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1
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Chidambaram K, Rekha A, Goyal A, Rana M. Targeting KRAS-G12C in lung cancer: The emerging role of PROTACs in overcoming resistance. Pathol Res Pract 2025; 270:155954. [PMID: 40233529 DOI: 10.1016/j.prp.2025.155954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
In lung cancer, KRAS mutations, especially the G12C, favor aggressive tumor growth and resistance to standard therapies. Although first-generation inhibitors of KRAS G12C, such as sotorasib and adagrasib, are highly effective in early-phase studies, resistance invariably develops under selective inhibition pressure and rarely leads to sustained long-term treatment benefits. As a novel approach to targeting KRAS mutations in lung cancer, PROTAC (Proteolysis Targeting Chimera) technology is explored in this review. The PROTACs take advantage of the cell's ubiquitin-proteasome system to selectively degrade KRAS proteins, overcoming the dilemma of a lack of traditional binding sites and the means of resistance. We review recent progress with KRAS-specific PROTACs and their mechanisms, clinical application, and effectiveness at targeting primary KRAS oncogenes and secondary drivers and signaling pathways contributing to therapeutic resistance. Also, the synergies between PROTACs and immunotherapies or chemotherapies are further amplified. This review also underscores PROTAC technology's promise to advance precision medicine by providing durable treatment options for KRAS-driven lung cancers. It addresses future directions for optimizing PROTAC efficacy, bioavailability, and patient-specific applications.
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Affiliation(s)
- Kumarappan Chidambaram
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
| | - A Rekha
- Dr DY Patil Medical college , Hospital and Research Centre, Pimpri , Pune, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP 281406, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
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2
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Garg P, Ramisetty S, Nair M, Kulkarni P, Horne D, Salgia R, Singhal SS. Strategic advancements in targeting the PI3K/AKT/mTOR pathway for Breast cancer therapy. Biochem Pharmacol 2025; 236:116850. [PMID: 40049296 DOI: 10.1016/j.bcp.2025.116850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/17/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025]
Abstract
Breast cancer (BC) is a complex disease that affects millions of women worldwide. Its growing impact calls for advanced treatment strategies to improve patient outcomes. The PI3K/AKT/mTOR pathway is a key focus in BC therapy because it plays a major role in important processes like tumor growth, survival, and resistance to treatment. Targeting this pathway could lead to better treatment options and outcomes. The present review explores how the PI3K/AKT/mTOR pathway becomes dysregulated in BC, focusing on the genetic changes like PIK3CA mutations and PTEN loss that leads to its aggravation. Current treatment options include the use of inhibitors targeting PI3K, AKT, and mTOR with combination therapies showing promise in overcoming drug resistance and improving effectiveness. Looking ahead, next-generation inhibitors and personalized treatment plans guided by biomarker analysis may provide more accurate and effective options for patients. Integrating these pathway inhibitors with immunotherapy offers an exciting opportunity to boost anti-tumor responses and improve survival rates. This review offers a comprehensive summary of the current progress in targeting the PI3K/AKT/mTOR pathway in BC. It highlights future research directions and therapeutic strategies aimed at enhancing patient outcomes and quality of life.
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Affiliation(s)
- Pankaj Garg
- Department of Chemistry, GLA University, Mathura, Uttar Pradesh 281406, India
| | - Sravani Ramisetty
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Meera Nair
- William J. Brennan High School, San Antonio, TX 78253, USA
| | - Prakash Kulkarni
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
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Jaroniek P, Brzeziński M, Chmiela M, Gonciarz W. Doxorubicin loaded polylactide nanoparticles functionalized histamine promote apoptosis of human gastric cancer cells AGS. Sci Rep 2025; 15:14243. [PMID: 40274948 PMCID: PMC12022340 DOI: 10.1038/s41598-025-99004-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/16/2025] [Indexed: 04/26/2025] Open
Abstract
Gastric cancer is a dominating cause of cancer-related deaths in the world. The modern perspective in gastric cancer treatment is the application of nanoparticles (NPs) affecting the growth of cancer cells to increase the effectiveness of anti-tumor therapy. The use of advanced nanosystems that deliver anti-cancer drugs and biologically active substances may strongly rely on the expression of cancer-associated targets. The aim of this study was to examine the synergistic effect of doxorubicin (DOX) and histamine (His) in NPs DOX-loaded composed of poly(lactic) acid -PLA with histamine end groups (NPs-His-DOX) towards human gastric cancer cells (AGS) in vitro in conjunction with increasing oxidative stress, DNA damage, and cell apoptosis, as well as diminishing cell proliferation. The influence of studied NPs on the expression of intracellular adhesion molecule (ICAM)-1, which may facilitate the cytotoxic reaction of lymphocytes against gastric cancer cells, has also been determined. We showed a significant (p < 0.05) synergistic effect of His and DOX in the NPs His-DOX in increasing oxidative stress as demonstrated by an increased level of 4-hydroxynonenal (4HNE), DNA damage, cell apoptosis, in conjunction with a significant (p < 0.05) inhibition of cell proliferation as well as the disintegration of the cell monolayer. Furthermore, NPs His-DOX upregulated a cell deposition of ICAM-1. This study shows that NPs His-DOX facilitates the delivery of the anticancer drug DOX into the milieu of cancer cells, which results in increased cell death. Furthermore, upregulation of ICAM-1 on gastric cancer cells may increase anti-tumor cytotoxic activity of immunocompetent cells.
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Affiliation(s)
- Patrycja Jaroniek
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237, Lodz, Poland
- BioMedChem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Matejki Street 21/23, 90-237, Lodz, Poland
| | - Marek Brzeziński
- Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza Street 112, 90-363, Lodz, Poland
| | - Magdalena Chmiela
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237, Lodz, Poland
| | - Weronika Gonciarz
- Department of Immunology and Infectious Biology, Institute of Microbiology, Biotechnology and Immunology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237, Lodz, Poland.
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Pallavi R, Soni BL, Jha GK, Sanyal S, Fatima A, Kaliki S. Tumor heterogeneity in retinoblastoma: a literature review. Cancer Metastasis Rev 2025; 44:46. [PMID: 40259075 PMCID: PMC12011974 DOI: 10.1007/s10555-025-10263-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/06/2025] [Indexed: 04/23/2025]
Abstract
Tumor heterogeneity, characterized by the presence of diverse cell populations within a tumor, is a key feature of the complex nature of cancer. This diversity arises from the emergence of cells with varying genomic, epigenetic, transcriptomic, and phenotypic profiles over the course of the disease. Host factors and the tumor microenvironment play crucial roles in driving both inter-patient and intra-patient heterogeneity. These diverse cell populations can exhibit different behaviors, such as varying rates of proliferation, responses to treatment, and potential for metastasis. Both inter-patient heterogeneity and intra-patient heterogeneity pose significant challenges to cancer therapeutics and management. In retinoblastoma, while heterogeneity at the clinical presentation level has been recognized for some time, recent attention has shifted towards understanding the underlying cellular heterogeneity. This review primarily focuses on retinoblastoma heterogeneity and its implications for therapeutic strategies and disease management, emphasizing the need for further research and exploration in this complex and challenging area.
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Affiliation(s)
- Rani Pallavi
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India.
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India.
| | - Bihari Lal Soni
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
| | - Gaurab Kumar Jha
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
| | - Shalini Sanyal
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
| | - Azima Fatima
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
| | - Swathi Kaliki
- The Operation Eyesight Universal Institute for Eye Cancer, LV Prasad Eye Institute, Hyderabad, Telangana, India.
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India.
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Wawrzak-Pienkowska K, Pienkowski T, Tankiewicz-Kwedlo A, Ciborowski M, Kurek K, Pawlak D. Differences in treatment outcome between translational platforms in developing therapies for gastrointestinal cancers. Eur J Pharmacol 2025; 991:177309. [PMID: 39870234 DOI: 10.1016/j.ejphar.2025.177309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/11/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025]
Abstract
The variability in translational models profoundly impacts the outcomes and predictive value of preclinical studies for gastrointestinal (GI) cancer treatments. Preclinical models, including 2D cell cultures, 3D organoids, patient-derived xenografts (PDXs), and animal models, provide distinct advantages and limitations in replicating the complex tumor microenvironment (TME) of human cancers. Each model's unique biological and structural differences contribute to discrepancies in treatment responses, challenging the direct translation of experimental results to clinical settings. While 2D cell cultures are cost-effective and suitable for high-throughput screening, they lack the 3D architecture and cellular interactions of the in vivo TME. Organoids offer a more comprehensive 3D structure that better mirrors tumor heterogeneity, yet they still face limitations in fully mimicking in vivo conditions, such as vascularization and immune cell interactions. PDXs, although more representative of human cancers due to their genetic fidelity and TME preservation, are costly and resource-intensive, with human stromal and immune components gradually replaced by murine counterparts over time. This review assesses the strengths and limitations of each model, highlighting recent advancements in translational platforms that incorporate complex TME features. Understanding the influence of model selection on treatment efficacy predictions is essential for enhancing the reliability of preclinical findings and advancing personalized therapeutic strategies for GI cancers.
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Affiliation(s)
- Katarzyna Wawrzak-Pienkowska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland; Department of Gastroenterology, Hepatology and Internal Diseases, Voivodeship Hospital in Bialystok, Sklodowskiej MC 26, 15-278, Bialystok, Poland
| | - Tomasz Pienkowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Anna Tankiewicz-Kwedlo
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland
| | - Michal Ciborowski
- Clinical Research Center, Medical University of Bialystok, Sklodowskiej MC 24A, 15-276, Bialystok, Poland
| | - Krzysztof Kurek
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowskiej MC 24A Street, 15-276, Bialystok, Poland
| | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222, Białystok, Poland.
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Yesupogu Moorthy Babu J, Manoharan R. NUAKs facilitate mTOR-mediated NSCLC proliferation and metastasis by modulating glucose metabolism and inhibiting p53 activity. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119922. [PMID: 39965261 DOI: 10.1016/j.bbamcr.2025.119922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 02/06/2025] [Accepted: 02/09/2025] [Indexed: 02/20/2025]
Abstract
Non-small cell lung cancer (NSCLC) cells frequently exhibit aberrant glucose metabolism, characterized by elevated aerobic glycolysis, pentose phosphate pathway (PPP), and reduced oxidative phosphorylation. However, the specific mechanisms underlying the abnormal activation of glucose metabolism and its contribution to NSCLC tumorigenesis remain incompletely elucidated. In this study, we observed that both NUAK1 and NUAK2 mRNA expression levels were significantly elevated in NSCLC tissues compared to non-tumor tissues, and that high NUAK1/2 expression correlated with poor prognosis in NSCLC patients. Furthermore, NUAK1/2 promotes aerobic glycolysis and PPP in NSCLC cells and stimulates cellular proliferation and migration. Depletion or inhibition of NUAK1/2 results in decreased aerobic glycolysis, PPP activity, cell proliferation, and migration, leading to increased apoptosis of NSCLC cells. Mechanistically, NUAK1/2 enhances mTOR activity by suppressing the activity of p53, thereby promoting NSCLC cell growth and metastasis through the promotion of aerobic glycolysis and PPP. Our findings suggest that NUAK1/2 plays a crucial role in glucose reprogramming and tumorigenesis in NSCLC cells, indicating that targeting NUAK1/2 may represent a potential therapeutic strategy for NSCLC metabolism.
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Affiliation(s)
- Jaithanya Yesupogu Moorthy Babu
- Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India
| | - Ravi Manoharan
- Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India.
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Daya T, Breytenbach A, Gu L, Kaur M. Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159578. [PMID: 39542394 DOI: 10.1016/j.bbalip.2024.159578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024]
Abstract
Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.
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Affiliation(s)
- Tasvi Daya
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Andrea Breytenbach
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Liang Gu
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa.
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8
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Mahmud MA, Siddique AB, Tajmim A, King JA, El Sayed KA. The Olive Oil Monophenolic Secoiridoid Ligstroside Aglycone Suppresses Melanoma Progression by Targeting the BRAF Signaling Pathway. Molecules 2025; 30:139. [PMID: 39795195 PMCID: PMC11721798 DOI: 10.3390/molecules30010139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
Melanoma is among the most abundant malignancies in the US and worldwide. Ligstroside aglycone (LA) is a rare extra-virgin olive oil-derived monophenolic secoiridoid with diverse bioactivities. LA dose-response screening at the NCI 60 cancer cells panel identified the high sensitivity of the Malme-3M cell line, which harbors a BRAF V600E mutation. Daily oral 10 mg/kg LA exhibited potent in vivo antitumor effects against Malme-3M cells xenograft in a nude mouse model by targeting the BRAF signaling pathway. A human Clariom S microarray analysis of the collected Malme- 3M tumors identified 571 dysregulated genes, with the downregulation of pathways critical for melanoma cells growth and survival. A Western blot analysis of the collected animal tumors further validated the downregulation of the mutated BRAF-MAPK axis, as well as the GPD1 and ELOVL6 expression levels. A histopathological analysis of Malme-3M tumor sections showed extensive focal tumor necrosis in treated mice. An immunofluorescence study of tumor sections showed notable reductions in proliferation marker ki67 and the vasculogenesis marker CD31 in treated tumors. These findings promote LA as a potential nutraceutical lead for the control of the BRAF V600E mutant melanoma.
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Affiliation(s)
- Md Ashiq Mahmud
- Department of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (M.A.M.); (A.B.S.); (A.T.)
| | - Abu Bakar Siddique
- Department of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (M.A.M.); (A.B.S.); (A.T.)
| | - Afsana Tajmim
- Department of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (M.A.M.); (A.B.S.); (A.T.)
| | - Judy Ann King
- Foundational and Clinical Sciences Department, Thomas F. Frist, Jr. College of Medicine, Belmont University, 1900 Belmont Boulevard, Nashville, TN 37212, USA;
| | - Khalid A. El Sayed
- Department of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA; (M.A.M.); (A.B.S.); (A.T.)
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Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology 2025; 174:30-72. [PMID: 39462179 DOI: 10.1111/imm.13871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical Science and Research, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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Chatterjee A, Khan R, Mukherjee T, Sahoo PP, Tiwari LN, Singh BN, Kumari R, Kumari A, Rai A, Ray S. Harnessing bacterial metabolites for enhanced cancer chemotherapy: unveiling unique therapeutic potentials. Arch Microbiol 2024; 206:449. [PMID: 39472338 DOI: 10.1007/s00203-024-04179-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/10/2024]
Abstract
Cancer poses a serious threat to health globally, with millions diagnosed every year. According to Global Cancer Statistics 2024, about 20 million new cases were reported in 2022, and 9.7 million people worldwide died of this condition. Advanced therapies include combination of one or more treatment procedures, depending on the type, stage, and particular genetic constitution of the cancer, which may include surgery, radiotherapy, chemotherapy, immunotherapy, hormone therapy, targeted therapy, and stem cell transplant. Also, awareness about lifestyle changes, preventive measures and screening at early stages has reduced the incidence of the disease; still, there is a major failure in controlling the incidence of cancer because of its complex and multifaceted nature. With increasing interest in bacterial metabolites as possible novel and effective treatment options in cancer therapy, their main benefits include not only direct anticancer effects but also the modulation of the immune system and potential for targeted and combination therapies. They can therefore be used in combination with chemotherapy, radiotherapy, or immunotherapy to improve outcomes or reduce side effects. Furthermore, nanoparticle-based delivery systems have the potential to enhance the potency and safety of anticancer drugs by providing improved stability, targeted release, and controlled delivery.
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Affiliation(s)
- Aroni Chatterjee
- Department of Biotechnology, School of Biotechnology and Biosciences, Brainware University, Barasat, Kolkata, 700125, West Bengal, India
| | - Rajni Khan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hajipur, Vaishali, 844102, Bihar, India
| | - Triparna Mukherjee
- Department of Biotechnology, School of Biotechnology and Biosciences, Brainware University, Barasat, Kolkata, 700125, West Bengal, India
| | - Preity Pragnya Sahoo
- Department of Medical Biotechnology, Gujarat Biotechnology University, Gandhinagar, Gujarat, 382355, India
| | - Laxmi Narayan Tiwari
- Department of Medical Biotechnology, Gujarat Biotechnology University, Gandhinagar, Gujarat, 382355, India
| | - Basant Narain Singh
- Department of Botany, Pandit Deendayal Upadhyaya Shekhawati University, Sikar, Nawalgarh Road, Katrathal, Rajasthan, 332024, India
| | - Rashmi Kumari
- Department of Zoology, ZA Islamia College Siwan, Affiliated Unit of Jai Prakash University, Chapra, Bihar, 841226, India
| | - Anisha Kumari
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, Bihar, 845401, India
| | - Ankit Rai
- Department of Medical Biotechnology, Gujarat Biotechnology University, Gandhinagar, Gujarat, 382355, India.
| | - Shashikant Ray
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, Bihar, 845401, India.
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11
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Arora R, Mukherjee A, Arthur G, Nachtigal MW, Schweizer F. Modulating polybasic character of galactose-based glycosylated antitumor ether lipids for enhanced cytotoxic response. RSC Med Chem 2024; 16:d4md00662c. [PMID: 39464652 PMCID: PMC11499978 DOI: 10.1039/d4md00662c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/11/2024] [Indexed: 10/29/2024] Open
Abstract
We describe the structure-activity relationship studies of galactose-based glycosylated antitumor ether lipids (GAELs) by installing amine groups at different positions of galactose and the glycerol backbone. Different dibasic and tribasic analogues of galacto-GAELs were synthesized and tested against a panel of human epithelial cancer cell lines. A β-anomeric triamino galactose scaffold, was the most active compound of the series and displayed CC50 in the range of 2.6 ± 0.2 μM to 6.5 ± 0.1 μM against various epithelial cancer cell lines. This compound exhibited superior activity to kill cancer cells than cisplatin. The hit GAEL compound did not induce caspase activation and therefore, the cell-killing effect does not occur due to caspase-mediated apoptosis. This observation is in line with the previously reported GAEL prototypes.
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Affiliation(s)
- Rajat Arora
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
| | - Ayan Mukherjee
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
| | - Gilbert Arthur
- Department of Biochemistry and Medical Genetics, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
| | - Mark W Nachtigal
- Department of Biochemistry and Medical Genetics, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
- Paul Albrechtsen Research Institute, CancerCare Manitoba Winnipeg Manitoba R3E 0V9 Canada
| | - Frank Schweizer
- Department of Chemistry, Faculty of Science, University of Manitoba Winnipeg Manitoba R3T 2N2 Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba Winnipeg Manitoba R3E 0J9 Canada
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12
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Cui Q, Ding W, Luo B, Lu W, Huang P, Wen S. Novel gold-based complex GC7 suppresses cancer cell proliferation via impacting energy metabolism mediated by mitochondria. Bioorg Med Chem 2024; 112:117897. [PMID: 39216383 DOI: 10.1016/j.bmc.2024.117897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024]
Abstract
Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (GC7) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of GC7 on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following GC7 treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess GC7's tumor-suppressing effects. The results showed that GC7 possessed a broad-spectrum anticancer effect, with IC50 values ranging from 0.43 to 1.2 μM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2-6 folds). GC7 (0.3 and 1 μM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 μM, and it completely eliminated colony at 0.3 μM. The preliminary mechanistic study showed that GC7 inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. GC7 was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, GC7 (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, GC7 showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.
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Affiliation(s)
- Qingbin Cui
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China
| | - Wenwen Ding
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China
| | - Bingling Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China
| | - Wenhua Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China
| | - Peng Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China.
| | - Shijun Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510006, China.
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13
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Jaiswal A, Shrivastav S, Kushwaha HR, Chaturvedi R, Singh RP. Oncogenic potential of SARS-CoV-2-targeting hallmarks of cancer pathways. Cell Commun Signal 2024; 22:447. [PMID: 39327555 PMCID: PMC11426004 DOI: 10.1186/s12964-024-01818-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/04/2024] [Indexed: 09/28/2024] Open
Abstract
The 2019 outbreak of SARS-CoV-2 has caused a major worldwide health crisis with high rates of morbidity and death. Interestingly, it has also been linked to cancer, which begs the issue of whether it plays a role in carcinogenesis. Recent studies have revealed various mechanisms by which SARS-CoV-2 can influence oncogenic pathways, potentially promoting cancer development. The virus encodes several proteins that alter key signaling pathways associated with cancer hallmarks. Unlike classical oncogenic viruses, which transform cells through viral oncogenes or by activating host oncogenes, SARS-CoV-2 appears to promote tumorigenesis by inhibiting tumor suppressor genes and pathways while activating survival, proliferation, and inflammation-associated signaling cascades. Bioinformatic analyses and experimental studies have identified numerous interactions between SARS-CoV-2 proteins and cellular components involved in cancer-related processes. This review explores the intricate relationship between SARS-CoV-2 infection and cancer, focusing on the regulation of key hallmarks driving initiation, promotion and progression of cancer by viral proteins. By elucidating the underlying mechanisms driving cellular transformation, the potential of SARS-CoV-2 as an oncovirus is highlighted. Comprehending these interplays is essential to enhance our understanding of COVID-19 and cancer biology and further formulating strategies to alleviate SARS-CoV-2 influence on cancer consequences.
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Affiliation(s)
- Aishwarya Jaiswal
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Sanah Shrivastav
- SRM Institute of Science and Technology, Delhi-NCR Campus, Ghaziabad, Uttar Pradesh, India
| | - Hemant R Kushwaha
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Rupesh Chaturvedi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India.
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
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14
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El-Tanani M, Rabbani SA, El-Tanani Y, Matalka II. Metabolic vulnerabilities in cancer: A new therapeutic strategy. Crit Rev Oncol Hematol 2024; 201:104438. [PMID: 38977145 DOI: 10.1016/j.critrevonc.2024.104438] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024] Open
Abstract
Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.
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Affiliation(s)
- Mohamed El-Tanani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Syed Arman Rabbani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Yahia El-Tanani
- Medical School, St George's University of London, Cranmer Terrace, Tooting, London, UK
| | - Ismail I Matalka
- RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates; Department of Pathology and Microbiology, Medicine, Jordan University of Science and Technology, Irbid, Jordan.
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15
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Bi X, Wang J, Liu C. Intratumoral Microbiota: Metabolic Influences and Biomarker Potential in Gastrointestinal Cancer. Biomolecules 2024; 14:917. [PMID: 39199305 PMCID: PMC11353126 DOI: 10.3390/biom14080917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024] Open
Abstract
Gastrointestinal (GI) cancers impose a substantial global health burden, highlighting the necessity for deeper understanding of their intricate pathogenesis and treatment strategies. This review explores the interplay between intratumoral microbiota, tumor metabolism, and major types of GI cancers (including esophageal, gastric, liver, pancreatic, and colorectal cancers), summarizing recent studies and elucidating their clinical implications and future directions. Recent research revealed altered microbial signatures within GI tumors, impacting tumor progression, immune responses, and treatment outcomes. Dysbiosis-induced alterations in tumor metabolism, including glycolysis, fatty acid metabolism, and amino acid metabolism, play critical roles in cancer progression and therapeutic resistance. The integration of molecular mechanisms and potential biomarkers into this understanding further enhances the prognostic significance of intratumoral microbiota composition and therapeutic opportunities targeting microbiota-mediated tumor metabolism. Despite advancements, challenges remain in understanding the dynamic interactions within the tumor microenvironment (TME). Future research directions, including advanced omics technologies and prospective clinical studies, offer promising avenues for precision oncology and personalized treatment interventions in GI cancer. Overall, integrating microbiota-based approaches and molecular biomarkers into GI cancer management holds promise for improving patient outcomes and survival.
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Affiliation(s)
- Xueyuan Bi
- Department of Pharmacy, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, China
| | - Jihan Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, China;
| | - Cuicui Liu
- Department of Science and Education, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, China
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16
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Becceneri AB, Martin MT, Graminha AE, Cominetti MR, Ford PC, Santana da Silva R. The effect of light irradiation on a nitro-ruthenium porphyrin complex in the induced death of lung cancer cells in two- and three-dimensional cultures: Insights into the effect of nitric oxide. Dalton Trans 2024; 53:11264-11275. [PMID: 38695514 DOI: 10.1039/d4dt00381k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Efforts to find compounds selectively affecting cancer cells while sparing normal ones have continued to grow. Nitric oxide (NO) is critical in physiology and pathology, including cancer. It influences cellular processes like proliferation, apoptosis, and angiogenesis. The intricate interaction of NO with cancer cells offers innovative treatment possibilities, but its effects can vary by concentration and site. Ruthenium complexes capable of releasing NO upon stimulation show for this purpose. These versatile compounds can also enhance photodynamic therapy (PDT), a light-activated approach, which induces cellular damage. Ruthenium-based photosensitizers (PSs), delivering NO and producing reactive oxygen species (ROS), offer a novel strategy for improved cancer treatments. In this study, a nitro-ruthenium porphyrin conjugate: {TPyP[Ru(NO2)(bpy)2]4}(PF6)4, designated RuNO2TPyP, which releases NO upon irradiation, was investigated for its effects on lung cells (non-tumor MRC-5 and tumor A549) in 2D and 3D cell cultures. The findings suggest that this complex has potential for PDT treatment in lung cancer, as it exhibits photocytotoxicity at low concentrations without causing cytotoxicity to normal lung cells. Moreover, treatment of cells with RuNO2TPyP followed by light irradiation (4 J cm-2) can induce apoptosis, generate ROS, promote intracellular NO formation, and has anti-migratory effects. Additionally, the complex can modify tumor cell structures and induce photocytotoxicity and apoptosis in a 3D culture. These outcomes are attributed to the internalization of the complex and its subsequent activation upon light irradiation, resulting in NO release and singlet oxygen production.
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Affiliation(s)
- Amanda Blanque Becceneri
- Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil.
| | - Matheus Torelli Martin
- Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil.
| | - Angelica Ellen Graminha
- Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil.
- Institute of Chemistry, São Paulo State University, Av. Prof. Francisco Degni, 55, 14800-900, Araraquara, São Paulo, Brazil
| | - Márcia Regina Cominetti
- Department of Gerontology, Federal University of São Carlos, Rod. Washington Luís, Km 235, São Carlos, São Paulo, 13565-905, Brazil
| | - Peter C Ford
- Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93110-9510, USA
| | - Roberto Santana da Silva
- Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil.
- Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93110-9510, USA
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17
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Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [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: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
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Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
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18
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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19
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Benabdelkamel H, Jaber MA, Akkour K, AlMalki RH, Alfadda AA, Masood A, Joy SS, Alhalal H, Alwehaibi MA, Arafah M, Alshehri E, Abdel Rahman AM. Metabolomic Profiling of Blood Plasma in Females with Hyperplasia and Endometrial Cancer. Metabolites 2024; 14:109. [PMID: 38393001 PMCID: PMC10890097 DOI: 10.3390/metabo14020109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/27/2024] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
Uterine cancer is the most prevalent gynecologic malignancy in women worldwide. Endometrial cancer (EC) has an 81% five-year survival rate, depending on disease stage and time of diagnosis. While endometrial cancer is largely treatable when detected early, no established screening techniques are available in clinical practice. As a result, one of the most significant issues in the medical field is the development of novel ways for early cancer identification, which could boost treatment success rates. Liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based metabolomics was employed to explore the metabolomic markers and pathways unique to this cancer type and link them to the benign endometrial hyperplasia that may progress to cancer in 5% to 25% of patients. The study involved 59 postmenopausal participants, 20 with EC type 1, 20 with benign hyperplasia, and 19 healthy participants. Metabolite distribution changes were analyzed, and 338 of these features were dysregulated and significant. The first two main components, PC1 and PC2, were responsible for 11.5% and 12.2% of the total metabolites, respectively. Compared with the control group (CO), EC samples had 203 differentially expressed metabolites (180 upregulated and 23 downregulated); in hyperplasia (HP), 157 metabolites were dysregulated (127 upregulated and 30 downregulated) compared to the CO group while 21 metabolites exhibited differential regulation (16 upregulated and 5 downregulated) in EC plasma samples compared to the HP group. Hyperplasia samples exhibited similar metabolic changes to those reported in cancer, except for alterations in triglyceride levels, 7a,12 b-dihydroxy-5b-Cholan-24-oic acid, and Hept-2-enedioyl carnitine levels. The metabolites N-heptanoyl glycine and -(Methylthio)-2,3-isopentyl phosphate and formimino glutamic acid can be specific markers for hyperplasia conditions and dimethyl phosphatidyl ethanolamine and 8-isoprostaglandin E2 can be specific markers for EC conditions. Metabolic activities rely on mitochondrial oxidative phosphorylation for energy generation. The changes in metabolites identified in our study indicate that endometrial cancer cells adopt alternative strategies to increase energy production to meet the energy demand, thereby supporting proliferation.
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Affiliation(s)
- Hicham Benabdelkamel
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Malak A Jaber
- Pharmaceutical Medicinal Chemistry & Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 1196, Jordan
| | - Khalid Akkour
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Reem H AlMalki
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11461, Saudi Arabia
| | - Assim A Alfadda
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
- Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Afshan Masood
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Salini Scaria Joy
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Hani Alhalal
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Moudi A Alwehaibi
- Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Maria Arafah
- Department of Pathology, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Eman Alshehri
- Obstetrics and Gynecology Department, College of Medicine, King Saud University Medical City, King Saud University, Riyadh 11461, Saudi Arabia
| | - Anas M Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia
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20
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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21
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Watabe S, Aruga Y, Kato R, Kawade G, Kubo Y, Tatsuzawa A, Onishi I, Kinowaki Y, Ishibashi S, Ikeda M, Fukawa Y, Akahoshi K, Tanabe M, Kurata M, Ohashi K, Kitagawa M, Yamamoto K. Regulation of 4-HNE via SMARCA4 Is Associated with Worse Clinical Outcomes in Hepatocellular Carcinoma. Biomedicines 2023; 11:2278. [PMID: 37626774 PMCID: PMC10452552 DOI: 10.3390/biomedicines11082278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/08/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
Accumulation of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, has various favorable and unfavorable effects on cancer cells; however, the clinicopathological significance of its accumulation in hepatocellular carcinoma (HCC) and its metabolic pathway remain unknown. This study analyzed 4-HNE accumulation and its clinicopathological significance in HCC. Of the 221 cases, 160 showed relatively low accumulation of 4-HNE in HCC tissues, which was an independent prognostic predictor. No correlation was found between 4-HNE accumulation and the expression of the antioxidant enzymes glutathione peroxidase 4, ferroptosis suppressor protein 1, and guanosine triphosphate cyclohydrolase 1. Therefore, we hypothesized that 4-HNE metabolism is up-regulated in HCC. A database search was focused on the transcriptional regulation of aldo-keto reductases, alcohol dehydrogenases, and glutathione-S-transferases, which are the metabolic enzymes of 4-HNE, and seven candidate transcription factor genes were selected. Among the candidate genes, the knockdown of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) increased 4-HNE accumulation. Immunohistochemical analysis revealed an inverse correlation between 4-HNE accumulation and SMARCA4 expression. These results suggest that SMARCA4 regulates 4-HNE metabolism in HCC. Therefore, targeting SMARCA4 provides a basis for a new therapeutic strategy for HCC via 4-HNE accumulation and increased cytotoxicity.
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Affiliation(s)
- Shiori Watabe
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yukari Aruga
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Ryoko Kato
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Genji Kawade
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuki Kubo
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Anna Tatsuzawa
- Department of Analytical Information of Clinical Laboratory Medicine, Graduate School of Health Care Science, Bunkyo Gakuin University, 1-19-1 Mukougaoka, Bunkyo-ku, Tokyo 113-8668, Japan
| | - Iichiroh Onishi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuko Kinowaki
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Sachiko Ishibashi
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Masumi Ikeda
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuki Fukawa
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Keiichi Akahoshi
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Morito Kurata
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Kenichi Ohashi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Masanobu Kitagawa
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Kouhei Yamamoto
- Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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22
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Begolli R, Chatziangelou M, Samiotaki M, Goutas A, Barda S, Goutzourelas N, Kevrekidis DP, Malea P, Trachana V, Liu M, Lin X, Kollatos N, Stagos D, Giakountis A. Transcriptome and proteome analysis reveals the anti-cancer properties of Hypnea musciformis marine macroalga extract in liver and intestinal cancer cells. Hum Genomics 2023; 17:71. [PMID: 37525271 PMCID: PMC10388463 DOI: 10.1186/s40246-023-00517-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/18/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Marine seaweeds are considered as a rich source of health-promoting compounds by the food and pharmaceutical industry. Hypnea musciformis is a marine red macroalga (seaweed) that is widely distributed throughout the world, including the Mediterranean Sea. It is known to contain various bioactive compounds, including sulfated polysaccharides, flavonoids, and phlorotannins. Recent studies have investigated the potential anticancer effects of extracts from H. musciformis demonstrating their cytotoxic effects on various cancer cell lines. The anticancer effects of these extracts are thought to be due to the presence of bioactive compounds, particularly sulfated polysaccharides, which have been shown to have anticancer and immunomodulatory effects. However, further studies are needed to fully understand the molecular mechanisms that underlie their anticancer effects and to determine their potential as therapeutic agents for cancer treatment. METHODS H. musciformis was collected from the Aegean Sea (Greece) and used for extract preparation. Transcriptome and proteome analysis was performed in liver and colon cancer human cell lines following treatment with H. musciformis seaweed extracts to characterize its anticancer effect in detail at the molecular level and to link transcriptome and proteome responses to the observed phenotypes in cancer cells. RESULTS We have identified that treatment with the seaweed extract triggers a p53-mediated response at the transcriptional and protein level in liver cancer cells, in contrast to colon cancer cells in which the effects are more associated with metabolic changes. Furthermore, we show that in treated HepG2 liver cancer cells, p53 interacts with the chromatin of several target genes and facilitates their upregulation possibly through the recruitment of the p300 co-activator. CONCLUSIONS Overall, the available evidence suggests that extracts from H. musciformis have the potential to serve as a source of anticancer agents in liver cancer cells mainly through activation of a p53-mediated anti-tumor response that is linked to inhibition of cellular proliferation and induction of cell death.
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Affiliation(s)
- Rodiola Begolli
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Myrto Chatziangelou
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | | | - Andreas Goutas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Sofia Barda
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Nikolaos Goutzourelas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Dimitrios Phaedon Kevrekidis
- Laboratory of Forensic Medicine and Toxicology, Department of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Paraskevi Malea
- Department of Botany, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Ming Liu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Xiukun Lin
- College of Marine Sciences, Beibu Gulf University, 12 Binhai Rd, Qinzhou, 535011, Guangxi, China
| | - Nikolaos Kollatos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Dimitrios Stagos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece.
| | - Antonis Giakountis
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece.
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23
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Al Bitar M, Hassanieh B, Awad R, Khalil M. Characterization and evaluation of the therapeutic benefits of pure and lanthanides mono- and co-doped zinc oxide nanoparticles. Saudi J Biol Sci 2023; 30:103608. [PMID: 36923212 PMCID: PMC10009547 DOI: 10.1016/j.sjbs.2023.103608] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/27/2023] [Accepted: 02/19/2023] [Indexed: 02/25/2023] Open
Abstract
The effect of Lanthanides-doping on the structural, optical, morphological, antibacterial and anticancer properties of zinc oxide (ZnO) nanoparticles was investigated. Pure ZnO, Zn0.9La0.1O, Zn0.9Ce0.1O, and Zn0.9La0.05Ce0.05O were fabricated through the chemical co-precipitation route. The structural and morphological properties were studied using the X-ray diffraction (XRD) and transmission electron microscopy (TEM), respectively. The optical properties were analyzed by photoluminescence spectroscopy (PL). The inhibitory effect of the synthesized nanoparticles (NPs) was assessed against six bacterial strains using the agar well diffusion and broth micro-dilution methods. The anticancer potential of the synthesized NPs was assessed against two human colon cancer cell lines Caco-2 and HCT-116. The appearance of the La2O3 and CeO2 secondary phases upon doping La3+ and Ce3+ ions induced structural and morphological changes. The large distorted hexagonal morphology of pure ZnO is transformed into small sized distorted hexagonal form. The photoluminescence spectra revealed the point defects resulting from Lanthanum (La) and cerium (Ce) doping. The prepared NPs significantly inhibited the growth of the six investigated bacteria and induced cytotoxic effects and morphological changes against Caco-2 and HCT-116 cell lines. This study showed that doping ZnO with lanthanide ions such as La3+ and Ce3+ provide promising biological applications. These NPs showed a potent antibacterial and anticancer effect towards the investigated bacterial strains and colon cancer cell lines. These findings point to the importance of the biological applications of NPs, and the possibility of investigating other biomedical applications for NPs.
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Affiliation(s)
- Maryam Al Bitar
- Department of Physics, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Bahaa Hassanieh
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - R Awad
- Department of Physics, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Mahmoud Khalil
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon.,Molecular Biology Unit, Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
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24
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The expression of ACAT1 in oral squamous cell carcinoma and the adjacent pre-tumour tissue. Biomedicine (Taipei) 2023; 12:55-62. [PMID: 36816175 PMCID: PMC9910229 DOI: 10.37796/2211-8039.1363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/15/2022] [Accepted: 03/22/2022] [Indexed: 11/27/2022] Open
Abstract
Background Altered acetyl CoA acetyltransferase 1 (ACAT1) expression has been reported in diverse cancers. However, the expression of ACAT1 and its prognostic value in oral squamous cell carcinoma (OSCC) has remained unexplored. Materials and methods In this study, the expression of ACAT1 was analysed by immunohistochemistry (IHC) in 61 OSCC patients and compared between OSCC and adjacent pre-tumour tissue of 21 patients. Results The expression of ACAT1 in OSCC tumours is heterogeneous between patients. More specifically, 52.38% of the patients show low expression of ACAT1 in both tumour and adjacent pre-tumour tissues, 9.52% of the patients show high expression of ACAT1 in both tumour and adjacent pre-tumour, 19.05% of the patients have high expression of ACAT1 in tumour tissue and low expression of ACAT1 in adjacent pre-tumour tissue and another 19.05% of the patients have low expression of ACAT1 in tumour tissue and high expression of ACAT1 in adjacent pre-tumour tissue. Conclusion Comparison of ACAT1 expression, one of the key enzymes in the ketone body metabolic pathway, divided OSCC patients into two groups: 1) similar expression and 2) different expression of ACAT1 in tumour and adjacent pre-tumour tissue. No significant association between ACAT1 levels and overall survival was observed.
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25
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Mosleh-Shirazi S, Abbasi M, Moaddeli MR, Vaez A, Shafiee M, Kasaee SR, Amani AM, Hatam S. Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview. Nanotheranostics 2022; 6:400-423. [PMID: 36051855 PMCID: PMC9428923 DOI: 10.7150/ntno.74613] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/25/2022] [Indexed: 12/01/2022] Open
Abstract
Over the last few years, progress has been made across the nanomedicine landscape, in particular, the invention of contemporary nanostructures for cancer diagnosis and overcoming complexities in the clinical treatment of cancerous tissues. Thanks to their small diameter and large surface-to-volume proportions, nanomaterials have special physicochemical properties that empower them to bind, absorb and transport high-efficiency substances, such as small molecular drugs, DNA, proteins, RNAs, and probes. They also have excellent durability, high carrier potential, the ability to integrate both hydrophobic and hydrophilic compounds, and compatibility with various transport routes, making them especially appealing over a wide range of oncology fields. This is also due to their configurable scale, structure, and surface properties. This review paper discusses how nanostructures can function as therapeutic vectors to enhance the therapeutic value of molecules; how nanomaterials can be used as medicinal products in gene therapy, photodynamics, and thermal treatment; and finally, the application of nanomaterials in the form of molecular imaging agents to diagnose and map tumor growth.
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Affiliation(s)
- Sareh Mosleh-Shirazi
- Department of Materials Science and Engineering, Shiraz University of Technology, Shiraz, Iran
| | - Milad Abbasi
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad reza Moaddeli
- Assistant Professor, Department of Oral and Maxillofacial Surgery, School of Dentistry, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ahmad Vaez
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mostafa Shafiee
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Reza Kasaee
- Shiraz Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Amani
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Hatam
- Assistant Lecturer, Azad University, Zarghan Branch, Shiraz, Iran
- ExirBitanic, Science and Technology Park of Fars, Shiraz, Iran
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26
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Partial Substitution of Glucose with Xylitol Prolongs Survival and Suppresses Cell Proliferation and Glycolysis of Mice Bearing Orthotopic Xenograft of Oral Cancer. Nutrients 2022; 14:nu14102023. [PMID: 35631164 PMCID: PMC9148106 DOI: 10.3390/nu14102023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/07/2022] [Accepted: 05/08/2022] [Indexed: 02/04/2023] Open
Abstract
Many types of cancer have metabolic alterations with increased glycolysis. Identification of alternative sweeteners that do not fuel cancer is a novel approach to cancer control. The present study aimed to investigate the effects of xylitol on tumor growth and survival of mice bearing orthotopic xenograft of tongue cancers. The results showed that partial substitution of glucose with xylitol (glucose 0.35 g plus xylitol 2.06 g/kg body weight) non-significantly reduced tumor volume, and significantly prolonged the median survival time from 19 days in the control to 30.5 days in the xylitol group. Immunohistochemical data of the tongue tissue shows significantly lower intense-to-mild staining ratios of the proliferation marker Ki-67 in the xylitol than those of the control group (p = 0.04). Furthermore, the xylitol substitution significantly reduced the expression of the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) (p = 0.03), and showed a non-significant inhibition of PFK activity. In summary, partial substitution of glucose with xylitol at the equivalent dose to human household use of 10 g/day slows down tumor proliferation and prolongs survival of mice bearing an orthotopic oral cancer xenograft, possibly through glycolytic inhibition, with minimal adverse events. The insight warrants clinical studies to confirm xylitol as a candidate sweetener in food products for cancer survivors.
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27
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Reddy VB, Boteju L, Boteju A, Shen L, Kassahun K, Reddy N, Sheldon A, Luther S, Hu K. In Vitro and In Vivo Metabolism of a Novel Antimitochondrial Cancer Metabolism Agent, CPI-613, in Rat and Human. Drug Metab Dispos 2022; 50:361-373. [PMID: 35086846 DOI: 10.1124/dmd.121.000726] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/20/2022] [Indexed: 11/22/2022] Open
Abstract
CPI-613, an inhibitor of pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) enzymes, is currently in development for the treatment of pancreatic cancer, acute myeloid leukemia, and other cancers. CPI-613 is an analog of lipoic acid, an essential cofactor for both PDH and KGDH. Metabolism and mass balance studies were conducted in rats after intravenous administration of [14C]-CPI-613. CPI-613 was eliminated via oxidative metabolism followed by excretion of the metabolites in feces (59%) and urine (22%). β-Oxidation was the major pathway of elimination for CPI-613. The most abundant circulating components in rat plasma were those derived from β-oxidation. In human hepatocytes, CPI-613 mainly underwent β-oxidation (M1), sulfur oxidation (M2), and glucuronidation (M3). The Michaelis-Menten kinetics (Vmax and Km) of the metabolism of CPI-613 to these three metabolites predicted the fraction metabolized leading to the formation of M1, M2, and M3 to be 38%, 6%, and 56%, respectively. In humans, after intravenous administration of CPI-613, major circulating species in plasma were the parent and the β-oxidation derived products. Thus, CPI-613 metabolites profiles in rat and human plasma were qualitatively similar. β-Oxidation characteristics and excretion patterns of CPI-613 are discussed in comparison with those reported for its endogenous counterpart, lipoic acid. SIGNIFICANCE STATEMENT: This work highlights the clearance mechanism of CPI-613 via β-oxidation, species differences in their ability to carry out β-oxidation, and subsequent elimination routes. Structural limitations for completion of terminal cycle of β-oxidation is discussed against the backdrop of its endogenous counterpart lipoic acid.
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Affiliation(s)
- Vijay Bhasker Reddy
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Lakmal Boteju
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Asela Boteju
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Li Shen
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Kelem Kassahun
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Nageshwar Reddy
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Adrian Sheldon
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Sanjeev Luther
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
| | - Ke Hu
- Rafael Pharmaceuticals, Cranbury, New Jersey (V.B.R., L.B., A.B., N.R., S.L., K.H.); Frontage Laboratories, Exton, Pennsylvania (L.S., K.K.); and Charles River Laboratories, Worcester, Massachusetts (A.S.)
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28
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Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time. Sci Rep 2022; 12:5518. [PMID: 35365706 PMCID: PMC8976067 DOI: 10.1038/s41598-022-09438-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/23/2022] [Indexed: 12/26/2022] Open
Abstract
Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.
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29
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Suksawat M, Phetcharaburanin J, Klanrit P, Namwat N, Khuntikeo N, Titapun A, Jarearnrat A, Vilayhong V, Sa-ngiamwibool P, Techasen A, Wangwiwatsin A, Mahalapbutr P, Li JV, Loilome W. Metabolic Phenotyping Predicts Gemcitabine and Cisplatin Chemosensitivity in Patients With Cholangiocarcinoma. Front Public Health 2022; 10:766023. [PMID: 35223723 PMCID: PMC8866176 DOI: 10.3389/fpubh.2022.766023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
Gemcitabine and cisplatin serve as appropriate treatments for patients with cholangiocarcinoma (CCA). Our previous study using histoculture drug response assay (HDRA), demonstrated individual response patterns to gemcitabine and cisplatin. The current study aimed to identify predictive biomarkers for gemcitabine and cisplatin sensitivity in tissues and sera from patients with CCA using metabolomics. Metabolic signatures of patients with CCA were correlated with their HDRA response patterns. The tissue metabolic signatures of patients with CCA revealed the inversion of the TCA cycle that is evident with increased levels of citrate and amino acid backbones as TCA cycle intermediates, and glucose which corresponds to cancer stem cell (CSC) properties. The protein expression levels of CSC markers were examined on tissues and showed the significantly inverse association with the responses of patients to cisplatin. Moreover, the elevation of ethanol level was observed in gemcitabine- and cisplatin-sensitive group. In serum, a lower level of glucose but a higher level of methylguanidine was observed in the gemcitabine-responders as non-invasive predictive biomarker for gemcitabine sensitivity. Collectively, our findings indicate that these metabolites may serve as the predictive biomarkers in clinical practice which not only predict the chemotherapy response in patients with CCA but also minimize the adverse effect from chemotherapy.
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Affiliation(s)
- Manida Suksawat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Khon Kaen University International Phenome Laboratory, Northeastern Science Park, Khon Kaen University, Khon Kaen, Thailand
| | - Jutarop Phetcharaburanin
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Khon Kaen University International Phenome Laboratory, Northeastern Science Park, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
| | - Poramate Klanrit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Attapon Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Apiwat Jarearnrat
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Vanlakhone Vilayhong
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Prakasit Sa-ngiamwibool
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Arporn Wangwiwatsin
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Khon Kaen University International Phenome Laboratory, Northeastern Science Park, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
| | - Panupong Mahalapbutr
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
| | - Jia V. Li
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, South Kensington Campus, London, United Kingdom
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
- Khon Kaen University International Phenome Laboratory, Northeastern Science Park, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
- *Correspondence: Watcharin Loilome
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The Wnt Signaling Pathway Inhibitors Improve the Therapeutic Activity of Glycolysis Modulators against Tongue Cancer Cells. Int J Mol Sci 2022; 23:ijms23031248. [PMID: 35163171 PMCID: PMC8835497 DOI: 10.3390/ijms23031248] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/27/2022] Open
Abstract
Excessive glucose metabolism and disruptions in Wnt signaling are important molecular changes present in oral cancer cells. The aim of this study was to evaluate the effects of the combinatorial use of glycolysis and Wnt signaling inhibitors on viability, cytotoxicity, apoptosis induction, cell cycle distribution and the glycolytic activity of tongue carcinoma cells. CAL 27, SCC-25 and BICR 22 tongue cancer cell lines were used. Cells were treated with inhibitors of glycolysis (2-deoxyglucose and lonidamine) and of Wnt signaling (PRI-724 and IWP-O1). The effects of the compounds on cell viability and cytotoxicity were evaluated with MTS and CellTox Green tests, respectively. Apoptosis was evaluated by MitoPotential Dye staining and cell cycle distribution by staining with propidium iodide, followed by flow cytometric cell analysis. Glucose and lactate concentrations in a culture medium were evaluated luminometrically. Combinations of 2-deoxyglucose and lonidamine with Wnt pathway inhibitors were similarly effective in the impairment of oral cancer cells’ survival. However, the inhibition of the canonical Wnt pathway by PRI-724 was more beneficial, based on the glycolytic activity of the cells. The results point to the therapeutic potential of the combination of low concentrations of glycolytic modulators with Wnt pathway inhibitors in oral cancer cells.
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Gao Y, Dai Z, Yang C, Wang D, Guo Z, Mao W, Chen Z. Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma. PeerJ 2022; 10:e12568. [PMID: 35036082 PMCID: PMC8740518 DOI: 10.7717/peerj.12568] [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] [Received: 05/21/2021] [Accepted: 11/08/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Malignant mesothelioma (MM) is a rare and highly aggressive cancer. Despite advances in multidisciplinary treatments for cancer, the prognosis for MM remains poor with no effective diagnostic biomarkers currently available. The aim of this study was to identify plasma metabolic biomarkers for better MM diagnosis and prognosis by use of a MM cell line-derived xenograft (CDX) model. METHODS The MM CDX model was confirmed by hematoxylin and eosin staining and immunohistochemistry. Twenty female nude mice were randomly divided into two groups, 10 for the MM CDX model and 10 controls. Plasma samples were collected two weeks after tumor cell implantation. Gas chromatography-mass spectrometry analysis was conducted. Both univariate and multivariate statistics were used to select potential metabolic biomarkers. Hierarchical clustering analysis, metabolic pathway analysis, and receiver operating characteristic (ROC) analysis were performed. Additionally, bioinformatics analysis was used to investigate differential genes between tumor and normal tissues, and survival-associated genes. RESULTS The MM CDX model was successfully established. With VIP > 1.0 and P-value < 0.05, a total of 23 differential metabolites were annotated, in which isoleucine, 5-dihydrocortisol, and indole-3-acetamide had the highest diagnostic values based on ROC analysis. These were mainly enriched in pathways for starch and sucrose metabolism, pentose and glucuronate interconversions, galactose metabolism, steroid hormone biosynthesis, as well as phenylalanine, tyrosine and tryptophan biosynthesis. Further, down-regulation was observed for amino acids, especially isoleucine, which is consistent with up-regulation of amino acid transporter genes SLC7A5 and SLC1A3 in MM. Overall survival was also negatively associated with SLC1A5, SLC7A5, and SLC1A3. CONCLUSION We found several altered plasma metabolites in the MM CDX model. The importance of specific metabolic pathways, for example amino acid metabolism, is herein highlighted, although further investigation is warranted.
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Affiliation(s)
- Yun Gao
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China,Zhejiang Key Laboratory of Diagnosis&Treatment Technology on Thoracic Oncology(Lung and Esophagus), Hangzhou, China
| | - Ziyi Dai
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Chenxi Yang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Ding Wang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China,Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhenying Guo
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Weimin Mao
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China,Zhejiang Key Laboratory of Diagnosis&Treatment Technology on Thoracic Oncology(Lung and Esophagus), Hangzhou, China
| | - Zhongjian Chen
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China,Zhejiang Key Laboratory of Diagnosis&Treatment Technology on Thoracic Oncology(Lung and Esophagus), Hangzhou, China
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Huang CC, Cheng YC, Lin YC, Chou CH, Ho CT, Wang HK, Way TD. CSC-3436 sensitizes triple negative breast cancer cells to TRAIL-induced apoptosis through ROS-mediated p38/CHOP/death receptor 5 signaling pathways. ENVIRONMENTAL TOXICOLOGY 2021; 36:2578-2588. [PMID: 34599545 DOI: 10.1002/tox.23372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 06/13/2023]
Abstract
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.
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Affiliation(s)
- Chun-Chen Huang
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Yi-Ching Cheng
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Ying-Chao Lin
- Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Chun-Hung Chou
- Ph.D. Program for Biotechnology Industry, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey, USA
| | - Hao-Kuang Wang
- Department of Neurosurgery, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
- School of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Tzong-Der Way
- Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan
- Ph.D. Program for Biotechnology Industry, College of Life Sciences, China Medical University, Taichung, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
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Sharma P, Sharma V, Ahluwalia TS, Dogra N, Kumar S, Singh S. Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4. Cancer Cell Int 2021; 21:629. [PMID: 34838007 PMCID: PMC8627041 DOI: 10.1186/s12935-021-02339-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/12/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND AND OBJECTIVES MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria. METHODS AND RESULTS Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells. CONCLUSION These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription.
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Affiliation(s)
- Praveen Sharma
- Molecular Medicine Laboratory, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Vibhuti Sharma
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
| | | | - Nilambra Dogra
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
| | | | - Sandeep Singh
- Molecular Medicine Laboratory, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India.
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Kaur J, Bhattacharyya S. Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy. Front Oncol 2021; 11:756888. [PMID: 34804950 PMCID: PMC8602811 DOI: 10.3389/fonc.2021.756888] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/18/2021] [Indexed: 02/02/2023] Open
Abstract
The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Altered SERCA Expression in Breast Cancer. ACTA ACUST UNITED AC 2021; 57:medicina57101074. [PMID: 34684111 PMCID: PMC8539028 DOI: 10.3390/medicina57101074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 11/26/2022]
Abstract
Background and Objectives: Calcium (Ca2+) signaling is critical for the normal functioning of various cellular activities. However, abnormal changes in cellular Ca2+ can contribute to pathological conditions, including various types of cancer. The maintenance of intracellular Ca2+ levels is achieved through tightly regulated processes that help maintain Ca2+ homeostasis. Several types of regulatory proteins are involved in controlling intracellular Ca2+ levels, including the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase pump (SERCA), which maintains Ca2+ levels released from the SR/ER. In total, three ATPase SR/ER Ca2+-transporting (ATP2A) 1-3 genes exist, which encode for several isoforms whose expression profiles are tissue-specific. Recently, it has become clear that abnormal SERCA expression and activity are associated with various types of cancer, including breast cancer. Breast carcinomas represent 40% of all cancer types that affect women, with a wide variety of pathological and clinical conditions. Materials and methods: Using cBioPortal breast cancer patient data, Kaplan–Meier plots demonstrated that high ATP2A1 and ATP2A3 expression was associated with reduced patient survival. Results: The present study found significantly different SERCA specific-type expressions in a series of breast cancer cell lines. Moreover, bioinformatics analysis indicated that ATP2A1 and ATP2A3 expression was highly altered in patients with breast cancer. Conclusion: Overall, the present data suggest that SERCA gene-specific expressioncan possibly be considered as a crucial target for the control of breast cancer development and progression.
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Jin JO, Puranik N, Bui QT, Yadav D, Lee PCW. The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer. Int J Mol Sci 2021; 22:9629. [PMID: 34502538 PMCID: PMC8431782 DOI: 10.3390/ijms22179629] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/03/2021] [Accepted: 09/03/2021] [Indexed: 12/25/2022] Open
Abstract
The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.
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Affiliation(s)
- Jun-O Jin
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Nidhi Puranik
- Biological Sciences Department, Bharathiar University, Coimbatore 641046, Tamil Nadu, India;
| | - Quyen Thu Bui
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
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Kleszcz R, Paluszczak J. The combinatorial inhibition of Wnt signaling and Akt kinase is beneficial for reducing the survival and glycolytic activity of tongue cancer cells. J Oral Pathol Med 2021; 51:231-239. [PMID: 34358376 DOI: 10.1111/jop.13233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/24/2021] [Accepted: 07/14/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Wnt signaling is important in the development of head and neck squamous cell carcinomas (HNSCC); however, Wnt pathway inhibitors lack satisfactory potency when used in monotherapy. The aim of this study was to assess the effects of the combinations of Wnt-signaling inhibitors and the inhibitor of Akt kinase on the survival and glycolytic activity of tongue carcinoma cells. METHODS CAL27, SCC-25, and BICR22 tongue cancer cell lines were used. Cells were treated with Wnt signaling (PRI-724 and IWP-O1) and Akt-kinase inhibitors. The effect of the chemicals on cell viability and cytotoxicity were evaluated by MTS and CellTox Green assays, respectively. Cell cycle distribution was analyzed cytometrically after propidium iodide staining. Annexin V binding to externalized phosphatidylserine and analysis of mitochondrial potential allowed the assessment of apoptosis. Glucose uptake and lactate release were evaluated luminometrically. Additionally, the viability of cells in spheroids was analyzed based on ATP content. RESULTS The Akt-kinase inhibitor showed significant cytotoxicity toward primary cancer cells. Moreover, its pro-apoptotic effects were enhanced by Wnt-pathway inhibitors. The activity of Akt inhibitor was even higher (by twofold) in 3D spheroids in comparison to cells grown in monolayer. The synergistic reduction in the growth of spheroids was observed between Akt inhibitor and IWP-O1. Reduced glucose consumption may play a part in the combinatorial effects of these chemicals. CONCLUSION The results point to the therapeutic potential of the combinatorial use of Wnt inhibitors together with Akt inhibitors in HNSCC.
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Affiliation(s)
- Robert Kleszcz
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland
| | - Jarosław Paluszczak
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland
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Mishra A, Srivastava A, Pateriya A, Tomar MS, Mishra AK, Shrivastava A. Metabolic reprograming confers tamoxifen resistance in breast cancer. Chem Biol Interact 2021; 347:109602. [PMID: 34331906 DOI: 10.1016/j.cbi.2021.109602] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/20/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023]
Abstract
Breast cancer is the most common cancer among females and the leading cause of cancer-related deaths. Approximately 70 % of breast cancers are estrogen receptor (ER) positive. An ER antagonist such as tamoxifen is used as adjuvant therapy in ER-positive patients. The major problem with endocrine therapy is the emergence of acquired resistance in approximately 40 % of patients receiving tamoxifen. Metabolic alteration is one of the hallmarks of cancer cells. Rapidly proliferating cancer cells require increased nutritional support to fuel various functions such as proliferation, cell migration, and metastasis. Recent studies have established that the metabolic state of cancer cells influences their susceptibility to chemotherapeutic drugs and that cancer cells reprogram their metabolism to develop into resistant phenotypes. In this review, we discuss the major findings on metabolic pathway alterations in tamoxifen-resistant (TAMR) breast cancer and the molecular mechanisms known to regulate the expression and function of metabolic enzymes and the respective metabolite levels upon tamoxifen treatment. It is anticipated that this in-depth analysis of specific metabolic pathways in TAMR cancer might be exploited therapeutically.
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Affiliation(s)
- Alok Mishra
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Anshuman Srivastava
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Ankit Pateriya
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Manendra Singh Tomar
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Anand Kumar Mishra
- Department of Endocrine Surgery, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Ashutosh Shrivastava
- Center for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India.
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Wijesiriwardhana P, Wetthasinghe K, Dissanayake VHW. Copy Number Variants Captured by the Array Comparative Genomic Hybridization in a Cohort of Patients Affected with Hereditary Colorectal Cancer in Sri Lanka: The First CNV Analysis Study of the Hereditary Colorectal Cancer in the Sri Lankan Population. Asian Pac J Cancer Prev 2021; 22:1957-1966. [PMID: 34181357 PMCID: PMC8418865 DOI: 10.31557/apjcp.2021.22.6.1957] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/08/2021] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder characterized by the development of multiple cancer types. Molecular diagnosis of HNPCC requires the precise identification of pathogenic germline variants in DNA mismatch repair (MMR) genes. Next Generation Sequencing (NGS) is now the gold standard test in practice, to identify these variants. However, large genomic rearrangements (LGR) in cancer predisposing genes (CPGs) are missed by NGS. This may lead to underestimation of the frequency of the variants, misleading the genetic diagnosis and delaying intervention in high risk individuals. Hence this study was aimed at identifying the presence of large genomic alterations that could explain the missing heritable risk of colon cancer in affected patients with family history strongly suggestive of hereditary colorectal cancer in Sri Lanka. METHODS A cohort of six patients affected with hereditary colorectal cancer who tested negative for pathogenic variants in next generation sequencing studies was investigated using Sure Print G3 Human CGH 4x180K microarray platform. Agilent Genomic-Workbench-v7.0.4.0 software was used to identify the Copy Number Variants (CNV). Four healthy individuals (>55years) were used as controls. Annotations of the CNV regions which were observed were done using the database of Genomic Variants. RESULTS We identified 150 CNVs including regions of both genomic gains and losses in the patient cohort. There was no difference in the average number or the average genomic burden of CNVs identified in the patients versus the controls. CNVs were residing on the positions of 1q21.2, 2q37.3, 2p11.2-p11.1, 5q13.2, 6p12.3, 7q31.33, 7p14.1, 14q32.33, 15q11.1-11.2, 16p11.2, 22q11.22, 22q13.1 that were assessed by the array platform used in the study. CNVs in any of the well-known common CPG s or CNVs that reside on or in close proximity to genes corresponding to MMR pathway were not identified. We found several distinct pathways that have previously been identified as having a direct association with the progression of HNPCC. CONCLUSION This study shows that CNVs are likely contributors to the colorectal cancer predisposition in a small but significant proportion of patients affected with hereditary colorectal cancer in this cohort. Further studies have to perform to get a better understanding on the contribution of CNVs to the cancer predisposition in this cohort of patients in the Sri Lankan population.
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Affiliation(s)
- Prabhavi Wijesiriwardhana
- Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Ruhuna, Sri Lanka.
- Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka.
| | - Kalum Wetthasinghe
- Human Genetics Unit, Faculty of Medicine, University of Colombo, Sri Lanka.
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Liu F, Yuan Q, Cao X, Zhang J, Cao J, Zhang J, Xia L. Isovitexin Suppresses Stemness of Lung Cancer Stem-Like Cells through Blockage of MnSOD/CaMKII/AMPK Signaling and Glycolysis Inhibition. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9972057. [PMID: 34195288 PMCID: PMC8203360 DOI: 10.1155/2021/9972057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/10/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Manganese superoxide dismutase (MnSOD) has been reported to promote stemness of lung cancer stem-like cells (LCSLCs) which had higher glycolytic rates compared with non-CSLCs. Isovitexin exhibited an inhibitory effect on the stemness of hepatocellular carcinoma cells. However, whether isovitexin could inhibit the promotion of stemness of LCSLCs mediated by MnSOD through glycolysis remains unclear. OBJECTIVE Our study was aimed at investigating whether isovitexin inhibits lung cancer stem-like cells (LCSLCs) through MnSOD signaling blockage and glycolysis suppression. METHODS Sphere formation and soft agar assays were conducted to determine self-renewal ability. The migration and invasion of LCSLCs were determined by wound healing and transwell assay. The glycolytic activity was assessed by determination of L-lactate metabolism rate. The influences of isovitexin on MnSOD, CaMKII, and AMPK activations as well as the metabolic shift to glycolysis were determined by manipulating MnSOD expression. RESULTS It was found that MnSOD and glycolysis enhanced simultaneously in LCSLCs compared with parental H460 cells. Overexpression of MnSOD activated CaMKII/AMPK signaling and glycolysis in LCSLCs with increased self-renewal, migration, invasion, and expression of stemness-associated markers in vitro and elevated carcinogenicity in vivo. Knockdown of MnSOD induced an inverse effect in LCSLCs. Isovitexin blocked MnSOD/CaMKII/AMPK signaling axis and suppressed glycolysis in LCSLCs, resulting in inhibition of stemness features in LCSLCs. The knockdown of MnSOD significantly augmented isovitexin-associated inhibition of CaMKII/AMPK signaling, glycolysis, and stemness in LCSLCs. However, the overexpression of MnSOD could attenuate the inhibition of isovitexin on LCSLCs. Importantly, isovitexin notably suppressed tumor growth in nude mice bearing LCSLCs by downregulation of MnSOD expression. CONCLUSION MnSOD promotion of stemness of LCSLCs derived from H460 cell line is involved in the activation of the CaMKII/AMPK pathway and induction of glycolysis. Isovitexin-associated inhibition of stemness in LCSLCs is partly dependent on blockage of the MnSOD/CaMKII/AMPK signaling axis and glycolysis suppression.
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Affiliation(s)
- Fei Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Provincial Key Laboratory of Microbial Molecular Biology, College of Life Science, Hunan Normal University, Changsha 410081, China
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, Hunan Province 410013, China
| | - Qing Yuan
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, Hunan Province 410013, China
| | - Xiaocheng Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha 410013, China
| | - Jinlin Zhang
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha 410013, China
| | - Jianguo Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha 410013, China
| | - Jiansong Zhang
- Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, Hunan Province 410013, China
| | - Liqiu Xia
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Provincial Key Laboratory of Microbial Molecular Biology, College of Life Science, Hunan Normal University, Changsha 410081, China
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Metabolomic Study on the Therapeutic Effect of the Jianpi Yangzheng Xiaozheng Decoction on Gastric Cancer Treated with Chemotherapy Based on GC-TOFMS Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8832996. [PMID: 33790982 PMCID: PMC7994103 DOI: 10.1155/2021/8832996] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 03/01/2021] [Indexed: 12/27/2022]
Abstract
Objective This study aimed to find new biomarkers of prognosis and metabolomic therapy for gastric carcinoma (GC) treated with chemotherapy and investigate the metabolic mechanism of the Jianpi Yangzheng Xiaozheng (JPYZXZ) decoction in the treatment of GC. Methods First, 36 patients with GC were randomly assigned to the treatment (chemotherapy plus JPYZXZ) and control (chemotherapy alone) groups. The clinical efficacy, side effects, and quality of life of patients in the two groups were evaluated after treatment. Then, the serum samples taken from 16 randomly selected patients (eight treatment cases and eight control cases with no evident pattern characters) and eight healthy volunteers were tested to identify the differential metabolite under the gas chromatography-time-of-fight mass spectrometry platform. The relevant metabolic pathways of differential substances were analyzed using multidimensional statistical analysis. Results JPYZXZ combined with chemotherapy resulted in a lower risk of leucopenia, thrombocytopenia, and gastrointestinal reaction (P < 0.05). Additionally, patients in the treatment group showed a higher Karnofsky (KPS) scale (P < 0.05). Compared with healthy persons, patients with GC were found to have 26 significant differential metabolites after chemotherapy; these metabolites are mainly involved in 12 metabolic pathways, such as valine, leucine, and isoleucine biosynthesis. JPYZXZ primarily influences the pentose phosphate pathway; glutathione metabolism; glyoxylate and dicarboxylate metabolism; porphyrin and chlorophyll metabolism; and glycine, serine, and threonine metabolism of patients with GC treated with chemotherapy. Conclusions The metabolic characteristics of patients with GC after chemotherapy are mainly various amino acid metabolic defects, especially L-glutamine, L-leucine, L-alloisoleucine, and L-valine. These defects lead to a series of problems, such as decreased tolerance and effectiveness of chemotherapy, increased side effects, decreased immunity, and shortened survival time. In addition, the remarkable upregulation of the gluconolactone level in patients with GC suggests the high proliferative activity of GC cells. Thus, gluconolactone may be used as a potential prognostic and diagnostic evaluation index. Moreover, JPYZXZ can reduce the incidence of ADRs and improve the life quality of patients by the correction of L-glutamine, L-leucine, L-alloisoleucine, and L-valine metabolism deficiency. In addition, gluconolactone metabolism is inhibited by JPYZXZ. Such inhibition may be one of the antitumor mechanisms of JPYZXZ.
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Chandel V, Sharma PP, Nayar SA, Jha NK, Jha SK, Rathi B, Kumar D. In silico identification of potential inhibitor for TP53-induced glycolysis and apoptosis regulator in head and neck squamous cell carcinoma. 3 Biotech 2021; 11:117. [PMID: 33604233 DOI: 10.1007/s13205-021-02665-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/20/2021] [Indexed: 12/20/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the six most common cancer globally and most common cancer in men in India. The metabolic regulation is highly altered and is considered as a hall mark of HNSCC. TP53-induced glycolysis and apoptosis regulator (TIGAR) plays very important role in the development and progression of HNSCC. The aim of our study is to identify a novel FDA approved anticancer inhibitor against mutated TP53-induced glycolysis and apoptosis regulator (TIGAR) through drug repurposing approach. A library of 105 FDA approved anticancer compounds were screened using molecular docking approach against TIGAR (PDB: 3DCY) both Wild-Type (WT) and mutated (Mut). Specific mutations in TIGAR were identified using cBioPortal, a cancer genomics database and mutated structure was modelled using SWISS-MODEL. Out of 510 sequenced cases/patients samples, 17(3%) patients showed alteration in TIGAR [TIGARWT and TIGARMut (R88W)]. The virtual drug screening showed 45 drugs out of 105 high binding affinity with TIGAR, Trabectedin showed highest binding affinity with both TIGARWT (- 13.3 kcal/mol) as well as TIGARMut (R88W) (- 13.8 kcal/mol). The molecular docking studies were validated using molecular dynamics simulation (MD Simulation) of protein-ligand complex of TIGAR and Trabectedin for 100 ns. The MD Simulation of Trabectedin complex showed more stable with TIGARMut (R88W) compared to TIGARWT. Moreover, the string analysis revealed that metabolic-related genes, HK2, PFKFB1, PFKM, PFKP, PFKL, FBP1 are closely associated with TIGAR in HNSCC. Our findings suggest that Trabectedin can be proposed as an inhibitor for [TIGARMut (R88W)] which can be used to target metabolic signalings in HNSCC. However, further investigation and in vitro and in vivo validation our findings required to understand the molecular mechanisms of regulation of Trabectedin in HNSCC.
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Sakharkar MK, Dhillon SK, Rajamanickam K, Heng B, Braidy N, Guillemin GJ, Yang J. Alteration in Gene Pair Correlations in Tryptophan Metabolism as a Hallmark in Cancer Diagnosis. Int J Tryptophan Res 2020; 13:1178646920977013. [PMID: 33354111 PMCID: PMC7734567 DOI: 10.1177/1178646920977013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/02/2020] [Indexed: 02/01/2023] Open
Abstract
Tryptophan metabolism plays essential roles in both immunomodulation and cancer development. Indoleamine 2,3-dioxygenase, a rate-limiting enzyme in the metabolic pathway, is overexpressed in different types of cancer. To get a better understanding of the involvement of tryptophan metabolism in cancer development, we evaluated the expression and pairwise correlation of 62 genes in the metabolic pathway across 12 types of cancer. Only gene AOX1, encoding aldehyde oxidase 1, was ubiquitously downregulated, Furthermore, we observed that the 62 genes were widely and strongly correlated in normal controls, however, the gene pair correlations were significantly lost in tumor patients for all 12 types of cancer. This implicated that gene pair correlation coefficients of the tryptophan metabolic pathway could be applied as a prognostic and/or diagnostic biomarker for cancer.
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Affiliation(s)
- Meena Kishore Sakharkar
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Sarinder Kaur Dhillon
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
| | - Karthic Rajamanickam
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Benjamin Heng
- Neuroinflammation Research Group, MND Research Centre, Department of Biological Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nady Braidy
- Neuroinflammation Research Group, MND Research Centre, Department of Biological Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Faculty of Medicine, Sydney, NSW, Australia
| | - Gilles J Guillemin
- Neuroinflammation Research Group, MND Research Centre, Department of Biological Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Jian Yang
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
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Park MK, Ji J, Haam K, Han TH, Lim S, Kang MJ, Lim SS, Ban HS. Licochalcone A inhibits hypoxia-inducible factor-1α accumulation by suppressing mitochondrial respiration in hypoxic cancer cells. Biomed Pharmacother 2020; 133:111082. [PMID: 33378978 DOI: 10.1016/j.biopha.2020.111082] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/18/2020] [Accepted: 11/28/2020] [Indexed: 12/28/2022] Open
Abstract
Hypoxia-inducible factor (HIF)-1 is an important regulator of the cellular response in the hypoxic tumor environment. While searching for HIF inhibitors derived from natural products that act as anticancer agents, we found that Glycyrrhiza uralensis exerts HIF-1 inhibitory activity in hypoxic cancer cells. Among the five components of G. uralensis, licochalcone A was found to potently suppress hypoxia-induced HIF-1α accumulation and expression of HIF-1α target genes, including GLUT1 and PDK1 in HCT116 cells. Licochalcone A also enhances intracellular oxygen content by directly inhibiting mitochondrial respiration, resulting in oxygen-dependent HIF-1α degradation. Hence, licochalcone A may effectively inhibit ATP production, primarily by reducing the mitochondrial respiration-mediated ATP production rate rather than the glycolysis-mediated ATP production rate. This effect subsequently suppresses cancer cell viability, including that of HCT116, H1299, and H322 cells. Consequently, these results suggest that licochalcone A has therapeutic potential in hypoxic cancer cells.
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Affiliation(s)
- Min Kyung Park
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, South Korea; Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Jun Ji
- Institute of Natural Medicine, Hallym University, Chuncheon, 24252, South Korea
| | - Keeok Haam
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Tae-Hee Han
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Seona Lim
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Mi-Jung Kang
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Soon Sung Lim
- Institute of Natural Medicine, Hallym University, Chuncheon, 24252, South Korea; Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252, South Korea.
| | - Hyun Seung Ban
- Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.
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Sonodynamic therapy-derived multimodal synergistic cancer therapy. Cancer Lett 2020; 497:229-242. [PMID: 33122099 DOI: 10.1016/j.canlet.2020.10.037] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 10/02/2020] [Accepted: 10/26/2020] [Indexed: 01/07/2023]
Abstract
Sonodynamic therapy (SDT) represents a promising modality that provides the possibility of non-invasively eliminating solid tumors in a site-directed manner. In light of the complexity and heterogeneity of tumors, more and more studies are attempting to combine SDT with other therapeutic methods so as to achieve better tumor treatment effect, which sheds new light on the potential of SDT-based synergistic therapeutics. Herein, the representative studies of SDT-instructed multimodal synergistic cancer therapy are comprehensively presented, such as sono-chemotherapy, sono-radiotherapy, sono-immunotherapy, and sono-chemodynamic therapy, etc., and their incorporate mechanisms are discussed in detail. The current challenges and future prospects to promote the advanced development of SDT-based nanomedicines in this burgeoning research field are highlighted. It is believed that such an emerging synergistic therapeutic modality based on SDT will play a more significant role in the field of tumor precision treatment medicine.
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Molecular mechanisms of interplay between autophagy and metabolism in cancer. Life Sci 2020; 259:118184. [PMID: 32763290 DOI: 10.1016/j.lfs.2020.118184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 07/26/2020] [Accepted: 07/28/2020] [Indexed: 12/19/2022]
Abstract
Autophagy is an essential mechanism of cellular degradation, a way to protect the cells under stress conditions, such as deprivation of nutrients, growth factors and cellular damage. However, in normal physiology autophagy plays a significant role in cancer cells. Current research is in progress to understand how autophagy and cancer cells go hand in hand to support cancer cell progression. The important aspect in cancer and autophagy is the interdependence of autophagy in the survival and progression of cancer cells. Autophagy is known to be a major cause of chemotherapeutic resistance in various cancer cell types. Therefore, inhibition of autophagy as an effective therapeutic approach is being actively studied and tested in clinical studies. Multiple metabolic pathways are linked with autophagy that could potentially be a significant target for chemotherapeutic strategy. The comprehension of the interconnection of autophagy with cancer metabolism can pave a novel findings for effective combinatorial therapeutic strategies.
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Comiran PK, Ribeiro MC, Silva JHG, Martins KO, Santos IA, Chiaradia AEF, Silva AZ, Dekker RFH, Barbosa-Dekker AM, Alegranci P, Queiroz EAIF. Botryosphaeran Attenuates Tumor Development and the Cancer Cachexia Syndrome in Walker-256 Tumor-Bearing Obese Rats and Improves the Metabolic and Hematological Profiles of These Rats. Nutr Cancer 2020; 73:1175-1192. [DOI: 10.1080/01635581.2020.1789681] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Patrícia K. Comiran
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Mariana C. Ribeiro
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - John H. G. Silva
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Kamila O. Martins
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Izabella A. Santos
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Ana Emilia F. Chiaradia
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Amadeu Z. Silva
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Robert F. H. Dekker
- Programa de Pós-Graduação em Engenharia Ambiental, Universidade Tecnológica Federal do Paraná, Londrina, PR, Brazil
| | | | - Pâmela Alegranci
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
| | - Eveline A. I. F. Queiroz
- Núcleo de Pesquisa e Apoio Didático em Saúde (NUPADS), Instituto de Ciências da Saúde, Câmpus Universitário de Sinop, Universidade Federal de Mato Grosso, Sinop, MT, Brazil
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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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Tayanloo-Beik A, Sarvari M, Payab M, Gilany K, Alavi-Moghadam S, Gholami M, Goodarzi P, Larijani B, Arjmand B. OMICS insights into cancer histology; Metabolomics and proteomics approach. Clin Biochem 2020; 84:13-20. [PMID: 32589887 DOI: 10.1016/j.clinbiochem.2020.06.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/01/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023]
Abstract
Metabolomics as a post-genomic research area comprising different analytical methods for small molecules analysis. One of the underlying applications of metabolomics technology for better disease diagnosis and prognosis is discovering the metabolic pathway differences between healthy individuals and patients. On the other hand, the other noteworthy applications of metabolomics include its effective role in biomarker screening for cancer detection, monitoring, and prediction. In other words, emerging of the metabolomics field can be hopeful to provide a suitable alternative for the common current cancer diagnostic methods especially histopathological tests. Indeed, cancer as a major global issue places a substantial burden on the health care system. Hence, proper management can be beneficial. In this respect, formalin-fixed paraffin-embedded tissue specimens (in histopathological tests) are considered as a valuable source for metabolomics investigations. Interestingly, formalin-fixed paraffin-embedded tissue specimens can provide informative data for cancer management. In general, using these specimens, determining the cancer stage, individual response to the different therapies, personalized risk prediction are possible and high-quality clinical services are the promise of OMICS technologies for cancer disease. However, considering all of these beneficial characteristics, there are still some limitations in this area that need to be addressed in order to optimize the metabolomics utilizations and advancement.
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Affiliation(s)
- Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Masoumeh Sarvari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Kambiz Gilany
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran; Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mahdi Gholami
- Department of Toxicology & Pharmacology, Faculty of Pharmacy; Toxicology and Poisoning Research Center, Tehran University of Medical Sciences, Tehran 1416753955, Iran.
| | - Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Raja G, Jang YK, Suh JS, Kim HS, Ahn SH, Kim TJ. Microcellular Environmental Regulation of Silver Nanoparticles in Cancer Therapy: A Critical Review. Cancers (Basel) 2020; 12:E664. [PMID: 32178476 PMCID: PMC7140117 DOI: 10.3390/cancers12030664] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 12/16/2022] Open
Abstract
Silver nanoparticles (AgNPs) play significant roles in various cancer cells such as functional heterogeneity, microenvironmental differences, and reversible changes in cell properties (e.g., chemotherapy). There is a lack of targets for processes involved in tumor cellular heterogeneity, such as metabolic clampdown, cytotoxicity, and genotoxicity, which hinders microenvironmental biology. Proteogenomics and chemical metabolomics are important tools that can be used to study proteins/genes and metabolites in cells, respectively. Chemical metabolomics have many advantages over genomics, transcriptomics, and proteomics in anticancer therapy. However, recent studies with AgNPs have revealed considerable genomic and proteomic changes, particularly in genes involved in tumor suppression, apoptosis, and oxidative stress. Metabolites interact biochemically with energy storage, neurotransmitters, and antioxidant defense systems. Mechanobiological studies of AgNPs in cancer metabolomics suggest that AgNPs may be promising tools that can be exploited to develop more robust and effective adaptive anticancer therapies. Herein, we present a proof-of-concept review for AgNPs-based proteogenomics and chemical metabolomics from various tumor cells with the help of several technologies, suggesting their promising use as drug carriers for cancer therapy.
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Affiliation(s)
- Ganesan Raja
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea;
| | - Yoon-Kwan Jang
- Integrated Biological Science, Pusan National University, Pusan 46241, Korea (S.H.A.)
| | - Jung-Soo Suh
- Integrated Biological Science, Pusan National University, Pusan 46241, Korea (S.H.A.)
| | - Heon-Su Kim
- Integrated Biological Science, Pusan National University, Pusan 46241, Korea (S.H.A.)
| | - Sang Hyun Ahn
- Integrated Biological Science, Pusan National University, Pusan 46241, Korea (S.H.A.)
| | - Tae-Jin Kim
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea;
- Integrated Biological Science, Pusan National University, Pusan 46241, Korea (S.H.A.)
- Institute of Systems Biology, Pusan National University, Pusan 46241, Korea
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