goldberg E, Feldman C, Xi R, Kim HR, Sahagian G, Baserga SJ, Mazar A, Ferrer M, Zheng W, Shilatifard A, Aubé J, Rudloff U, Marugan JJ, Huang S. Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Sci Transl Med 2018; 10:eaap8307. [PMID: 29769289 PMCID: PMC6176865 DOI: 10.1126/scitranslmed.aap8307] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 04/24/2018] [Indexed: 12/16/2022]
Abstract
Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.
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Affiliation(s)
- Kevin J Frankowski
- Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047, USA
| | - Chen Wang
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Samarjit Patnaik
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Frank J Schoenen
- Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047, USA
| | - Noel Southall
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Dandan Li
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yaroslav Teper
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Wei Sun
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Irawati Kandela
- Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL 60208, USA
| | - Deqing Hu
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Christopher Dextras
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Zachary Knotts
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yansong Bian
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - John Norton
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Steve Titus
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Marzena A Lewandowska
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Yiping Wen
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Katherine I Farley
- Departments of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University and Yale School of Medicine, New Haven, CT 06520, USA
| | - Lesley Mathews Griner
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Jamey Sultan
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Zhaojing Meng
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA
| | - Ming Zhou
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA
| | - Tomas Vilimas
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Fort Detrick, Frederick, MD 21702, USA
| | - Astin S Powers
- Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Fort Detrick, Frederick, MD 21702, USA
| | - Kunio Nagashima
- Electron Microscope Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Humair S Quadri
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Min Fang
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Charles Long
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Ojus Khanolkar
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Warren Chen
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Jinsol Kang
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Helen Huang
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Eric Chow
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Esthermanya Goldberg
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Coral Feldman
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Romi Xi
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA
| | - Hye Rim Kim
- Department of Human Genetics, Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Gary Sahagian
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Susan J Baserga
- Departments of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University and Yale School of Medicine, New Haven, CT 06520, USA
| | - Andrew Mazar
- Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL 60208, USA
| | - Marc Ferrer
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Wei Zheng
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA
| | - Ali Shilatifard
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jeffrey Aubé
- Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047, USA
| | - Udo Rudloff
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
| | - Juan Jose Marugan
- NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA.
| | - Sui Huang
- Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA.
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Lleonart ME, Abad E, Graifer D, Lyakhovich A. Reactive Oxygen Species-Mediated Autophagy Defines the Fate of Cancer Stem Cells. Antioxid Redox Signal 2018; 28:1066-1079. [PMID: 28683561 DOI: 10.1089/ars.2017.7223] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Significance: A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. Critical Issues: The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Future Directions: Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 28, 1066-1079.
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Affiliation(s)
- Matilde E Lleonart
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Etna Abad
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Dmitry Graifer
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Alex Lyakhovich
- Biomedical Research in Cancer Stem Cells, Vall d'Hebron Research Institute, Barcelona, Spain.,Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.,ICRC-FNUSA, International Clinical Research Center and St. Anne's University Hospital Brno, Brno, Czech Republic
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Dzobo K, Senthebane DA, Rowe A, Thomford NE, Mwapagha LM, Al-Awwad N, Dandara C, Parker MI. Cancer Stem Cell Hypothesis for Therapeutic Innovation in Clinical Oncology? Taking the Root Out, Not Chopping the Leaf. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2017; 20:681-691. [PMID: 27930094 DOI: 10.1089/omi.2016.0152] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Clinical oncology is in need of therapeutic innovation. New hypotheses and concepts for translation of basic research to novel diagnostics and therapeutics are called for. In this context, the cancer stem cell (CSC) hypothesis rests on the premise that tumors comprise tumor cells and a subset of tumor-initiating cells, CSCs, in a quiescent state characterized by slow cell cycling and expression of specific stem cell surface markers with the capability to maintain a tumor in vivo. The CSCs have unlimited self-renewal abilities and propagate tumors through division into asymmetric daughter cells. This differentiation is induced by both genetic and environmental factors. Another characteristic of CSCs is their therapeutic resistance, which is due to their quiescent state and slow dividing. Notably, the CSC phenotype differs greatly between patients and different cancer types. The CSCs may differ genetically and phenotypically and may include primary CSCs and metastatic stem cells circulating within the blood system. Targeting CSCs will require the knowledge of distinct stem cells within the tumor. CSCs can differentiate into nontumorigenic cells and this has been touted as the source of heterogeneity observed in many solid tumors. The latter cannot be fully explained by epigenetic regulation or by the clonal evolution theory. This heterogeneity markedly influences how tumors respond to therapy and prognosis. The present expert review offers an analysis and synthesis of the latest research and concepts on CSCs, with a view to truly disruptive innovation for future diagnostics and therapeutics in clinical oncology.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa .,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
| | - Dimakatso Alice Senthebane
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa .,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
| | - Arielle Rowe
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa .,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
| | - Nicholas Ekow Thomford
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , South Africa
| | - Lamech M Mwapagha
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa .,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
| | - Nasir Al-Awwad
- 4 Department of Clinical Pharmacy, Faculty of Clinical Pharmacy, Albaha University , Albaha, Saudi Arabia
| | - Collet Dandara
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town , South Africa
| | - M Iqbal Parker
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory 7925, Cape Town, South Africa .,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
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Li Y, Wang Y, Zhou Y, Li J, Chen K, Zhang L, Deng M, Deng S, Li P, Xu B. Cooperative effect of chidamide and chemotherapeutic drugs induce apoptosis by DNA damage accumulation and repair defects in acute myeloid leukemia stem and progenitor cells. Clin Epigenetics 2017; 9:83. [PMID: 28814980 PMCID: PMC5556349 DOI: 10.1186/s13148-017-0377-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 07/21/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Many conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed. RESULTS We report that a low-dose chidamide, a novel orally active benzamide-type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34+CD38- KG1α cells, CD34+CD38- Kasumi cells, and primary refractory or relapsed AML CD34+ cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro. Mechanistically, these events were associated with DNA damage accumulation and repair defects. Co-treatment with chidamide and the DNA-damaging agent IDA gave rise to the production of γH2A.X and inhibited posttranslationally but not transcriptionally the repair gene of ATM, BRCA1, and checkpoint kinase 1 (CHK1) and 2 (CHK2) phosphorylation. Finally, the combination of chidamide and IDA initiated caspase-3 and PARP cleavage, but not caspase-8 and caspase-9, and ultimately induced CD34+CD38- KG1α cell apoptosis. Further analysis of AML patients' clinical characteristics revealed that the ex vivo efficacy of chidamide in combination with IDA in primary CD34+ samples was significantly correlated to peripheral blood WBC counts at diagnosis, while LDH levels and karyotype status had no effect, indicating that the combination regimen of chidamide and IDA could rapidly diminish tumor burden in patients with R/R AML. CONCLUSIONS These findings provide preclinical evidence for low-dose chidamide in combination with chemotherapeutic agents in treating recurrent/resistant AML as an alternative salvage regimen, especially those possessing stem and progenitor cells.
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Affiliation(s)
- Yin Li
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Yan Wang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Yong Zhou
- Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003 People's Republic of China
| | - Jie Li
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Kai Chen
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Leisi Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Manman Deng
- Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003 People's Republic of China
| | - Suqi Deng
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 People's Republic of China
| | - Peng Li
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 People's Republic of China
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003 People's Republic of China
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Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance. Biomed Pharmacother 2017; 93:1238-1245. [PMID: 28738540 DOI: 10.1016/j.biopha.2017.07.035] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 06/28/2017] [Accepted: 07/06/2017] [Indexed: 11/20/2022] Open
Abstract
DNA damaging agents are most common in chemotherapeutic molecules that act against cancer. However, cancer cells possess inherent biological features to overcome DNA damages by activating various distinct repair mechanisms and pathways. Importantly, various oncogenes, cancer stem cells (CSCs), hypoxic environment, transcription factors and bystander signaling that are activated in the cancer cells influence DNA repair, thereby effectively repairing the DNA damage. Repaired cancer cells often become more resistance to further therapy and results in disease recurrence. In this review, we summarize how the various signaling pathways in cancer cells regulates DNA repair and induce chemoresistance.
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Abstract
Cellular chromosomal DNA is the principal target through which ionising radiation exerts it diverse biological effects. This chapter summarises the relevant DNA damage signalling and repair pathways used by normal and tumour cells in response to irradiation. Strategies for tumour radiosensitisation are reviewed which exploit tumour-specific DNA repair deficiencies or signalling pathway addictions, with a special focus on growth factor signalling, PARP, cancer stem cells, cell cycle checkpoints and DNA replication. This chapter concludes with a discussion of DNA repair-related candidate biomarkers of tumour response which are of crucial importance for implementing precision medicine in radiation oncology.
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Oei AL, Vriend LEM, Krawczyk PM, Horsman MR, Franken NAP, Crezee J. Targeting therapy-resistant cancer stem cells by hyperthermia. Int J Hyperthermia 2017; 33:419-427. [PMID: 28100096 DOI: 10.1080/02656736.2017.1279757] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs.
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Affiliation(s)
- A L Oei
- a Laboratory for Experimental Oncology and Radiobiology (LEXOR) , Center for Experimental and Molecular Medicine , Amsterdam , The Netherlands.,b Department of Radiotherapy , Academic Medical Center (AMC) and Cancer Center Amsterdam , Amsterdam , The Netherlands
| | - L E M Vriend
- c Department of Cell Biology and Histology , Academic Medical Center (AMC) and Cancer Center Amsterdam , Amsterdam , The Netherlands
| | - P M Krawczyk
- c Department of Cell Biology and Histology , Academic Medical Center (AMC) and Cancer Center Amsterdam , Amsterdam , The Netherlands
| | - M R Horsman
- d Department for Experimental Clinical Oncology , Aarhus University Hospital , Aarhus C , Denmark
| | - N A P Franken
- a Laboratory for Experimental Oncology and Radiobiology (LEXOR) , Center for Experimental and Molecular Medicine , Amsterdam , The Netherlands.,b Department of Radiotherapy , Academic Medical Center (AMC) and Cancer Center Amsterdam , Amsterdam , The Netherlands
| | - J Crezee
- b Department of Radiotherapy , Academic Medical Center (AMC) and Cancer Center Amsterdam , Amsterdam , The Netherlands
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Manna A, Banerjee S, Khan P, Bhattacharya A, Das T. Contribution of nuclear events in generation and maintenance of cancer stem cells: revisiting chemo-resistance. THE NUCLEUS 2017. [DOI: 10.1007/s13237-017-0193-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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36
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Liu Y, Burness ML, Martin-Trevino R, Guy J, Bai S, Harouaka R, Brooks MD, Shang L, Fox A, Luther TK, Davis A, Baker TL, Colacino J, Clouthier SG, Shao ZM, Wicha MS, Liu S. RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer. Clin Cancer Res 2016; 23:514-522. [DOI: 10.1158/1078-0432.ccr-15-1348] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 07/29/2016] [Accepted: 08/01/2016] [Indexed: 11/16/2022]
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Large-scale pharmacological profiling of 3D tumor models of cancer cells. Cell Death Dis 2016; 7:e2492. [PMID: 27906188 PMCID: PMC5261027 DOI: 10.1038/cddis.2016.360] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 08/22/2016] [Accepted: 09/19/2016] [Indexed: 12/21/2022]
Abstract
The discovery of chemotherapeutic agents for the treatment of cancer commonly uses cell proliferation assays in which cells grow as two-dimensional (2D) monolayers. Compounds identified using 2D monolayer assays often fail to advance during clinical development, most likely because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three-dimensional (3D) cellular systems have been explored as enabling more predictive in vitro tumor models for drug discovery. To date, small-scale screens have demonstrated that pharmacological responses tend to differ between 2D and 3D cancer cell growth models. However, the limited scope of screens using 3D models has not provided a clear delineation of the cellular pathways and processes that differentially regulate cell survival and death in the different in vitro tumor models. Here we sought to further understand the differences in pharmacological responses between cancer tumor cells grown in different conditions by profiling a large collection of 1912 chemotherapeutic agents. We compared pharmacological responses obtained from cells cultured in traditional 2D monolayer conditions with those responses obtained from cells forming spheres versus cells already in 3D spheres. The target annotation of the compound library screened enabled the identification of those key cellular pathways and processes that when modulated by drugs induced cell death in all growth conditions or selectively in the different cell growth models. In addition, we also show that many of the compounds targeting these key cellular functions can be combined to produce synergistic cytotoxic effects, which in many cases differ in the magnitude of their synergism depending on the cellular model and cell type. The results from this work provide a high-throughput screening framework to profile the responses of drugs both as single agents and in pairwise combinations in 3D sphere models of cancer cells.
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Ramakodi MP, Devarajan K, Blackman E, Gibbs D, Luce D, Deloumeaux J, Duflo S, Liu JC, Mehra R, Kulathinal RJ, Ragin CC. Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma. Cancer 2016; 123:849-860. [PMID: 27906459 DOI: 10.1002/cncr.30457] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 09/26/2016] [Accepted: 10/28/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival. METHODS Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P < .001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P = .002). An association was observed between these eQTLs and OS (P < .037; FDR < 0.0363) as well as DFS (P = .018 to .0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele. CONCLUSIONS Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society.
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Affiliation(s)
- Meganathan P Ramakodi
- Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,Department of Biology, Temple University, Philadelphia, Pennsylvania.,Center for Computational Genetics and Genomics, Temple University, Philadelphia, Pennsylvania.,Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania.,African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania
| | - Karthik Devarajan
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, Pennsylvania.,Center for High-Dimensional Statistics, Big Data Institute, Temple University, Philadelphia, Pennsylvania
| | - Elizabeth Blackman
- Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania
| | - Denise Gibbs
- Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania
| | - Danièle Luce
- African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania.,National Institute for Health and Medical Research (INSERM), Unit 1085;, Institute for Research in Health, Environment, and Work (IRSET), Pointe-à-Pitre, Guadeloupe, French West Indies
| | - Jacqueline Deloumeaux
- African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania.,General Cancer Registry of Guadeloupe, University Hospital of Pointe-à-Pitre, Pointe-a-Pitre, Guadeloupe, French West Indies
| | - Suzy Duflo
- Department of Oto-Rhino-Laryngology and Head and Neck Surgery, University Hospital of Pointe à Pitre, Pointe-a-Pitre, Guadeloupe, French West Indies
| | - Jeffrey C Liu
- Head and Neck Surgery, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,Department of Otolaryngology-Head and Neck Surgery, Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
| | - Ranee Mehra
- Department of Hematology/Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, Pennsylvania.,Center for Computational Genetics and Genomics, Temple University, Philadelphia, Pennsylvania.,Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania.,African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania
| | - Camille C Ragin
- Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.,African-Caribbean Cancer Consortium, Philadelphia, Pennsylvania.,Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, Pennsylvania.,Department of Otolaryngology-Head and Neck Surgery, Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
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Investigating genetic characteristics of hepatitis B virus-associated and -non-associated hepatocellular carcinoma. Genet Res (Camb) 2016; 98:e14. [PMID: 27834158 DOI: 10.1017/s0016672316000124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a primary liver malignancy that mainly occurs in patients with chronic liver disease and cirrhosis. Risk factors for HCC include hepatitis B virus (HBV) infection. However, the specific role of HBV infection in HCC development is not yet completely understood. In order to reveal the effects of HBV on HCC, we compare the genes of HCC patients infected with HBV with those who are not infected. METHODS We encoded the genes of these two types of HCC in databases using enrichment scores of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway terms. A random forest algorithm was employed in order to distinguish these two types in the classifier, and a series of feature selection approaches was used in order to select their optimal features. Novel HBV-associated and -non-associated HCC genes were predicted, respectively, based on their optimal features in the classifier. A shortest-path algorithm was also employed in order to find all of the shortest-paths genes connecting the known related genes. RESULTS A total of 54 different features between HBV-associated and -non-associated HCC genes were identified. In total, 1236 and 881 novel related genes were predicted for HBV-associated and -non-associated HCC, respectively. By integrating the predicted genes and shortest path genes in their gene interaction network, we identified 679 common genes involved in the two types of HCC. CONCLUSION We identified the significantly different genetic features between two types of HCC. We also predicted related genes for the two types based on their specific features. Finally, we determined the common genes and features that were involved in both of these two types of HCC.
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40
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Predicting novel salivary biomarkers for the detection of pancreatic cancer using biological feature-based classification. Pathol Res Pract 2016; 213:394-399. [PMID: 28283209 DOI: 10.1016/j.prp.2016.09.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 04/20/2016] [Accepted: 09/19/2016] [Indexed: 01/05/2023]
Abstract
AIM The use of saliva as a diagnostic fluid enables non-invasive sampling and thus is a prospective sample for disease tests. This study fully utilized the information from the salivary transcriptome to characterize pancreatic cancer related genes and predict novel salivary biomarkers. METHODS We calculated the enrichment scores of gene ontology (GO) and pathways annotated in Kyoto Encyclopedia of Genes and Genomes database (KEGG) for pancreatic cancer-related genes. Annotation of GO and KEGG pathway characterize the molecular features of genes. We employed Random Forest classification and incremental feature selection to identify the optimal features among them and predicted novel pancreatic cancer-related genes. RESULTS A total of 2175 gene ontology and 79 KEGG pathway terms were identified as the optimal features to identify pancreatic cancer-related genes. A total of 516 novel genes were predicted using these features. We discovered 29 novel biomarkers based on the expression of these 516 genes in saliva. Using our new biomarkers, we achieved a higher accuracy (92%) for the detection of pancreatic cancer. Another independent expression dataset confirmed that these novel biomarkers performed better than the previously described markers alone. CONCLUSION By analyzing the information of the salivary transcriptome, we predict pancreatic cancer-related genes and novel salivary gene markers for detection.
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41
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Cancer Stem Cell Quiescence and Plasticity as Major Challenges in Cancer Therapy. Stem Cells Int 2016; 2016:1740936. [PMID: 27418931 PMCID: PMC4932171 DOI: 10.1155/2016/1740936] [Citation(s) in RCA: 269] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/15/2016] [Indexed: 02/06/2023] Open
Abstract
Cells with stem-like properties, tumorigenic potential, and treatment-resistant phenotypes have been identified in many human malignancies. Based on the properties they share with nonneoplastic stem cells or their ability to initiate and propagate tumors in vivo, such cells were designated as cancer stem (stem-like) or tumor initiating/propagating cells. Owing to their implication in treatment resistance, cancer stem cells (CSCs) have been the subject of intense investigation in past years. Comprehension of CSCs' intrinsic properties and mechanisms they develop to survive and even enhance their aggressive phenotype within the hostile conditions of the tumor microenvironment has reoriented therapeutic strategies to fight cancer. This report provides selected examples of malignancies in which the presence of CSCs has been evidenced and briefly discusses methods to identify, isolate, and functionally characterize the CSC subpopulation of cancer cells. Relevant biological targets in CSCs, their link to treatment resistance, proposed targeting strategies, and limitations of these approaches are presented. Two major aspects of CSC physiopathology, namely, relative in vivo quiescence and plasticity in response to microenvironmental cues or treatment, are highlighted. Implications of these findings in the context of the development of new therapies are discussed.
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42
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Gavande NS, VanderVere-Carozza PS, Hinshaw HD, Jalal SI, Sears CR, Pawelczak KS, Turchi JJ. DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol Ther 2016; 160:65-83. [PMID: 26896565 DOI: 10.1016/j.pharmthera.2016.02.003] [Citation(s) in RCA: 280] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.
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Affiliation(s)
- Navnath S Gavande
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | | | - Hilary D Hinshaw
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Shadia I Jalal
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Catherine R Sears
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | | | - John J Turchi
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States; NERx Biosciences, Indianapolis, IN 46202, United States; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
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Wang X, Zhang Y, Jiang L, Zhou F, Zhai H, Zhang M, Wang J. Interpreting the distinct and shared genetic characteristics between Epstein-Barr virus associated and non-associated gastric carcinoma. Gene 2016; 576:798-806. [PMID: 26584536 DOI: 10.1016/j.gene.2015.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 11/06/2015] [Accepted: 11/10/2015] [Indexed: 12/26/2022]
Abstract
Gastric carcinoma is one of the major causes of cancer mortality worldwide. There is a better prognosis for patients with Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) compared with those with EBV negative gastric carcinoma (EBVnGC). It is partly due to the fact that EBV infection recruits lymphocytes infiltrating the tumor. It has been reported that this infection indeed resulted in the changes in immune response genes and thus preventing the development of tumor. It is worthwhile to do a systematic study of EBVaGC and EBVnGC based on genetic characteristics and pathways. In this study, we investigated the information of gene ontology (GO) and KEGG pathway annotations to characterize EBVaGC and EBVnGC-related genes. By applying minimum redundancy maximum relevance (mRMR) algorithm, we provided an optimal set of features for identifying the EBVaGC and EBVnGC. We also employed the shortest path algorithm to probe the novel EBVaGC- and EBVnGC-related genes based on the interaction network of genes that differently expressed in them respectively. We obtained 1039 and 1003 features to identify these two types of gastric carcinoma respectively. Based on the optimal features of classification, we predicted 1881 and 2475 novel genes as additional candidates to support clinical research respectively for these two types of gastric cancers. We compared the differences and similarities of molecular traits between EBVaGC and EBVnGC, which would facilitate the understanding of gastric cancer and its therapy and was thus clinically relevant.
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Affiliation(s)
- Xixun Wang
- Department of Abodomenal Surgery, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Yifei Zhang
- Department of Abodomenal Surgery, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Lixin Jiang
- Department of Abodomenal Surgery, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Furun Zhou
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Huiyuan Zhai
- Department of Abodomenal Surgery, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Menglai Zhang
- Department of Abodomenal Surgery, Yantai Yuhuangding Hospital, Shandong, PR China
| | - Jinglin Wang
- Department of Emergency Center, Yantai Yuhuangding Hospital, Shandong, PR China.
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[Cancer stem cells: Radiotherapeutic features and therapeutic targets]. Bull Cancer 2015; 103:48-54. [PMID: 26702506 DOI: 10.1016/j.bulcan.2015.10.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 10/27/2015] [Accepted: 10/30/2015] [Indexed: 02/08/2023]
Abstract
Recent evidences suggest that many types of cancers contain a cell population presenting stem cell properties. While the great majority of tumor cells are destined to differentiate, and eventually stop dividing, only a minority population of cells, termed cancer stem cells (CSCs), possesses extensive self-renewal capability and can recapitulate tumor pathophysiology in an immune-compromised animal model. Tumor initiating cells have been identified and isolated in many tumor types including brain, colon and prostate. They are virtually resistant to radiation and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. The present study reviews published reports identifying the mechanisms of radioresistance of CSCs and potential targets based on the pathways of self-renewal. Further elucidation of pathways that regulate CSCs may provide insights into the development of novel innovative therapies.
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Dando I, Dalla Pozza E, Biondani G, Cordani M, Palmieri M, Donadelli M. The metabolic landscape of cancer stem cells. IUBMB Life 2015; 67:687-93. [DOI: 10.1002/iub.1426] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 08/14/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Ilaria Dando
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Elisa Dalla Pozza
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Giulia Biondani
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Marco Cordani
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Marta Palmieri
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
| | - Massimo Donadelli
- Department of Life and Reproduction Sciences; Section of Biochemistry, University of Verona; Verona Italy
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Wang QE. DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies. World J Biol Chem 2015; 6:57-64. [PMID: 26322164 PMCID: PMC4549769 DOI: 10.4331/wjbc.v6.i3.57] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 04/16/2015] [Accepted: 05/28/2015] [Indexed: 02/05/2023] Open
Abstract
The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.
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Sotiropoulou PA, Christodoulou MS, Silvani A, Herold-Mende C, Passarella D. Chemical approaches to targeting drug resistance in cancer stem cells. Drug Discov Today 2014; 19:1547-62. [PMID: 24819719 DOI: 10.1016/j.drudis.2014.05.002] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/24/2014] [Accepted: 05/01/2014] [Indexed: 12/16/2022]
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells with high clonogenic capacity and ability to reform parental tumors upon transplantation. Resistance to therapy has been shown for several types of CSC and, therefore, they have been proposed as the cause of tumor relapse. Consequently, much effort has been made to design molecules that can target CSCs specifically and sensitize them to therapy. In this review, we summarize the mechanisms underlying CSC resistance, the potential biological targets to overcome resistance and the chemical compounds showing activity against different types of CSC. The chemical compounds discussed here have been divided according to their origin: natural, natural-derived and synthetic compounds.
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Affiliation(s)
- Panagiota A Sotiropoulou
- Interdisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles (ULB), 808 route de Lennik, BatC, 1070 Bruxelles, Belgium
| | - Michael S Christodoulou
- Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
| | - Alessandra Silvani
- Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
| | - Christel Herold-Mende
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
| | - Daniele Passarella
- Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy.
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Millard M, Gallagher JD, Olenyuk BZ, Neamati N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J Med Chem 2013; 56:9170-9. [PMID: 24147900 DOI: 10.1021/jm4012438] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.
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Affiliation(s)
- Melissa Millard
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, United States
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Sun L, Mathews LA, Cabarcas SM, Zhang X, Yang A, Zhang Y, Young MR, Klarmann KD, Keller JR, Farrar WL. Epigenetic regulation of SOX9 by the NF-κB signaling pathway in pancreatic cancer stem cells. Stem Cells 2013; 31:1454-66. [PMID: 23592398 PMCID: PMC3775871 DOI: 10.1002/stem.1394] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 03/10/2013] [Accepted: 03/18/2013] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related mortality in the world. Pancreatic cancer can be localized, locally advanced, or metastatic. The median 1- and 5-year survival rates are 25% and 6%, respectively. Epigenetic modifications such as DNA methylation play a significant role during both normal human development and cancer progression. To investigate epigenetic regulation of genes in the tumor-initiating population of pancreatic cancer cells, which are also termed cancer stem cells (CSCs), we conducted epigenetic arrays in PANC1 and HPAC pancreatic cancer cell lines and compared the global DNA methylation status of CpG promoters in invasive cells, demonstrated to be CSCs, to their noninvasive counterparts, or non-CSCs. Our results suggested that the NF-κB pathway is one of the most activated pathways in pancreatic CSCs. In agreement with this, we determined that upon treatment with NF-κB pathway inhibitors, the stem cell-like properties of cells are significantly disrupted. Moreover, SOX9, demethylated in CSCs, is shown to play a crucial role in the invasion process. Additionally, we found a potential NF-κB binding site located in the SOX9 promoter and determined that the NF-κB subunit p65 positively regulates SOX9 expression by binding to its promoter directly. This interaction can be efficiently blocked by NF-κB inhibitors. Thus, our work establishes a link between the classic NF-κB signaling transduction pathway and the invasiveness of pancreatic CSCs, which may result in the identification of novel signals and molecules that function at an epigenetic level, and could potentially be targeted for pharmaceutical investigations and clinical trials.
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Affiliation(s)
- Lei Sun
- Cancer Stem Cell Section, Laboratory of Cancer Prevention, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
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Hindriksen S, Bijlsma MF. Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors. Cancers (Basel) 2012; 4:989-1035. [PMID: 24213498 PMCID: PMC3712732 DOI: 10.3390/cancers4040989] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 10/02/2012] [Accepted: 10/09/2012] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer.
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Affiliation(s)
- Sanne Hindriksen
- Laboratory for Experimental Oncology and Radiobiology, Academic Medical Centre, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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