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Utpal BK, Bouenni H, Zehravi M, Sweilam SH, Mortuza MR, Arjun UVNV, Shanmugarajan TS, Mahesh PG, Roja P, Dodda RK, Thilagam E, Almahjari MS, Rab SO, Koula D, Emran TB. Exploring natural products as apoptosis modulators in cancers: insights into natural product-based therapeutic strategies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03876-8. [PMID: 40014131 DOI: 10.1007/s00210-025-03876-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/02/2025] [Indexed: 02/28/2025]
Abstract
Cancer remains a leading cause of mortality globally, necessitating ongoing research and development of innovative therapeutic strategies. Natural products from plants, herbs, and marine species have shown great promise as anti-cancer therapies due to their bioactive components that alter cellular pathways, particularly apoptosis. This review explores the mechanism by which natural chemicals trigger the apoptosis of cancerous cells, which is crucial for eliminating them and halting tumor growth. These can affect the mitochondrial process by controlling the Bcl-2 protein family, increasing cytochrome c release, and activating caspases. They also activate death receptors like Fas and TRAIL to enhance the extrinsic apoptotic pathway. We focus on the main signaling channels involved, such as the endoplasmic reticulum (ER) stress-mediated apoptosis, extrinsic death receptor, and intrinsic mitochondrial pathways. The review explores the role of natural substances such as polyphenols, terpenoids, alkaloids, and flavonoids in promoting apoptotic cell death and increasing cancer cell susceptibility, potentially aiding in cancer treatments and the potential of combining natural products with traditional chemotherapeutic medicines to combat medication resistance and enhance therapeutic efficacy. Understanding cancer development involves inhibiting cell proliferation, regulating it, targeting apoptosis pathways, and using plant and marine extracts as apoptotic inducers.
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Affiliation(s)
- Biswajit Kumar Utpal
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1216, Bangladesh.
| | - Hasna Bouenni
- Laboratory of Agrobiotechnology and Nutrition in Semi-Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, 51418, Buraydah, Saudi Arabia.
| | - Sherouk Hussein Sweilam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Egyptian Russian University, Cairo-Suez Road, Badr City, 11829, Cairo, Egypt
| | | | - Uppuluri Varuna Naga Venkata Arjun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Thukani Sathanantham Shanmugarajan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Ponnammal Ganesan Mahesh
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - Pathakota Roja
- Department of Pharmacology, Sree Dattha Institute of Pharmacy, Sheriguda, Ibrahimpatnam, Hyderabad, Telangana, 501510, India
| | - Ravi Kalyan Dodda
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, 600117, Tamil Nadu, India
| | - E Thilagam
- Department of Pharmacognosy, JKKMMRF'S-ANNAI JKK Sampooorani Ammal College of Pharmacy, Ethirmedu, Komarapalayam (Affiliated to The Tamil Nadu Dr. M.G.R. Medical University, Chennai), India
| | - Mohammed Saeed Almahjari
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Doukani Koula
- Laboratory of Agrobiotechnology and Nutrition in Semi-Arid Zones, Faculty of Nature and Life Sciences, University of Ibn Khaldoun, Tiaret, Algeria
- Laboratory of Animal Production Sciences and Techniques, University of Abdelhamid Ibn Badis, Mostaganem, Algeria
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Dhaka, 1216, Bangladesh
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Khurram I, Khan MU, Ibrahim S, Ghani MU, Amin I, Falzone L, Herrera-Bravo J, Setzer WN, Sharifi-Rad J, Calina D. Thapsigargin and its prodrug derivatives: exploring novel approaches for targeted cancer therapy through calcium signaling disruption. Med Oncol 2024; 42:7. [PMID: 39557802 DOI: 10.1007/s12032-024-02541-z] [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: 08/14/2024] [Accepted: 10/14/2024] [Indexed: 11/20/2024]
Abstract
Thapsigargin, a sesquiterpene lactone derived from Thapsia garganica L., has demonstrated mixed potential as an anticancer agent due to its potent ability to disrupt calcium signaling and induce apoptosis. This review evaluates the chemopreventive and chemotherapeutic potential of thapsigargin, focusing on its molecular mechanisms and toxicity. An extensive literature review of studies published since 2015 was conducted using databases such as PubMed/MedLine and Science Direct. Findings indicate that thapsigargin's primary mechanism is the inhibition of sarco/endoplasmic reticulum calcium ATPase, leading to endoplasmic reticulum stress and cell death in various cancer types. Despite these effects, thapsigargin's non-specific cytotoxicity results in significant side effects, including organ damage and histamine-related reactions. Recent advances in targeted delivery, especially with the prodrug mipsagargin, initially suggested promise in minimizing these toxicities by selectively activating in cancer cells expressing prostate-specific membrane antigen (PSMA). However, the completion of clinical trials with no ongoing studies suggests that the viability of mipsagargin and other prodrugs remains uncertain, especially in light of the toxicities observed. While thapsigargin and its derivatives present a potential pathway in cancer treatment, their future role in oncology requires careful re-evaluation.
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Affiliation(s)
- Iqra Khurram
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Umer Khan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
| | - Saooda Ibrahim
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Muhammad Usman Ghani
- Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Iram Amin
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Jesús Herrera-Bravo
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomas, Santiago, Chile.
| | - William N Setzer
- Aromatic Plant Research Center, 230 N 1200 E, Suite 102, Lehi, UT, 84043, USA
- Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL, 35899, USA
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, Ecuador.
- Centro de Estudios Tecnológicos y, Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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Cho S, McDonough E, Graf J, Shia J, Firat C, Urganci N, Surrette C, Lindner A, Salvucci M, Matveeva A, Kisakol B, O’Grady A, Azimi M, Burke JP, McNamara DA, McDade S, Longley DB, Prehn JHM, Ginty F. Integrated multiplex analysis of cell death regulators in stage II colorectal cancer suggests patients with 'persister' cell profiles fail to benefit from adjuvant chemotherapy. BMJ ONCOLOGY 2024; 3:e000362. [PMID: 39886119 PMCID: PMC11347685 DOI: 10.1136/bmjonc-2024-000362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 06/25/2024] [Indexed: 02/01/2025]
Abstract
Objective Inducing tumour cell apoptosis is a primary objective of chemotherapy but, to date, there are no validated biomarkers of apoptosis sensitivity or resistance. Our objective was to image multiple apoptosis pathway proteins at single cell level and determine multi-protein associations with recurrence risk and chemotherapy response in patients with stage II colorectal cancer (CRC). Methods and analysis Multiplexed imaging of 16 proteins in the intrinsic and extrinsic apoptosis pathways at single cell resolution on resected tissue from 194 patients with stage II CRC who either received adjuvant chemotherapy (n=108) or were treated with surgery only (n=86). K-means clustering of >600 000 cancer cells and cell level intensities of APAF1, procaspase-9, procaspase-3, XIAP, SMAC, BAX, BAK, BCL2, BCL-XL, MCL-1, procaspase-8, BID, FADD, FLIP, RIP3 and CIAP1 identified distinct cell cluster profiles. Results Chemotherapy-treated patients with a higher percentage of cell clusters with low procaspase-3 and high XIAP had a higher risk of recurrence. This was validated in an independent cohort of adjuvant chemotherapy-treated high-risk patients with stage II CRC. We also applied two established system models of apoptosis initiation and execution to estimate cellular apoptosis sensitivity and show that these cell clusters do not appear to have impaired mitochondrial outer membrane permeabilisation sensitivity, but downstream procaspase-3 cleavage is compromised. This represents a key characteristic of drug-tolerant 'persister' cells. Conclusion This study represents the most comprehensive analysis to date of apoptosis protein distribution at single cell level in CRC tumours. Our study identifies a subgroup of patients with stage II CRC with an apoptosis-resistant 'persister' cell profile who do not benefit from adjuvant chemotherapy.
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Affiliation(s)
- Sanghee Cho
- Technology & Innovation Center, GE HealthCare, Niskayuna, NY, USA
| | | | - John Graf
- Technology & Innovation Center, GE HealthCare, Niskayuna, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nil Urganci
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Andreas Lindner
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Manuela Salvucci
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Anna Matveeva
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Batuhan Kisakol
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Anthony O’Grady
- Department of Pathology, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland
| | - Mohammadreza Azimi
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
| | | | - Simon McDade
- Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Daniel B Longley
- Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast, UK
| | - Jochen HM Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Fiona Ginty
- Technology & Innovation Center, GE HealthCare, Niskayuna, NY, USA
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González A, Fullaondo A, Odriozola A. Microbiota-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:123-205. [PMID: 39396836 DOI: 10.1016/bs.adgen.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Vu A, Glassman I, Campbell G, Yeganyan S, Nguyen J, Shin A, Venketaraman V. Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection. Int J Mol Sci 2024; 25:6255. [PMID: 38892443 PMCID: PMC11172987 DOI: 10.3390/ijms25116255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.
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Affiliation(s)
| | | | | | | | | | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA (G.C.); (A.S.)
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Saadh MJ, Mohamed AH, Almoyad MAA, Allela OQB, Amin AH, Malquisto AA, Jin WT, Sârbu I, AlShamsi F, Elsaid FG, Akhavan-Sigari R. Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer. Cell Biochem Funct 2024; 42:e3962. [PMID: 38491792 DOI: 10.1002/cbf.3962] [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: 12/30/2023] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 03/18/2024]
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, Jordan
- Applied Science Research Center, Applied Science Private University, Amman, Jordan
| | - Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Babil, Hilla, Iraq
| | - Muhammad Ali Abdullah Almoyad
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Mushait, Saudi Arabia
| | | | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - April Ann Malquisto
- Abuyog Community College, Abuyog Leyte, Philippines
- ESL Science Teacher, Tacloban City, Tacloban, Philippines
- Department of Art Sciences and Education, Tacloban City, Philippines
| | - Wong Tze Jin
- Department of Science and Technology, Faculty of Humanities, Management and Science, Universiti Putra Malaysia Bintulu Campus, Sarawak, Malaysia
- Institute for Mathematical Research, Universiti Putra Malaysia, Selangor, Malaysia
| | - Ioan Sârbu
- 2nd Department of Surgery-Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, Romania
| | - Faisal AlShamsi
- Dubai Health Authority, Primary Health Care Department, Dubai, United Arab Emirates
| | - Fahmy Gad Elsaid
- Biology Department, College of Science, King Khalid University, Asir, Abha, Al-Faraa, Saudi Arabia
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Lim ES, Lee SE, Park MJ, Han DH, Lee HB, Ryu B, Kim EY, Park SP. Piperine improves the quality of porcine oocytes by reducing oxidative stress. Free Radic Biol Med 2024; 213:1-10. [PMID: 38159890 DOI: 10.1016/j.freeradbiomed.2023.12.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/08/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
Oxidative stress caused by light and high temperature arises during in vitro maturation (IVM), resulting in low-quality embryos compared with those obtained in vivo. To overcome this problem, we investigated the influence of piperine (PIP) treatment during maturation of porcine oocytes on subsequent embryo development in vitro. Porcine oocytes were cultured in IVM medium supplemented with 0, 50, 100, 200, or 400 μM PIP. After parthenogenetic activation, the blastocyst (BL) formation was significantly higher and the apoptosis rate was significantly lower using 200 μM PIP-treated oocytes (200 PIP). In the 200 PIP group, the level of reactive oxygen species at the metaphase II stage was decreased, accompanied by an increased level of glutathione and increased expression of antioxidant processes (Nrf2, CAT, HO-1, SOD1, and SOD2). Consistently, chromosome misalignment and aberrant spindle organization were alleviated and phosphorylated p44/42 mitogen-activated protein kinase activity was increased in the 200 PIP group. Expression of development-related (CDX2, NANOG, POU5F1, and SOX2), anti-apoptotic (BCL2L1 and BIRC5), and pro-apoptotic (BAK, FAS, and CASP3) processes was altered in the 200 PIP group. Ultimately, embryo development was improved in the 200 PIP group following somatic cell nuclear transfer. These findings suggest that PIP improves the quality of porcine oocytes by reducing oxidative stress, which inevitably arises via IVM. In-depth mechanistic studies of porcine oocytes will improve the efficiencies of assisted reproductive technologies.
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Affiliation(s)
- Eun-Seo Lim
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea
| | - Seung-Eun Lee
- Department of Bio Medical Informatics, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Cronex Co., 110 Hwangtalli-gil, Gangnae-myeon, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, 28174, South Korea
| | - Min-Jee Park
- Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea
| | - Dong-Hun Han
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea
| | - Han-Bi Lee
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea
| | - Bokyeong Ryu
- Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Department of Bio Medical Informatics, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea
| | - Eun-Young Kim
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Mirae Cell Bio, 1502 isbiz-tower 147, Seongsui-ro, Seongdong-gu, Seoul, 04795, South Korea
| | - Se-Pill Park
- Stem Cell Research Center, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Department of Bio Medical Informatics, College of Applied Life Sciences, Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju Special Self-Governing Province, 63243, South Korea; Mirae Cell Bio, 1502 isbiz-tower 147, Seongsui-ro, Seongdong-gu, Seoul, 04795, South Korea.
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Ratan Y, Rajput A, Pareek A, Pareek A, Jain V, Sonia S, Farooqui Z, Kaur R, Singh G. Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson's Disease. Biomolecules 2024; 14:73. [PMID: 38254673 PMCID: PMC10813470 DOI: 10.3390/biom14010073] [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: 11/21/2023] [Revised: 12/15/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative movement disorder worldwide, which is primarily characterized by motor impairments. Even though multiple hypotheses have been proposed over the decades that explain the pathogenesis of PD, presently, there are no cures or promising preventive therapies for PD. This could be attributed to the intricate pathophysiology of PD and the poorly understood molecular mechanism. To address these challenges comprehensively, a thorough disease model is imperative for a nuanced understanding of PD's underlying pathogenic mechanisms. This review offers a detailed analysis of the current state of knowledge regarding the molecular mechanisms underlying the pathogenesis of PD, with a particular emphasis on the roles played by gene-based factors in the disease's development and progression. This study includes an extensive discussion of the proteins and mutations of primary genes that are linked to PD, including α-synuclein, GBA1, LRRK2, VPS35, PINK1, DJ-1, and Parkin. Further, this review explores plausible mechanisms for DAergic neural loss, non-motor and non-dopaminergic pathologies, and the risk factors associated with PD. The present study will encourage the related research fields to understand better and analyze the current status of the biochemical mechanisms of PD, which might contribute to the design and development of efficacious and safe treatment strategies for PD in future endeavors.
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Affiliation(s)
- Yashumati Ratan
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aishwarya Rajput
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Ashutosh Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aaushi Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Vivek Jain
- Department of Pharmaceutical Sciences, Mohan Lal Sukhadia University, Udaipur 313001, Rajasthan, India;
| | - Sonia Sonia
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India;
| | - Zeba Farooqui
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA;
| | - Ranjeet Kaur
- Adesh Institute of Dental Sciences and Research, Bathinda 151101, Punjab, India;
| | - Gurjit Singh
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA;
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Coppola V, Marino I, Warnken U, Falchi M, Pasquini L, Biffoni M, De Maria R, Haas TL. The autophagic protein FYCO1 controls TNFRSF10/TRAIL receptor induced apoptosis and is inactivated by CASP8 (caspase 8). Autophagy 2023; 19:2733-2751. [PMID: 37418591 PMCID: PMC10472876 DOI: 10.1080/15548627.2023.2229656] [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: 05/13/2022] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/09/2023] Open
Abstract
Apoptosis is a tightly controlled cell death program executed by proteases, the so-called caspases. It plays an important role in tissue homeostasis and is often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end-directed transport of autophagic and endosomal vesicles as a molecular interaction partner of activated CASP8 (caspase 8). The absence of FYCO1 sensitized cells to basal and TNFSF10/TRAIL-induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC). Loss of FYCO1 resulted in impaired transport of TNFRSF10B/TRAIL-R2/DR5 (TNF receptor superfamily member 10b) to the lysosomes in TNFSF10/TRAIL-stimulated cells. More in detail, we show that FYCO1 interacted via its C-terminal GOLD domain with the CCZ1-MON1A complex, which is necessary for RAB7A activation and for the fusion of autophagosomal/endosomal vesicles with lysosomes. We demonstrated that FYCO1 is a novel and specific CASP8 substrate. The cleavage at aspartate 1306 resulted in the release of the C-terminal GOLD domain, inactivating FYCO1 function, and allowing for the progression of apoptosis. Furthermore, the lack of FYCO1 resulted in a stronger and prolonged formation of the TNFRSF1A/TNF-R1 signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a control mechanism that fine-tunes both apoptotic and inflammatory answers.Abbreviations: AP: affinity purification; CHX: cycloheximide; co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DISC: death-inducing signaling complex; DR: death receptors; doxy: doxycycline; GEF: guanine nucleotide exchange factor; ind: inducible; KD: knockdown; KO: knockout; MS: mass spectrometry; shRNA: short hairpin RNA; siRNA: small interfering RNA; TIP: two-step co-immunoprecipitation; WB: western blot.
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Affiliation(s)
- Valeria Coppola
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, RM, Italy
| | - Ilaria Marino
- Department of Translational Medicine and Surgery, Università Cattolica Del Sacro Cuore, Rome, RM, Italy
| | - Uwe Warnken
- Functional Proteomic Analysis, German Cancer Research Center (DKFZ), Heidelberg, BW, Germany
- Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, BW, Germany
| | | | - Luca Pasquini
- Servizio Tecnico Scientifico Grandi Strumentazioni E Core Facilities – FAST, Rome, RM, Italy
| | - Mauro Biffoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, RM, Italy
| | - Ruggero De Maria
- Department of Translational Medicine and Surgery, Università Cattolica Del Sacro Cuore, Rome, RM, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, RM, Italy
| | - Tobias Longin Haas
- Department of Translational Medicine and Surgery, Università Cattolica Del Sacro Cuore, Rome, RM, Italy
- Section of Immunotherapy, IIGM-Italian Institute for Genomic Medicine, Candiolo, TO, Italy
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10
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Haagsma J, Kolendowski B, Buensuceso A, Valdes YR, DiMattia GE, Shepherd TG. Gain-of-function p53 R175H blocks apoptosis in a precursor model of ovarian high-grade serous carcinoma. Sci Rep 2023; 13:11424. [PMID: 37452087 PMCID: PMC10349050 DOI: 10.1038/s41598-023-38609-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023] Open
Abstract
Ovarian high-grade serous carcinoma (HGSC) is a highly lethal malignancy for which early detection is a challenge and treatment of late-stage disease is ineffective. HGSC initiation involves exfoliation of fallopian tube epithelial (FTE) cells which form multicellular clusters called spheroids that colonize and invade the ovary. HGSC contains universal mutation of the tumour suppressor gene TP53. However, not all TP53 mutations are the same, as specific p53 missense mutants contain gain-of-function (GOF) properties that drive tumour formation. Additionally, the role of GOF p53 in spheroid-mediated spread is poorly understood. In this study, we developed and characterized an in vitro model of HGSC based on mutation of TP53 in mouse oviductal epithelial cells (OVE). We discovered increased bulk spheroid survival and increased anchorage-independent growth in OVE cells expressing the missense mutant p53R175H compared to OVE parental and Trp53ko cells. Transcriptomic analysis on spheroids identified decreased apoptosis signaling due to p53R175H. Further assessment of the apoptosis pathway demonstrated decreased expression of intrinsic and extrinsic apoptosis signaling molecules due to Trp53 deletion and p53R175H, but Caspase-3 activation was only decreased in spheroids with p53R175H. These results highlight this model as a useful tool for discovering early HGSC transformation mechanisms and uncover a potential anti-apoptosis GOF mechanism of p53R175H.
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Affiliation(s)
- Jacob Haagsma
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Bart Kolendowski
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
| | - Adrian Buensuceso
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Yudith Ramos Valdes
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
| | - Gabriel E DiMattia
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Trevor G Shepherd
- The Mary and John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada.
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
- Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
- London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada.
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11
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Richtig G, Kienzl M, Rittchen S, Roula D, Eberle J, Sarif Z, Pichler M, Hoefler G, Heinemann A. Cannabinoids Reduce Melanoma Cell Viability and Do Not Interfere with Commonly Used Targeted Therapy in Metastatic Melanoma In Vivo and In Vitro. BIOLOGY 2023; 12:biology12050706. [PMID: 37237519 DOI: 10.3390/biology12050706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/06/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023]
Abstract
Background: Cannabinoids are mainly used for recreational purposes, but also made their way into oncology, since these substances can be taken to increase appetite in tumour cachexia. Since there are some hints in the literature that cannabinoids might have some anti-cancerous effects, the aim of this study was to study if and how cannabinoids mediate pro-apoptotic effects in metastatic melanoma in vivo and in vitro and its value besides conventional targeted therapy in vivo. Methods: Several melanoma cell lines were treated with different concentrations of cannabinoids, and anti-cancerous efficacy was assessed by proliferation and apoptosis assays. Subsequent pathway analysis was performed using apoptosis, proliferation, flow cytometry and confocal microscopy data. The efficacy of cannabinoids in combination with trametinib was studied in NSG mice in vivo. Results: Cannabinoids reduced cell viability in multiple melanoma cell lines in a dose-dependent way. The effect was mediated by CB1, TRPV1 and PPARα receptors, whereby pharmacological blockade of all three receptors protected from cannabinoid-induced apoptosis. Cannabinoids initiated apoptosis by mitochondrial cytochrome c release with consecutive activation of different caspases. Essentially, cannabinoids significantly decreased tumour growth in vivo and were as potent as the MEK inhibitor trametinib. Conclusions: We could demonstrate that cannabinoids reduce cell viability in several melanoma cell lines, initiate apoptosis via the intrinsic apoptotic pathway by cytochrome c release and caspase activation and do not interfere with commonly used targeted therapy.
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Affiliation(s)
- Georg Richtig
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Melanie Kienzl
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
| | - Sonja Rittchen
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
| | - David Roula
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
| | - Jürgen Eberle
- Department of Dermatology, Venereology and Allergology, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin (University Medical Center Charité), 10117 Berlin, Germany
| | - Zina Sarif
- Department of Dermatology, Venereology and Allergology, Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin (University Medical Center Charité), 10117 Berlin, Germany
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Gerald Hoefler
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Akos Heinemann
- Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
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12
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Yang W, Chen Y, Su C, Chen M, Yeh C, Chen Y, Tsai M, Yang S, Lin C. Hispolon induces apoptosis in oral squamous cell carcinoma cells through
JNK
/
HO
‐1 pathway activation. J Cell Mol Med 2023; 27:1250-1260. [PMID: 36967712 PMCID: PMC10148051 DOI: 10.1111/jcmm.17729] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) has a high recurrence rate and poor prognosis. Hispolon, a polyphenolic compound with antiviral, antioxidant, and anticancer activities, is a potential chemotherapy agent. However, few studies have investigated the anti-cancer mechanism of hispolon in oral cancer. This present study used the cell viability assay, clonogenic assay, fluorescent nuclear staining, and flow cytometry assay to analyse the apoptosis-inducing effects of hispolon in OSCC cells. After hispolon treatment, the apoptotic initiators, cleaved caspase-3, -8, and - 9, were upregulated, whereas the cellular inhibitor of apoptosis protein-1 (cIAP1) was downregulated. Furthermore, a proteome profile analysis using a human apoptosis array revealed the overexpression of heme oxygenase-1 (HO-1) by hispolon, which was determined to be involved in caspase-dependent apoptosis. Moreover, cotreatment with hispolon and mitogen-activated protein kinase (MAPK) inhibitors revealed that hispolon induces apoptosis in OSCC cells through activation of the c-Jun N-terminal kinase (JNK) pathway and not the extracellular signal-regulated kinase (ERK) or p38 pathway. These findings indicate that hispolon may exert an anticancer effect on oral cancer cells by upregulating HO-1 and inducing caspase-dependent apoptosis by activating the JNK pathway.
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Affiliation(s)
- Wei‐En Yang
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
| | - Yi‐Tzu Chen
- School of DentistryChung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Chun‐Wen Su
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
| | - Mu‐Kuan Chen
- Department of Otorhinolaryngology‐Head and Neck Surgery, Changhua Christian HospitalChanghuaTaiwan
- Oral cancer Research Center, Changhua Christian HospitalChanghuaTaiwan
| | - Chia‐Ming Yeh
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
| | - Yen‐Lin Chen
- School of DentistryChung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Meng‐Ying Tsai
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
| | - Shun‐Fa Yang
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
| | - Chiao‐Wen Lin
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
- Institute of Oral Sciences, Chung Shan Medical UniversityTaichungTaiwan
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13
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Bruserud Ø, Mosevoll KA, Bruserud Ø, Reikvam H, Wendelbo Ø. The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients. Cells 2023; 12:cells12071003. [PMID: 37048076 PMCID: PMC10093057 DOI: 10.3390/cells12071003] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.
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Affiliation(s)
- Øystein Bruserud
- Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
- Correspondence:
| | - Knut Anders Mosevoll
- Section for Infectious Diseases, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
- Section for Infectious Diseases, Department of Clinical Research, University of Bergen, 5021 Bergen, Norway
| | - Øyvind Bruserud
- Department for Anesthesiology and Intensive Care, Haukeland University Hospital, 5021 Bergen, Norway
| | - Håkon Reikvam
- Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| | - Øystein Wendelbo
- Section for Infectious Diseases, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
- Faculty of Health, VID Specialized University, Ulriksdal 10, 5009 Bergen, Norway
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14
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Karami Fath M, Moayedi Banan Z, Barati R, Mohammadrezakhani O, Ghaderi A, Hatami A, Ghiabi S, Zeidi N, Asgari K, Payandeh Z, Barati G. Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 178:1-16. [PMID: 36781149 DOI: 10.1016/j.pbiomolbio.2023.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/24/2023] [Accepted: 02/10/2023] [Indexed: 02/13/2023]
Abstract
Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Moayedi Banan
- School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Barati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Omid Mohammadrezakhani
- Faculty of Pharmacy, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Aliasghar Ghaderi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hatami
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Zeidi
- Division of Pharmaceutical Science, Long Island University, Brooklyn, NY, USA
| | - Katayoon Asgari
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
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15
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Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia. Curr Issues Mol Biol 2023; 45:1536-1567. [PMID: 36826044 PMCID: PMC9954984 DOI: 10.3390/cimb45020099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum (syn. Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri. Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others.
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16
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Karlowitz R, van Wijk SJL. Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis. FEBS J 2023; 290:37-54. [PMID: 34710282 DOI: 10.1111/febs.16255] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/14/2021] [Accepted: 10/27/2021] [Indexed: 01/14/2023]
Abstract
Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL-mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post-translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well-explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site-specific ubiquitination of RIPK3 and MLKL regulates, fine-tunes and reverses the execution of necroptotic cell death.
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Affiliation(s)
- Rebekka Karlowitz
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany
| | - Sjoerd J L van Wijk
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Germany
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17
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Behrens LM, van Egmond M, van den Berg TK. Neutrophils as immune effector cells in antibody therapy in cancer. Immunol Rev 2022; 314:280-301. [PMID: 36331258 DOI: 10.1111/imr.13159] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Tumor-targeting monoclonal antibodies are available for a number of cancer cell types (over)expressing the corresponding tumor antigens. Such antibodies can limit tumor progression by different mechanisms, including direct growth inhibition and immune-mediated mechanisms, in particular complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity (ADCC). ADCC can be mediated by various types of immune cells, including neutrophils, the most abundant leukocyte in circulation. Neutrophils express a number of Fc receptors, including Fcγ- and Fcα-receptors, and can therefore kill tumor cells opsonized with either IgG or IgA antibodies. In recent years, important insights have been obtained with respect to the mechanism(s) by which neutrophils engage and kill antibody-opsonized cancer cells and these findings are reviewed here. In addition, we consider a number of additional ways in which neutrophils may affect cancer progression, in particular by regulating adaptive anti-cancer immunity.
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Affiliation(s)
- Leonie M. Behrens
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Vrije Universiteit Amsterdam HV Amsterdam The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology HV Amsterdam The Netherlands
- Amsterdam institute for Infection and Immunity, Cancer Immunology HV Amsterdam The Netherlands
| | - Marjolein van Egmond
- Department of Molecular Cell Biology and Immunology, Amsterdam UMC Vrije Universiteit Amsterdam HV Amsterdam The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology HV Amsterdam The Netherlands
- Amsterdam institute for Infection and Immunity, Cancer Immunology HV Amsterdam The Netherlands
- Department of Surgery, Amsterdam UMC Vrije Universiteit Amsterdam HV Amsterdam The Netherlands
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18
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Anticancer peptides mechanisms, simple and complex. Chem Biol Interact 2022; 368:110194. [PMID: 36195187 DOI: 10.1016/j.cbi.2022.110194] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/12/2022] [Accepted: 09/22/2022] [Indexed: 11/22/2022]
Abstract
Peptide therapy has started since 1920s with the advent of insulin application, and now it has emerged as a new approach in treatment of diseases including cancer. Using anti-cancer peptides (ACPs) is a promising way of cancer therapy as ACPs are continuing to be approved and arrived at major pharmaceutical markets. Traditional cancer treatments face different problems like intensive adverse effects to patient's body, cell resistance to conventional chemical drugs and in some worse cases the occurrence of cell multidrug resistance (MDR) of cancerous tissues against chemotherapy. On the other hand, there are some benefits conceived for peptides usage in treatment of diseases specifically cancer, as these compounds present favorable characteristics such as smaller size, high activity, low immunogenicity, good biocompatibility in vivo, convenient and rapid way of synthesis, amenable to sequence modification and revision and there is no limitation for the type of cargo they carry. It is possible to achieve an optimum molecular and functional structure of peptides based on previous experience and bank of peptide motif data which may result in novel peptide design. Bioactive peptides are able to form pores in cell membrane and induce necrosis or apoptosis of abnormal cells. Moreover, recent researches have focused on the tumor recognizing peptide motifs with the ability to permeate to cancerous cells with the aim of cancer treatment at earlier stages. In this strategy the most important factors for addressing cancer are choosing peptides with easy accessibility to tumor cell without cytotoxicity effect towards normal cells. The peptides must also meet acceptable pharmacokinetic requirements. In this review, the characteristics of peptides and cancer cells are discussed. The various mechanisms of peptides' action proposed against cancer cells make the next part of discussion. It will be followed by giving information on peptides application, various methods of peptide designing along with introducing various databases. Future aspects of peptides for employing in area of cancer treatment come as conclusion at the end.
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19
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Peltzer N, Annibaldi A. Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men. Biomedicines 2022; 10:biomedicines10061436. [PMID: 35740456 PMCID: PMC9219782 DOI: 10.3390/biomedicines10061436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant cell death can cause inflammation and inflammation-related diseases. While the link between cell death and inflammation has been widely established in mouse models, evidence supporting a role for cell death in the onset of inflammatory and autoimmune diseases in patients is still missing. In this review, we discuss how the lessons learnt from mouse models can help shed new light on the initiating or contributing events leading to immune-mediated disorders. In addition, we discuss how multiomic approaches can provide new insight on the soluble factors released by dying cells that might contribute to the development of such diseases.
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Affiliation(s)
- Nieves Peltzer
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Köln, Germany
- Department of Translational Genomics, University of Cologne, Weyertal 115b, 50931 Köln, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center, University of Cologne, Joseph-Steltzmann-Strasse 26, 50931 Köln, Germany
- Correspondence: (N.P.); (A.A.)
| | - Alessandro Annibaldi
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Köln, Germany
- Correspondence: (N.P.); (A.A.)
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20
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Xiong Y, He Q, Yu X, Li B, Song Z. The anti-ovarian carcinoma activity of L-amino acid oxidase from Crotalus adamanteus venom in vivo and in vitro. Med Oncol 2022; 39:112. [PMID: 35666342 DOI: 10.1007/s12032-022-01729-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022]
Abstract
Snake venom L-Amino-acid oxidase (svLAAO) has become a critical research target in molecular biology and medical science since its widespread presence and diverse biological roles, including antitumor application. Our research confirmed that Crotalus adamanteus (C. adamanteus) venom LAAO exhibited potential anti-ovarian cancer activity both in vivo and in vitro. C. adamanteus venom LAAO significantly reduced viability of ovarian cancer cells and caused morphological changes that preceded cell death. The results of molecular biology experiments showed that C. adamanteus venom LAAO caused expression changes of genes related to apoptotic pathways either intrinsically or extrinsically in ovarian cancer cells. Animal experiments and histological analysis also proved that C. adamanteus venom LAAO could effectively inhibit the tissue damage caused by ovarian cancer, and animals treated with C. adamanteus venom LAAO showed higher survival time. Catalase blocked the major apoptosis induction of C. adamanteus venom LAAO on ovarian cancer cells, suggesting that the cytotoxicity of C. adamanteus venom LAAO on ovarian cancer cells was mainly mediated by H2O2. These results infer that C. adamanteus venom LAAO will have some advantages in new drug research and antitumor drug development in future.
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Affiliation(s)
- Yan Xiong
- College of Life Science, Chongqing Normal University, Chongqing, 401331, China
| | - Qiyi He
- College of Life Science, Chongqing Normal University, Chongqing, 401331, China
| | - Xiaodong Yu
- College of Life Science, Chongqing Normal University, Chongqing, 401331, China
| | - Bo Li
- School of Education, Chongqing Normal University, Chongqing, 401331, China.
| | - Ziwei Song
- Chongqing Vocational College of Media, Chongqing, 400020, China
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21
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Van Doren SR. MMP-7 marks severe pancreatic cancer and alters tumor cell signaling by proteolytic release of ectodomains. Biochem Soc Trans 2022; 50:839-851. [PMID: 35343563 PMCID: PMC10443904 DOI: 10.1042/bst20210640] [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: 01/31/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 11/17/2022]
Abstract
Pancreatic cancer incurs the worst survival rate of the major cancers. High levels of the protease matrix metalloproteinase-7 (MMP-7) in circulation correlate with poor prognosis and limited survival of patients. MMP-7 is required for a key path of pancreatic tumorigenesis in mice and is present throughout tumor progression. Enhancements to chemotherapies are needed for increasing the number of pancreatic tumors that can be removed and for preventing relapses after surgery. With these ends in mind, selective inhibition of MMP-7 may be worth investigation. An anti-MMP-7 monoclonal antibody was recently shown to increase the susceptibility of several pancreatic cancer cell lines to chemotherapeutics, increase their apoptosis, and decrease their migration. MMP-7 activities are most apparent at the surfaces of innate immune, epithelial, and tumor cells. Proteolytic shedding of multiple protein ectodomains by MMP-7 from such cell surfaces influence apoptosis, proliferation, migration, and invasion. These activities warrant targeting of MMP-7 selectively in pancreatic cancer and other tumors of mucosal epithelia. Competitive and non-competitive modes of MMP-7 inhibition are discussed.
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Affiliation(s)
- Steven R. Van Doren
- Department of Biochemistry, University of Missouri, Columbia, MO 65211 USA
- Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211 USA
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22
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Immunogenic Cell Death, DAMPs and Prothymosin α as a Putative Anticancer Immune Response Biomarker. Cells 2022; 11:cells11091415. [PMID: 35563721 PMCID: PMC9102069 DOI: 10.3390/cells11091415] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 12/13/2022] Open
Abstract
The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100–109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100–109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100–109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation.
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23
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Agnihotri SK, Kumar B, Jain A, Anjali A, Negi MPS, Sachan R, Bhatt MLB, Tripathi RK, Sachdev M. Clinical Significance of Circulating Serum Levels of sCD95 and TNF-α in Cytoprotection of Cervical Cancer. Rep Biochem Mol Biol 2022; 10:711-721. [PMID: 35291617 PMCID: PMC8903371 DOI: 10.52547/rbmb.10.4.711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/01/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND This study correlates the serum levels of sCD95 & TNF-α with a simple cell-based assay to evaluate the capacity of the serum sample to induce apoptosis in Jurkat cells. Interlinking of these parameters can be explored to design a minimum invasive diagnostic strategy for cervical cancer (CC). METHODS Sera samples were assessed to induce apoptosis in Jurkat cells through FACS. Serum levels of sCD95 and TNF-α were measured by ELISA. JNK phosphorylation was evaluated in sera incubated Jurkat cells. Data was scrutinized through statistical analysis. RESULTS Significantly higher serum levels of sCD95 and lower TNF-α levels were observed in CC patients; their sera samples inhibited induction of apoptosis in Jurkat cells through reduced JNK phosphorylation. Statistical analysis linked these three parameters for the early screening of CC. CONCLUSION Distinct sera levels of sCD95 & TNF-α in CC patients showed an anti-apoptotic effect, which can be considered for early detection of CC.
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Affiliation(s)
- Saurabh Kumar Agnihotri
- Department of Radiotherapy, King George’s Medical University, Lucknow 226 003, India.
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
- The first and the second authors contributed equally to this work.
| | - Balawant Kumar
- Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
- The first and the second authors contributed equally to this work.
| | - Ankita Jain
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
| | - Anjali Anjali
- Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
- Department of Obstetrics & Gynaecology, King George’s Medical University, Lucknow 226 003, India.
| | - Mahendra Pal Singh Negi
- Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
| | - Rekha Sachan
- Department of Obstetrics & Gynaecology, King George’s Medical University, Lucknow 226 003, India.
| | | | - Raj Kamal Tripathi
- Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
- Department of Obstetrics & Gynaecology, King George’s Medical University, Lucknow 226 003, India.
| | - Monika Sachdev
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India.
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24
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Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy. Int J Mol Sci 2021; 22:ijms222212466. [PMID: 34830349 PMCID: PMC8618802 DOI: 10.3390/ijms222212466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023] Open
Abstract
Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.
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25
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Abstract
The multipotent mesenchymal stem/stromal cells (MSCs), initially discovered from bone marrow in 1976, have been identified in nearly all tissues of human body now. The multipotency of MSCs allows them to give rise to osteocytes, chondrocytes, adipocytes, and other lineages. Moreover, armed with the immunomodulation capacity and tumor-homing property, MSCs are of special relevance for cell-based therapies in the treatment of cancer. However, hampered by lack of knowledge about the controversial roles that MSC plays in the crosstalk with tumors, limited progress has been made with regard to translational medicine. Therefore, in this review, we discuss the prospects of MSC-associated anticancer strategies in light of therapeutic mechanisms and signal transduction pathways. In addition, the clinical trials designed to appraise the efficacy and safety of MSC-based anticancer therapies will be assessed according to published data.
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Affiliation(s)
- Tianxia Lan
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Min Luo
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
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26
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Tufano M, Cesaro E, Martinelli R, Pacelli R, Romano S, Romano MF. FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma. Front Cell Dev Biol 2021; 9:718947. [PMID: 34589486 PMCID: PMC8473884 DOI: 10.3389/fcell.2021.718947] [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: 06/01/2021] [Accepted: 08/02/2021] [Indexed: 12/03/2022] Open
Abstract
Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.
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Affiliation(s)
- Martina Tufano
- Dipartimento di Medicina Molecolaree Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Elena Cesaro
- Dipartimento di Medicina Molecolaree Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Rosanna Martinelli
- Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Salerno, Baronissi, Italy
| | - Roberto Pacelli
- Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Simona Romano
- Dipartimento di Medicina Molecolaree Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Maria Fiammetta Romano
- Dipartimento di Medicina Molecolaree Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy
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27
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Programmed cell death in aortic aneurysm and dissection: A potential therapeutic target. J Mol Cell Cardiol 2021; 163:67-80. [PMID: 34597613 DOI: 10.1016/j.yjmcc.2021.09.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/07/2021] [Accepted: 09/23/2021] [Indexed: 12/20/2022]
Abstract
Rupture of aortic aneurysm and dissection (AAD) remains a leading cause of death. Progressive smooth muscle cell (SMC) loss is a crucial feature of AAD that contributes to aortic dysfunction and degeneration, leading to aortic aneurysm, dissection, and, ultimately, rupture. Understanding the molecular mechanisms of SMC loss and identifying pathways that promote SMC death in AAD are critical for developing an effective pharmacologic therapy to prevent aortic destruction and disease progression. Cell death is controlled by programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Although these pathways share common stimuli and triggers, each type of programmed cell death has unique features and activation pathways. A growing body of evidence supports a critical role for programmed cell death in the pathogenesis of AAD, and inhibitors of various types of programmed cell death represent a promising therapeutic strategy. This review discusses the different types of programmed cell death pathways and their features, induction, contributions to AAD development, and therapeutic potential. We also highlight the clinical significance of programmed cell death for further studies.
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28
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Targeting Immune Modulators in Glioma While Avoiding Autoimmune Conditions. Cancers (Basel) 2021; 13:cancers13143524. [PMID: 34298735 PMCID: PMC8306848 DOI: 10.3390/cancers13143524] [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: 05/28/2021] [Revised: 07/02/2021] [Accepted: 07/10/2021] [Indexed: 02/06/2023] Open
Abstract
Communication signals and signaling pathways are often studied in different physiological systems. However, it has become abundantly clear that the immune system is not self-regulated, but functions in close association with the nervous system. The neural-immune interface is complex; its balance determines cancer progression, as well as autoimmune disorders. Immunotherapy remains a promising approach in the context of glioblastoma multiforme (GBM). The primary obstacle to finding effective therapies is the potent immunosuppression induced by GBM. Anti-inflammatory cytokines, induction of regulatory T cells, and the expression of immune checkpoint molecules are the key mediators for immunosuppression in the tumor microenvironment. Immune checkpoint molecules are ligand-receptor pairs that exert inhibitory or stimulatory effects on immune responses. In the past decade, they have been extensively studied in preclinical and clinical trials in diseases such as cancer or autoimmune diseases in which the immune system has failed to maintain homeostasis. In this review, we will discuss promising immune-modulatory targets that are in the focus of current clinical research in glioblastoma, but are also in the precarious position of potentially becoming starting points for the development of autoimmune diseases like multiple sclerosis.
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29
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Cheng YC, Chen PY, Way TDER, Cheng CL, Huang YP, Hsia TC, Chou YC, Peng SF. Pre-Treatment of Pterostilbene Enhances H 2O 2-induced Cell Apoptosis Through Caspase-dependent Pathway in Human Keratinocyte Cells. In Vivo 2021; 35:833-843. [PMID: 33622876 DOI: 10.21873/invivo.12324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/06/2020] [Accepted: 12/16/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Hydrogen peroxide (H2O2) is one of the reactive oxygen species (ROS), which can induce apoptotic cell death in numerous cancer cells. Pterostilbene (PTE), a natural polyphenolic compound, induces cell apoptosis in many human cancer cells. MATERIALS AND METHODS We investigated whether PTE could enhance H2O2-induced cell apoptosis in human keratinocyte HaCaT cells in vitro. The morphological change of HaCaT cells was observed and photographed under a contrast-phase microscope. The percentage of cell viability was measured by propidium iodide exclusion assay. Cell apoptosis was performed by Annexin V/PI double staining and assayed by flow cytometer. DNA condensation was measured by DAPI staining. The protein expression was determined by western blotting. ROS production-associated proteins were also assayed by confocal laser scanning microscopy. RESULTS PTE pre-treatment enhanced H2O2 (600 μM)-induced cell morphological changes and reduced the total cell number (cell viability). The decreased cell viability in HaCaT cells was through induction of apoptotic cell death, which was confirmed by Annexin V/PI double staining and DAPI staining. Western blotting studies indicated that HaCaT cells which were pre-treated with PTE (100 μM) and then co-treated with H2O2 (600 μM) for 12 h showed significantly increased levels of SOD (Cu/Zn), SOD (Mn), Bax, caspase-3, caspase-8, caspase-9, PARP, p53, p-p53, and p-H2A.X but decreased levels Bcl-2 and catalase. Results also showed that HaCaT cells pre-treated with PTE and then co-treated with H2O2 had increased expression of SOD (Cu/Zn) and glutathione but decreased catalase. CONCLUSION These observations suggest that PTE pre-treatment can enhance the H2O2-induced apoptotic cell death in keratinocyte cells and may be an effective candidate for the treatment of proliferative keratinocytes.
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Affiliation(s)
- Yi-Ching Cheng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - Po-Yuan Chen
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - Tzong-DER Way
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - Ching-Ling Cheng
- Program of Digital Health Innovation, China Medical University, Taichung, Taiwan, R.O.C
| | - Yi-Ping Huang
- Department of Physiology, College of Medicine, China Medical University, Taichung, Taiwan, R.O.C
| | - Te-Chun Hsia
- Department of Respiratory Therapy, China Medical University, Taichung, Taiwan, R.O.C.,Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Yu-Cheng Chou
- Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.; .,Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Shu-Fen Peng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C.; .,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
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30
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Dadgostar E, Tajiknia V, Shamsaki N, Naderi-Taheri M, Aschner M, Mirzaei H, Tamtaji OR. Aquaporin 4 and brain-related disorders: Insights into its apoptosis roles. EXCLI JOURNAL 2021; 20:983-994. [PMID: 34267610 PMCID: PMC8278210 DOI: 10.17179/excli2021-3735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/17/2021] [Indexed: 12/11/2022]
Abstract
Brain-related disorders are leading global health problems. Various internal and external factors are involved in the progression of brain-related disorders. Inflammatory pathways, oxidative stresses, apoptosis, and deregulations of various channels are critical players in brain-related disorder pathogenesis. Among these players, aquaporins (AQP) have critical roles in various physiological and pathological conditions. AQPs are water channel molecules that permit water to cross the hydrophobic lipid bilayers of cellular membranes. AQP4 is one of the important members of AQP family. AQPs are involved in controlling apoptosis pathways in brain-related disorders. In this regard, several reports have evaluated the pathological effects of AQP4 by targeting the apoptosis-related processes in brain-related disorders. Here, for the first time, we highlight the impact of AQP4 on apoptosis-related processes in brain-related disorders.
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Affiliation(s)
- Ehsan Dadgostar
- Department of Psychiatry, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Vida Tajiknia
- Department of Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Negar Shamsaki
- Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojtaba Naderi-Taheri
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Omid Reza Tamtaji
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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31
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El-Readi MZ, Al-Abd AM, Althubiti MA, Almaimani RA, Al-Amoodi HS, Ashour ML, Wink M, Eid SY. Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites. Front Pharmacol 2021; 12:658513. [PMID: 34093189 PMCID: PMC8176113 DOI: 10.3389/fphar.2021.658513] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/12/2021] [Indexed: 12/20/2022] Open
Abstract
Plant secondary metabolites (SMs) common natural occurrences and the significantly lower toxicities of many SM have led to the approaching development and use of these compounds as effective pharmaceutical agents; especially in cancer therapy. A combination of two or three of plant secondary metabolites together or of one SM with specific anticancer drugs, may synergistically decrease the doses needed, widen the chemotherapeutic window, mediate more effective cell growth inhibition, and avoid the side effects of high drug concentrations. In mixtures they can exert additive or even synergistic activities. Many SM can effectively increase the sensitivity of cancer cells to chemotherapy. In phytotherapy, secondary metabolites (SM) of medicinal plants can interact with single or multiple targets. The multi-molecular mechanisms of plant secondary metabolites to overcome multidrug resistance (MDR) are highlighted in this review. These mechanisms include interaction with membrane proteins such as P-glycoprotein (P-gp/MDR1); an ATP-binding cassette (ABC) transporter, nucleic acids (DNA, RNA), and induction of apoptosis. P-gp plays an important role in the development of MDR in cancer cells and is involved in potential chemotherapy failure. Therefore, the ingestion of dietary supplements, food or beverages containing secondary metabolites e.g., polyphenols or terpenoids may alter the bioavailability, therapeutic efficacy and safety of the drugs that are P-gp substrates.
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Affiliation(s)
- Mahmoud Zaki El-Readi
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.,Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Ahmed M Al-Abd
- Department of Pharmaceutical Sciences, College of Pharmacy & Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.,Pharmacology Department, Medical Division, National Research Centre, Cairo, Egypt
| | - Mohammad A Althubiti
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Riyad A Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Hiba Saeed Al-Amoodi
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohamed Lotfy Ashour
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia.,Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Michael Wink
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
| | - Safaa Yehia Eid
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
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32
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Renu K, Pureti LP, Vellingiri B, Valsala Gopalakrishnan A. Toxic effects and molecular mechanism of doxorubicin on different organs – an update. TOXIN REV 2021. [DOI: 10.1080/15569543.2021.1912099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Kaviyarasi Renu
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
| | - Lakshmi Prasanna Pureti
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, India
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33
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Al-Shun SA, El-Senduny FF, Ismail MA, El-Sayed WM, Badria FA, Youssef MM. Anticancer activity of new cationic arylthiophenes against hepatocellular carcinoma. Life Sci 2021; 269:119028. [PMID: 33444618 DOI: 10.1016/j.lfs.2021.119028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/25/2020] [Accepted: 12/31/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the second most common cancer-related death in the world. No effective curative option exists for the treatment of HCC. The available drugs exhibit severe toxic effects and low therapeutic index. AIM This work aimed to examine different monocationic arylthiophene derivatives for possible use as chemotherapeutic agents against HCC. METHODS The IC50 values for the compounds were determined. The mechanism of cytotoxicity was further investigated using different methods. RESULTS Compound 2j proved to retain the highest cytotoxicity in comparison to as a positive control. The selectivity index of compound 2j revealed the safety to normal cells. Moreover, compound 2j was able to inhibit HepG2 cells´ migration and division. The anticancer effect of compound 2j was found to be partially via cell cycle arrest, activation of the tumour suppressor p53 protein, and induction of apoptosis via both intrinsic and extrinsic pathways. Compound 2j has a potential sensitization activity and significantly reduced the IC50 values for the anticancer drugs doxorubicin, cisplatin, and taxol. CONCLUSION The tested arylthiophenes showed a potent cytotoxicity against HepG2 cells and were safe to normal cells. The most active compound 2j was found to be able to inhibit cell division and migration and also to induce apoptosis. Compound 2j also proved to have a sensitization effect on standard anticancer drugs.
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Affiliation(s)
- Sara A Al-Shun
- Division of Biochemistry, Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
| | - Fardous F El-Senduny
- Division of Biochemistry, Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
| | - Mohamed A Ismail
- Division of Organic Chemistry, Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
| | - Wael M El-Sayed
- Department of Zoology, Faculty of Science, Ain Shams University, Abbassia 11566, Cairo, Egypt.
| | - Farid A Badria
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
| | - Magdy M Youssef
- Division of Biochemistry, Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt.
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Sokkar HH, Abo Dena AS, Mahana NA, Badr A. Artichoke extracts in cancer therapy: do the extraction conditions affect the anticancer activity? FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2020. [DOI: 10.1186/s43094-020-00088-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Artichoke is an edible plant that is grown in the Mediterranean region and is known for its antimicrobial, antifungal, antibacterial, antioxidant and anticancer activities. Different artichoke extraction methods can impressively affect the nature as well as the yield of the extracted components.
Main body
The different methods of artichoke extraction and the influence of the extraction conditions on the extraction efficiency are summarized herein. In addition, cancer causalities and hallmarks together with the molecular mechanisms of artichoke active molecules in cancer treatment are also discussed. Moreover, a short background is given on the common types of cancer that can be treated with artichoke extracts as well as their pathogenesis. A brief discussion of the previous works devoted to the application of artichoke extracts in the treatment of these cancers is also given.
Conclusion
This review article covers the extraction methods, composition, utilization and applications of artichoke extracts in the treatment of different cancers.
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Jisha N, Vysakh A, Vijeesh V, Latha MS. Ethyl acetate fraction of Muntingia calabura L. exerts anti-colorectal cancer potential via regulating apoptotic and inflammatory pathways. JOURNAL OF ETHNOPHARMACOLOGY 2020; 261:113064. [PMID: 32505842 DOI: 10.1016/j.jep.2020.113064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 01/28/2020] [Accepted: 05/31/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Muntingia calabura L. is a plant with traditional pharmacological relevance. The various plant parts are used by tribal communities for treating gastric ulcers, prostate gland swellings, headache, cold etc. Hence, an attempt was made to evaluate the anti-colorectal cancer potential of ethyl acetate fraction of M. calabura (EFMC). MATERIALS AND METHODS HR LC-MS analysis was carried out for the identification of compounds present in EFMC. 1,2 Dimethylhydrazine (DMH) induced animal model was used for the evaluation of anti-CRC potential of EFMC. Antioxidant enzyme status, oxidative stress marker status, hepatic and renal function marker level were determined. Evaluation of mRNA level expression of inflammatory and apoptotic genes, hematological and histopathological examinations were also carried out to figure out the extent of colorectal cancer (CRC) and the beneficial role offered by EFMC. RESULTS HR LC-MS analysis of EFMC revealed the presence of ten pharmacologically active compounds. EFMC treatment made the altered levels of antioxidant enzymes, oxidative stress markers, liver and renal function markers to retain near to its normal range. The hematological and histopathological evaluations also confirmed the anti-CRC effects exhibited by EFMC. EFMC offered a regulatory control over the inflammatory and apoptotic genes thereby mitigating the damaging effects of CRC. CONCLUSION The present study depicted the presence of therapeutically active compounds exhibiting strong antioxidant, anti-inflammatory and anticancer potential. The beneficial role offered by these compounds could be responsible for the amelioration of DMH induced CRC. Hence, EFMC can be used as an anti-CRC agent in human subjects.
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Affiliation(s)
- Ninan Jisha
- School of Biosciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala, India
| | - A Vysakh
- School of Biosciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala, India
| | - V Vijeesh
- School of Biosciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala, India
| | - M S Latha
- School of Biosciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala, India.
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Cui J, Raychaudhuri S, Karlson EW, Speyer C, Malspeis S, Guan H, Sparks JA, Ni H, Liu X, Stevens E, Williams JN, Davenport EE, Knevel R, Costenbader KH. Interactions Between Genome-Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus. Arthritis Rheumatol 2020; 72:1863-1871. [PMID: 32969204 DOI: 10.1002/art.41414] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). METHODS For the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only. RESULTS The mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry. CONCLUSION The strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.
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Affiliation(s)
- Jing Cui
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Soumya Raychaudhuri
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Elizabeth W Karlson
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Cameron Speyer
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Susan Malspeis
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hongshu Guan
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jeffrey A Sparks
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hongru Ni
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Xinyi Liu
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Emma Stevens
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jessica N Williams
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Emma E Davenport
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rachel Knevel
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Leiden University Medical Center, Leiden, The Netherlands
| | - Karen H Costenbader
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Jiang Y, Wen T, Yan R, Kim SR, Stowell SR, Wang W, Wang Y, An G, Cummings RD, Ju T. O-glycans on death receptors in cells modulate their sensitivity to TRAIL-induced apoptosis through affecting on their stability and oligomerization. FASEB J 2020; 34:11786-11801. [PMID: 32692906 DOI: 10.1096/fj.201900053rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 01/14/2020] [Accepted: 06/19/2020] [Indexed: 11/11/2022]
Abstract
The TNF-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in cells by signaling through the O-glycosylated death receptors (DR4 and DR5), but the sensitivity to TRAIL-induced apoptosis of cells varies, and the attributes of this phenomenon are complex. Human carcinoma cells often express truncated O-glycans, Tn (GalNAcα1-Ser/Thr), and Sialyl-Tn (Siaα2-6GalNAcα1-Ser/Thr, STn) on their surface glycoproteins, yet molecular mechanisms in terms of advantages for tumor cells to have these truncated O-glycans remain elusive. Normal extended O-glycan biosynthesis is regulated by a specific molecular chaperone Cosmc through assisting of the correct folding of Core 1 β3 Galactosyltransferase (T-synthase). Here, we use tumor cell lines harboring mutations in Cosmc, and therefore expressing Tn and STn antigens to study the role of O-glycans in TRAIL-induced apoptosis. Expression of Tn and STn in tumor cells attenuates their sensitivity to TRAIL treatment; when transfected with wild-type Cosmc, these tumor cells thus express normal extended O-glycans and become more sensitive to TRAIL treatment. Mechanistically, Tn/STn antigens impair homo-oligomerization and stability of DR4 and DR5. These results represent the first mechanistic insight into how O-glycan structures on cell surface modulate their sensitivity to apoptotic stimuli, suggesting expression of Tn/STn may offer tumor cell survival advantages through altering DR4 and/or DR5 activity.
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Affiliation(s)
- Yuliang Jiang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Tao Wen
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Rui Yan
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Su-Ryun Kim
- Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
| | - Sean R Stowell
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Wenyi Wang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Yingchun Wang
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Guangyu An
- Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Richard D Cummings
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Tongzhong Ju
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.,Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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Fadaka AO, Bakare OO, Pretorius A, Klein A. Genomic profiling of microRNA target genes in colorectal cancer. Tumour Biol 2020; 42:1010428320933512. [PMID: 32552466 DOI: 10.1177/1010428320933512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer is the second and third most common cancer in men and women, respectively, worldwide. Alterations such as genetic and epigenetic are common in colorectal cancer and are the basis of tumor formation. The exploration of the molecular basis of colorectal cancer can drive a better understanding of the disease as well as guide the prognosis, therapeutics, and disease management. This study is aimed at investigating the genetic mutation profile of five candidate microRNAs (hsa-miR-513b-3p, hsa-miR-500b-3p, hsa-miR-500a-3p, hsa-miR-450b-3p, hsa-miR-193a-5p) targeted by seven genes (APC, KRAS, TCF7L2, EGFR, IGF1R, CASP8, and GNAS)) using in silico approaches. Two datasets (dataset 1 from our previous study and dataset two (The Cancer Genome Atlas, Nature 2012) were considered for this study. Protein-protein interaction, expression analysis, and genetic profiling were carried out using STRING, FireBrowse, and cBioPortal, respectively. Protein-protein interaction network showed that epidermal growth factor receptor has the highest connection among the target genes and this can be considered as the hub gene. Relative to other solid tumors, in colorectal cancer, six of the target genes were downregulated and only CASP8 was upregulated. Genes with protein tyrosine kinases domain were frequently altered in colorectal cancer and the most common alteration in these genes/domain are missense mutation. These results could serve as a lead in the identification of driver genes responsible for colorectal cancer initiation and progression. However, the intense mechanism of these results remains unclear and further experimental validation and molecular approaches are the focal points in the nearest future.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- Department of Science and Technology/Mintek Nanotechnology Innovation Centre, Biolabels Node, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa.,Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Olalekan Olanrewaju Bakare
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashley Pretorius
- Bioinformatics Research Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
| | - Ashwil Klein
- Plant Omics Group, Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Bellville, South Africa
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Hao L, Dong L, Yu Q, Shen W, Wei X. Edaravone inhibits procaspase-3 denitrosylation and activation through FasL-Trx2 pathway in KA-induced seizure. Fundam Clin Pharmacol 2020; 34:662-670. [PMID: 32215950 DOI: 10.1111/fcp.12556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 03/11/2020] [Accepted: 03/18/2020] [Indexed: 01/26/2023]
Abstract
Previous studies have demonstrated that excessive free radicals play an essential role in the initiation and progression of epilepsy and that a novel exogenous free radical scavenger edaravone (Ed) exerts some neuroprotective effects on seizure-induced neuronal damage. The purpose of this study was to elucidate the possible molecular mechanisms of Ed associated with procaspase-3 denitrosylation and activation through the FasL-Trx2 pathway in seizures rats. In this study, we investigated the effects of Ed on the regulation of the combination of Fas ligand/Fas receptor and the major components of the death-inducing signaling complex (DISC) in the hippocampus of kainic acid (KA)-treated Sprague Dawley (SD) rats. Treatment with Ed can attenuate the increased expression of FasL induced by KA and prevent procaspase-3 denitrosylation and activation via suppression of the FasL-Trx2 signaling pathway, which alleviates the neuronal damage in seizures. These results provide experimental evidence that Ed functions by preventing the denitrosylation and activation of procaspase-3 and that Ed acts as a therapeutic option for epilepsy.
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Affiliation(s)
- Lingyun Hao
- Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Jiangsu, 221002, China
| | - Ling Dong
- Department of Laboratory Medicine, Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Qiuxing Yu
- Faculty of Laboratory Medicine, The Second Clinical Medical College of Soochow University, Suzhou, Jiangsu, 215004, China
| | - Wen Shen
- Department of Pain Management, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
| | - Xuewen Wei
- Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Jiangsu, 221002, China.,Department of Laboratory Medicine, Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China
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Prasanna PL, Renu K, Valsala Gopalakrishnan A. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sci 2020; 250:117599. [PMID: 32234491 DOI: 10.1016/j.lfs.2020.117599] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/17/2020] [Accepted: 03/24/2020] [Indexed: 02/07/2023]
Abstract
Chemotherapeutic antibiotic doxorubicin belongs to the anthracycline class, slaughters not only the cancer cells but also non-cancerous cells even in the non-targeted organs thereby resulting in the toxicity. The liver is primarily involved in the process of detoxification and this mini-review we focused mainly to investigate the molecular mechanisms heading hepatotoxicity caused due to doxorubicin administration. The alterations in the doxorubicin treated liver tissue include vacuolation of hepatocytes, degeneration of hepatocyte cords, bile duct hyperplasia and focal necrosis. About the literature conducted, hepatotoxicity caused by doxorubicin has been explained by estimating the levels of liver serum biomarkers, ROS production, antioxidant enzymes, lipid peroxidation, and mitochondrial dysfunction. The liver serum biomarkers such as ALT and AST, elated levels of free radicals inducing oxidative stress characterized by a surge in Nrf-2, FOXO-1 and HO-1 genes and diminution of anti-oxidant activity characterized by a decline in SOD, GPx, and CAT genes. The augmented levels of SGOT, SGPT, LDH, creatine kinase, direct and total bilirubin levels also reveal the toxicity in the hepatic tissue due to doxorubicin treatment. The molecular insight of hepatotoxicity is mainly due to the production of ROS, ameliorated oxidative stress and inflammation, deteriorated mitochondrial production and functioning, and enhanced apoptosis. Certain substances such as extracts from medicinal plants, natural products, and chemical substances have been shown to produce an alleviating effect against the doxorubicin-induced hepatotoxicity are also discussed.
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Affiliation(s)
- Pureti Lakshmi Prasanna
- Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu 632014, India
| | - Kaviyarasi Renu
- Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu 632014, India
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Anggraeni TD, Rustamadji P, Aziz MF. Fas Ligand (FasL) in Association with Tumor-Infiltrating Lymphocytes (TILs) in Early Stage Cervical Cancer. Asian Pac J Cancer Prev 2020; 21:831-835. [PMID: 32212814 PMCID: PMC7437346 DOI: 10.31557/apjcp.2020.21.3.831] [Citation(s) in RCA: 5] [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: 05/16/2019] [Accepted: 11/10/2019] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE To date, little is known about the roles of FasL and TILs in cervical cancer. This study aims to determine the correlation between FasL expression and TILs presence in cervical cancer. METHODS In this study, we analysed the FasL and TIL presence in 32 squamous cell carcinoma or adenocarcinoma that were obtained from early stage (≤ IIA2) cervical cancer patients using immunohistochemistry. The level of FasL and TIL was assessed qualitatively, and then quantified with the H-Score system. RESULTS Most of the patients were between 30 to 50 years old (59,4%), and had never taken pap smear examination before (96,9%). Based on the Pearson analysis of FasL and TIL presence, we found that FasL was inversely correlated with CD45 or TIL number when the level of FasL is above 140 and the CD45 is below 160. Based on Chi-Square test of FasL and TIL classification, there was a nine-fold odds ratio (OR) of lower TILs classification in high expression of FasL classification (OR 9, p=0.01). CONCLUSION An inverse correlation between FasL expression and TILs level, that might indicate FasL-induced TILs apoptosis in tumor tissue, was observed. The strong inverse correlation between FasL and TILs presence showed some insight about the interactions between cancer cells and its surroundings inside of the cervical cancer tissue. This might also be further developed to tailor a prognostic marker that can predict the outcome of therapy in patients, not only in cervical cancer, but generally in all cancer.
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Affiliation(s)
| | - Primariadewi Rustamadji
- Department of Anatomic Pathology , Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Indonesia.
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Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts. Cells 2020; 9:cells9020411. [PMID: 32053892 PMCID: PMC7072292 DOI: 10.3390/cells9020411] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/04/2020] [Accepted: 02/07/2020] [Indexed: 12/20/2022] Open
Abstract
A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts' accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.
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Hseu YC, Cho HJ, Gowrisankar YV, Thiyagarajan V, Chen XZ, Lin KY, Huang HC, Yang HL. Kalantuboside B induced apoptosis and cytoprotective autophagy in human melanoma A2058 cells: An in vitro and in vivo study. Free Radic Biol Med 2019; 143:397-411. [PMID: 31442557 DOI: 10.1016/j.freeradbiomed.2019.08.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 08/17/2019] [Accepted: 08/17/2019] [Indexed: 12/28/2022]
Abstract
Kalantuboside B (KB), a natural bufadienolide derivative extracted from the succulent plant Kalanchoe tubiflora, is well-known for its cardiotonic, immunomodulatory, and anti-inflammatory properties. In this study, we tested in vitro and in vivo anti-cancer efficacy with low concentrations of KB (5-30 ng/mL; 8.7-52.2 nM) on A2058 melanoma cells; and for the molecular mechanisms that underlie them. KB significantly inhibited the cell viability and colony formation via arresting the cell cycle at G2/M phase. There was an association with a decrease in Cyclin A/B1, Cdc25C, and Cdc2 expressions. Further, this treatment indicated the induction of apoptosis, DNA fragmentation, cytochrome c release, and caspase-3, -8, -9, and -12 activation, and PARP cleavage, which shows that mitochondrial, death-receptor, and ER-stress signaling pathways are involved. KB-induced autophagy was apparent from enhanced LC3-II accumulation, GFP-LC3 puncta, and AVO formation. Surprisingly, KB-mediated cell death was potentiated by 3-MA and CQ to suggest the role of autophagy as a cytoprotective mechanism. Moreover, KB-treated A2058 cells enhanced intracellular ROS generation and antioxidant NAC prevented apoptosis and reversed cytoprotective autophagy. Interestingly, KB-induced apoptosis (PARP cleavage) and cytoprotective autophagy (LC3-II accumulation) were mediated by the up-regulation of the ERK signaling pathway. It was also shown that KB promoted cytoprotective autophagy by a calcium dependent-p53 downregulation pathway. In vivo data showed that KB suppressed tumor growth significantly in A2058-xenografted nude mice. A Western blot indicated cell-cycle inhibition (cyclin A reduction), apoptosis induction (PARP cleavage and Bcl-2 inhibition), and cytoprotective autophagy (LC3-II upregulation and p53 downregulation) in KB-treated A2058-xenografted mice. Our findings suggested that KB-induced ROS pathway plays a role in mediating the apoptosis and cytoprotective autophagy in human melanoma cells. Thus, KB is considered to be a putative anti-tumor agent.
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Affiliation(s)
- You-Cheng Hseu
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, 40402, Taiwan; Research Center of Chinese Herbal Medicine, China Medical University, Taichung, 40402, Taiwan
| | - Hsin-Ju Cho
- Institute of Nutrition, China Medical University, Taichung, 40402, Taiwan
| | - Yugandhar Vudhya Gowrisankar
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Varadharajan Thiyagarajan
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Xuan-Zao Chen
- Department of Cosmeceutics, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Kai-Yuan Lin
- Department of Medical Research, Chi-Mei Medical Center, Tainan, 71004, Taiwan
| | - Hui-Chi Huang
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
| | - Hsin-Ling Yang
- Institute of Nutrition, China Medical University, Taichung, 40402, Taiwan.
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Zhong HH, Wang HY, Li J, Huang YZ. TRAIL-based gene delivery and therapeutic strategies. Acta Pharmacol Sin 2019; 40:1373-1385. [PMID: 31444476 PMCID: PMC6889127 DOI: 10.1038/s41401-019-0287-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022]
Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), also known as APO2L, belongs to the tumor necrosis factor family. By binding to the death receptor 4 (DR4) or DR5, TRAIL induces apoptosis of tumor cells without causing side toxicity in normal tissues. In recent years TRAIL-based therapy has attracted great attention for its promise of serving as a cancer drug candidate. However, the treatment efficacy of TRAIL protein was under expectation in the clinical trials because of the short half-life and the resistance of cancer cells. TRAIL gene transfection can produce a "bystander effect" of tumor cell killing and provide a potential solution to TRAIL-based cancer therapy. In this review we focus on TRAIL gene therapy and various design strategies of TRAIL DNA delivery including non-viral vectors and cell-based TRAIL therapy. In order to sensitize the tumor cells to TRAIL-induced apoptosis, combination therapy of TRAIL DNA with other drugs by the codelivery methods for yielding a synergistic antitumor efficacy is summarized. The opportunities and challenges of TRAIL-based gene delivery and therapy are discussed.
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Affiliation(s)
- Hui-Hai Zhong
- Shanghai University College of Sciences, Shanghai, 200444, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hui-Yuan Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jian Li
- Shanghai University College of Sciences, Shanghai, 200444, China
| | - Yong-Zhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
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Choo Z, Loh AHP, Chen ZX. Destined to Die: Apoptosis and Pediatric Cancers. Cancers (Basel) 2019; 11:cancers11111623. [PMID: 31652776 PMCID: PMC6893512 DOI: 10.3390/cancers11111623] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 01/10/2023] Open
Abstract
Apoptosis (programmed cell death) is a systematic and coordinated cellular process that occurs in physiological and pathophysiological conditions. Sidestepping or resisting apoptosis is a distinct characteristic of human cancers including childhood malignancies. This review dissects the apoptosis pathways implicated in pediatric tumors. Understanding these pathways not only unraveled key molecules that may serve as potential targets for drug discovery, but also molecular nodes that integrate with other signaling networks involved in processes such as development. This review presents current knowledge of the complex regulatory system that governs apoptosis with respect to other processes in pediatric cancers, so that fresh insights may be derived regarding treatment resistance or for more effective treatment options.
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Affiliation(s)
- Zhang'e Choo
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
| | - Amos Hong Pheng Loh
- VIVA-KKH Pediatric Brain and Solid Tumor Program, KK Women's and Children's Hospital, Singapore 229899, Singapore.
- Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore 229899, Singapore.
| | - Zhi Xiong Chen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
- VIVA-KKH Pediatric Brain and Solid Tumor Program, KK Women's and Children's Hospital, Singapore 229899, Singapore.
- National University Cancer Institute, Singapore, Singapore 119074, Singapore.
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46
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Reddy GP, Reddy LV, Kim S. CANCER BIOLOGY AND PATHOLOGY. Cancer 2019. [DOI: 10.1002/9781119645214.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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47
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Javan MR, Khosrojerdi A, Moazzeni SM. New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment. Front Oncol 2019; 9:840. [PMID: 31555593 PMCID: PMC6722482 DOI: 10.3389/fonc.2019.00840] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment interacts with tumor cells, establishing an atmosphere to contribute or suppress the tumor development. Among the cells which play a role in the tumor microenvironment, mesenchymal stem cells (MSCs) have been demonstrated to possess the ability to orchestrate the fate of tumor cells, drawing the attention to the field. MSCs have been considered as cells with double-bladed effects, implicating either tumorigenic or anti-tumor activity. On the other side, the promising potential of MSCs in treating human cancer cells has been observed from the clinical studies. Among the beneficial characteristics of MSCs is the natural tumor-trophic migration ability, providing facility for drug delivery and, therefore, targeted treatment to detach tumor and metastatic cells. Moreover, these cells have been the target of engineering approaches, due to their easily implemented traits, in order to obtain the desired expression of anti-angiogenic, anti-proliferative, and pro-apoptotic properties, according to the tumor type. Tumor angiogenesis is the key characteristic of tumor progression and metastasis. Manipulation of angiogenesis has become an attractive approach for cancer therapy since the introduction of the first angiogenesis inhibitor, namely bevacizumab, for metastatic colorectal cancer therapy. This review tries to conclude the approaches, with focus on anti-angiogenesis approach, in implementing the MSCs to combat against tumor cell progression.
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Affiliation(s)
- Mohammad Reza Javan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Moazzeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Amiri S, Dastghaib S, Ahmadi M, Mehrbod P, Khadem F, Behrouj H, Aghanoori MR, Machaj F, Ghamsari M, Rosik J, Hudecki A, Afkhami A, Hashemi M, Los MJ, Mokarram P, Madrakian T, Ghavami S. Betulin and its derivatives as novel compounds with different pharmacological effects. Biotechnol Adv 2019; 38:107409. [PMID: 31220568 DOI: 10.1016/j.biotechadv.2019.06.008] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 05/30/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023]
Abstract
Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.
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Affiliation(s)
- Shayan Amiri
- Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Sanaz Dastghaib
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Parvaneh Mehrbod
- Influenza and Respiratory Viruses Department, Pasteur Institute of IRAN, Tehran, Iran
| | - Forough Khadem
- Department of Immunology, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Hamid Behrouj
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad-Reza Aghanoori
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - Filip Machaj
- Department of Pathology, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-344 Szczecin, Poland
| | - Mahdi Ghamsari
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Jakub Rosik
- Department of Pathology, Pomeranian Medical University, ul. Unii Lubelskiej 1, 71-344 Szczecin, Poland
| | - Andrzej Hudecki
- Institue of Non-Ferrous Metals, ul. Sowińskiego 5, 44-100 Gliwice, Poland
| | - Abbas Afkhami
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Marek J Los
- Biotechnology Center, Silesian University of Technology, ul Bolesława Krzywoustego 8, Gliwice, Poland; Linkocare Life Sciences AB, Teknikringen 10, Plan 3, 583 30 Linköping, Sweden
| | - Pooneh Mokarram
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
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Conserva MR, Anelli L, Zagaria A, Specchia G, Albano F. The Pleiotropic Role of Retinoic Acid/Retinoic Acid Receptors Signaling: From Vitamin A Metabolism to Gene Rearrangements in Acute Promyelocytic Leukemia. Int J Mol Sci 2019; 20:ijms20122921. [PMID: 31207999 PMCID: PMC6627493 DOI: 10.3390/ijms20122921] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/07/2019] [Accepted: 06/13/2019] [Indexed: 12/18/2022] Open
Abstract
The family of retinoic acid receptors (RARs: RARα, -β, and -γ) has remarkable pleiotropy characteristics, since the retinoic acid/RARs pathway is involved in numerous biological processes not only during embryonic development, but also in the postnatal phase and during adulthood. In this review, we trace the roles of RA/RARs signaling in the immune system (where this pathway has both an immunosuppressive role or is involved in the inflammatory response), in hematopoiesis (enhancing hematopoietic stem cell self-renewal, progenitor cells differentiation or maintaining the bone marrow microenvironment homeostasis), and in bone remodeling (where this pathway seems to have controversial effects on bone formation or osteoclast activation). Moreover, in this review is shown the involvement of RAR genes in multiple chromosomal rearrangements generating different fusion genes in hematological neoplasms, with a particular focus on acute promyelocytic leukemia and its variant subtypes. The effect of different RARs fusion proteins on leukemic transformation, on patients’ outcome, and on therapy response is also discussed.
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Affiliation(s)
- Maria Rosa Conserva
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Giorgina Specchia
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy.
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Antitumor activity of methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide against leukemia cell lines via mitotic arrest and apoptotic pathways. Biochim Biophys Acta Gen Subj 2019; 1863:1332-1342. [PMID: 31170497 DOI: 10.1016/j.bbagen.2019.05.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 01/07/2023]
Abstract
In a previous study, we described a series of 28 aryl- and alkyl-substituted isothiouronium salts with antitumor activity and selectivity toward a leukemia cell line. Among the synthesized compounds, methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide (IS-MF08) showed conspicuous activity. In the present study, we investigated the mechanism of action of IS-MF08. Our results showed that its mechanism most likely is related with the membrane receptor Fas and subsequent activation of the extrinsic cell death pathway, triggered by a decrease in the levels of the anti-apoptotic protein Bcl-2 and caspase-8 and -3 cascade activation, causing DNA damage and mitotic arrest. IS-MF08 also caused an increase in intracellular ROS, endoplasmic reticulum (ER) stress, and mitochondrial membrane permeabilization, resulting in organelle degradation as an attempt to reestablish cell homeostasis. Furthermore, cells exposed to IS-MF08 combined to an autophagy inhibitor were less susceptible to compound's cytotoxicity, suggesting that autophagy makes part of its mechanism of action. These data support the hypothesis that IS-MF08 acts by the apoptosis extrinsic pathway and possibly by autophagy as mechanisms of cell death.
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