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Alexandru I, Nistor D, Motofelea AC, Cadar (Andone) BA, Crintea A, Tatu C, Pop GN, Csep AN. Vitamins, Coenzyme Q10, and Antioxidant Strategies to Improve Oocyte Quality in Women with Gynecological Cancers: A Comprehensive Review. Antioxidants (Basel) 2024; 13:1567. [PMID: 39765895 PMCID: PMC11672914 DOI: 10.3390/antiox13121567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/07/2024] [Accepted: 12/12/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Gynecological cancers, including ovarian, cervical, and endometrial cancers, significantly affect both survival and reproductive health in women. Cancer treatments such as chemotherapy and radiotherapy can impair ovarian function, reducing oocyte quality and fertility potential. OBJECTIVE This review aims to evaluate how vitamins and antioxidants can enhance fertility and fertility preservation outcomes for women diagnosed with gynecological cancers, particularly in the context of assisted reproductive technologies (ART). Standard treatments for these cancers, including hysterectomy, bilateral salpingo-oophorectomy, radiation, and chemotherapy, often compromise ovarian function and oocyte quality. This review focuses on the potential role of these interventions in improving oocyte quality, thereby supporting successful fertility preservation and ART outcomes. METHODS A comprehensive narrative review of the current literature was conducted, examining the effects of vitamins A, C, D3, E, and Coenzyme Q10 on oocyte quality, particularly in the context of oxidative stress and inflammation induced by cancer and its treatments. RESULTS The evidence suggests that certain vitamins and antioxidants may mitigate oxidative damage and enhance oocyte quality. Vitamin A supports cumulus-oocyte complex integrity, while vitamins C and E act as potent antioxidants, reducing oxidative stress in ovarian tissues. Vitamin D3 enhances ovarian reserve markers and modulates inflammatory cytokines. Coenzyme Q10 improves mitochondrial function and reduces DNA damage, increasing oocyte viability and fertilization potential. CONCLUSIONS The incorporation of specific vitamins and antioxidants into fertility preservation strategies may enhance oocyte quality in women with gynecological cancers. Although the preliminary findings are promising, further research is needed to determine optimal dosages and establish standardized protocols for clinical use.
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Affiliation(s)
- Isaic Alexandru
- Department of General Surgery, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania;
| | - Daciana Nistor
- Department of Functional Sciences, Physiology, Centre of Imuno-Physiology and Biotechnologies (CIFBIOTEH), “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Centre for Gene and Cellular Therapies in Cancer, 3000723 Timisoara, Romania
| | - Alexandru Catalin Motofelea
- Center for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Bianca-Astrid Cadar (Andone)
- Interdisciplinary Research Institute in Bio-Nano-Sciences, Babes-Bolyai University, 42 T. Laurian Str., 400271 Cluj-Napoca, Romania;
- Faculty of Physics, Babes-Bolyai University, 1 M. Kogalniceanu Str., 400084 Cluj-Napoca, Romania
| | - Andreea Crintea
- Department of Molecular Sciences, University of Medicine and Pharmacy “Iuliu Hațieganu”, 400349 Cluj-Napoca, Romania;
| | - Carmen Tatu
- Department of Functional Sciences, Physiology, Centre of Imuno-Physiology and Biotechnologies (CIFBIOTEH), “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Centre for Gene and Cellular Therapies in Cancer, 3000723 Timisoara, Romania
| | - Gheorghe Nicusor Pop
- Center for Modeling Biological Systems and Data Analysis (CMSBAD), “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Andrei Nicolae Csep
- Department of Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania;
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Jiang Q, Liao J, Tan J, Hu H. Comparison of minimal access and open breast surgery: a propensity score-matched study on postoperative immune function in breast cancer. World J Surg Oncol 2024; 22:183. [PMID: 39010087 PMCID: PMC11251114 DOI: 10.1186/s12957-024-03447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 06/16/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Minimal access breast surgery (MABS) is commonly employed in the management of breast cancer, but there is limited research on the postoperative immune function associated with MABS. OBJECTIVE This study aimed to assess the postoperative immune function in breast patients who underwent MABS or conventional open breast surgery (COBS). METHODS We retrospectively analyzed the medical records of 829 breast cancer patients treated with either MABS or COBS at a single hospital between January 2020 and June 2023. Among them, 116 matched pairs were obtained through 1:1 propensity score matching (PSM). Flow cytometry was used to measure the percentages of CD3+, CD4+, and CD8+ cells, as well as the CD4+/CD8+ ratio, on three different time points: preoperative day 1 (PreD1), postoperative day 1 (PostD1), and postoperative day 7 (PostD7). RESULTS Both the MABS and COBS groups demonstrated a significant reduction in the percentages of CD3+, CD4+, and CD8+ cells, along with the CD4+/CD8+ ratio, from PreD1 to PostD1. Interestingly, the MABS group showed a reversal of these parameters, returning to preoperative levels by PostD7. Conversely, the COBS group showed an increase in these parameters from PostD1 to PostD7, but they still remained significantly lower than preoperative levels at PostD7. CONCLUSION MABS treatment may result in reduced postoperative immune suppression and faster recovery of preoperative immune function compared to COBS in patients.
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Affiliation(s)
- QiHua Jiang
- Department of Breast Surgery, Third Hospital of Nanchang, No. 2, Xiangshan South Road, Xi hu District, Nanchang City, Jiangxi Province, China
| | - Jing Liao
- Department of Breast Surgery, Third Hospital of Nanchang, No. 2, Xiangshan South Road, Xi hu District, Nanchang City, Jiangxi Province, China
| | - JunTao Tan
- Department of Breast Surgery, Third Hospital of Nanchang, No. 2, Xiangshan South Road, Xi hu District, Nanchang City, Jiangxi Province, China
- Jiangxi Province Key Laboratory of Breast Diseases, Third Hospital of Nanchang, No. 1268, Jiuzhou Street, Chaoyang New Town, Xihu District, Nanchang City, Jiangxi Province, China
| | - Hai Hu
- Department of Breast Surgery, Third Hospital of Nanchang, No. 2, Xiangshan South Road, Xi hu District, Nanchang City, Jiangxi Province, China.
- Department of General Surgery, Third Hospital of Nanchang, No. 2, Xiangshan South Road, Xi hu District, Nanchang City, Jiangxi Province, China.
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Rizk MA, El-Sayed SAES, Igarashi I. Ascorbic acid co-administration with a low dose of diminazene aceturate inhibits the in vitro growth of Theileria equi, and the in vivo growth of Babesia microti. Parasitol Int 2022; 90:102596. [DOI: 10.1016/j.parint.2022.102596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/12/2022] [Accepted: 05/03/2022] [Indexed: 10/18/2022]
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Rizk MA, El-Sayed SAES, Salman D, Marghani BH, Gadalla HE, Sayed-Ahmed MZ. Immunomodulatory Effect of Vitamin C on Proinflammatory Cytokines Production in Ossimi Lambs (Ovis aries) with Pneumonic Pasteurellosis. Animals (Basel) 2021; 11:ani11123374. [PMID: 34944151 PMCID: PMC8697947 DOI: 10.3390/ani11123374] [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: 10/22/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 11/16/2022] Open
Abstract
In this study, we have investigated the impact of vitamin C on the production of pro-inflammatory cytokines (interleukin 1 β (IL-1 β), interleukin 6 (IL-6), interleukin 12p40 (IL-12p40), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNF-α)) in lambs naturally infected by pneumonic pasteurellosis. Of 37 lambs, 18 lambs were identified to have pneumonic pasteurellosis and randomly allocated into two equal groups. Single subcutaneous dose of tulathromycine alone (2.5 mg kg−1) or tulathromycine combined with vitamin C (3 gm kg−1) were administrated to the diseased lambs. The serum levels of IL-1β, IL-6, IFN-γ, and TNF-α were returned to the normal levels in pneumonic lambs treated with the combination therapy. The obtained results indicate the selective influences of vitamin C on pro-inflammatory cytokines production in sera of lambs with pneumonic pasteurellosis and highlights the value of vitamin C as a potential anti-inflammatory drug and ideal immunomodulatory agent.
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Affiliation(s)
- Mohamed Abdo Rizk
- Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt;
- Correspondence:
| | - Shimaa Abd El-Salam El-Sayed
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt;
| | - Doaa Salman
- Department of Animal Medicine, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt;
| | - Basma H. Marghani
- Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt;
| | - Hossam Elshahat Gadalla
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt;
| | - Mohamed Z. Sayed-Ahmed
- Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt;
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jizan 82722, Saudi Arabia
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Ozmen HK, Erdemci B, Askin S, Sezen O. Carnitine and Adiponectin Levels in Breast Cancer after Radiotherapy. Open Med (Wars) 2017; 12:189-194. [PMID: 28730178 PMCID: PMC5506391 DOI: 10.1515/med-2017-0028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 04/28/2017] [Indexed: 01/04/2023] Open
Abstract
In this study, serum carnitine (CRNT) and adiponectin (APN) levels and the correlation of these parameters in patients with breast cancer before and after treatment with radiotherapy (RT) were determined.
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Affiliation(s)
- Hilal Kiziltunc Ozmen
- Departments of Radiation Oncology, Ataturk University School of Medicine, 25240, Erzurum, Turkey
| | - Burak Erdemci
- Departments of Radiation Oncology, Ataturk University School of Medicine, 25240, Erzurum, Turkey
| | - Seda Askin
- Departments of Medical Biochemistry, Ataturk University School of Medicine, Erzurum, Turkey
| | - Orhan Sezen
- Departments of Radiation Oncology, Ataturk University School of Medicine, 25240, Erzurum, Turkey
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Aly HAA, Mansour AM, Hassan MH, Abd-Ellah MF. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats. ENVIRONMENTAL TOXICOLOGY 2016; 31:913-922. [PMID: 25533183 DOI: 10.1002/tox.22101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 12/05/2014] [Accepted: 12/07/2014] [Indexed: 06/04/2023]
Abstract
The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016.
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Affiliation(s)
- Hamdy A A Aly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed M Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
| | - Memy H Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, El-Madinah El-Munaworah, Saudi Arabia
| | - Mohamed F Abd-Ellah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
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Hosseinimehr SJ. The protective effects of trace elements against side effects induced by ionizing radiation. Radiat Oncol J 2015; 33:66-74. [PMID: 26157675 PMCID: PMC4493430 DOI: 10.3857/roj.2015.33.2.66] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 06/18/2015] [Accepted: 06/22/2015] [Indexed: 12/14/2022] Open
Abstract
Trace elements play crucial role in the maintenance of genome stability in the cells. Many endogenous defense enzymes are containing trace elements such as superoxide dismutase and metalloproteins. These enzymes are contributing in the detoxification of reactive oxidative species (ROS) induced by ionizing radiation in the cells. Zinc, copper, manganese, and selenium are main trace elements that have protective roles against radiation-induced DNA damages. Trace elements in the free salt forms have protective effect against cell toxicity induced by oxidative stress, metal-complex are more active in the attenuation of ROS particularly through superoxide dismutase mimetic activity. Manganese-complexes in protection of normal cell against radiation without any protective effect on cancer cells are more interesting compounds in this topic. The aim of this paper to review the role of trace elements in protection cells against genotoxicity and side effects induced by ionizing radiation.
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Affiliation(s)
- Seyed Jalal Hosseinimehr
- Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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Couch ME, Dittus K, Toth MJ, Willis MS, Guttridge DC, George JR, Chang EY, Gourin CG, Der-Torossian H. Cancer cachexia update in head and neck cancer: Pathophysiology and treatment. Head Neck 2015; 37:1057-72. [PMID: 24634283 DOI: 10.1002/hed.23696] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2014] [Indexed: 01/10/2023] Open
Abstract
The pathophysiology of cancer cachexia remains complex. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and the Google search engine. In this review, we focus on the different mediators of impaired anabolism and upregulated catabolism that alter the skeletal muscle homeostasis resulting in the wasting of cancer cachexia. We present recent evidence of targeted treatment modalities from clinical trials along with their potential mechanisms of action. We also report on the most current evidence from randomized clinical trials using multimodal treatments in patients with cancer cachexia, but also the evidence from head and neck cancer-specific trials. A more complete understanding of the pathophysiology of the syndrome may lead to more effective targeted therapies and improved outcomes for patients.
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Affiliation(s)
- Marion E Couch
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, Vermont
| | - Kim Dittus
- Division of Hematology-Oncology, Department of Medicine, Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, Vermont
| | - Michael J Toth
- Department of Molecular Physiology and Biophysics, University of Vermont, College of Medicine, Burlington, Vermont
| | - Monte S Willis
- Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina
| | - Denis C Guttridge
- Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio
| | - Jonathan R George
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, California
| | - Eric Y Chang
- University of Vermont, College of Medicine, Burlington, Vermont
| | - Christine G Gourin
- Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, Maryland
| | - Hirak Der-Torossian
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, Vermont
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Shao M, Lu X, Cong W, Xing X, Tan Y, Li Y, Li X, Jin L, Wang X, Dong J, Jin S, Zhang C, Cai L. Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress. PLoS One 2014; 9:e92574. [PMID: 24651118 PMCID: PMC3961432 DOI: 10.1371/journal.pone.0092574] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/24/2014] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR) plays a critical role in attenuating insulin resistance, inflammation and oxidative stress. OBJECTIVE The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms. METHODS Mice were fed with a high-fat diet (HFD, 40% of calories from fat) for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg) to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy) for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured. RESULTS HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2) expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks. CONCLUSION These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.
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Affiliation(s)
- Minglong Shao
- School of Public Health of Jilin University, Changchun, China
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, the Third Affiliated Hospital of the Wenzhou Medical University, Wenzhou, China
| | - Xuemian Lu
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, the Third Affiliated Hospital of the Wenzhou Medical University, Wenzhou, China
| | - Weitao Cong
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmacy, Wenzhou Medical College, Wenzhou, China
| | - Xiao Xing
- School of Public Health of Jilin University, Changchun, China
- Changchun Institute for Food and Drug Control, Changchun, China
| | - Yi Tan
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- Kosair Children’s Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, Kentucky, United States of America
| | - Yunqian Li
- Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China
| | - Xiaokun Li
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmacy, Wenzhou Medical College, Wenzhou, China
| | - Litai Jin
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- School of Pharmacy, Wenzhou Medical College, Wenzhou, China
| | - Xiaojie Wang
- School of Pharmacy, Wenzhou Medical College, Wenzhou, China
| | - Juancong Dong
- School of Public Health of Jilin University, Changchun, China
| | - Shunzi Jin
- School of Public Health of Jilin University, Changchun, China
| | - Chi Zhang
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- Ruian Center of Chinese-American Research Institute for Diabetic Complications, the Third Affiliated Hospital of the Wenzhou Medical University, Wenzhou, China
| | - Lu Cai
- Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China
- Kosair Children’s Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, Kentucky, United States of America
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Trivedi P, Jena G. Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: Studies on inflammation, oxidative stress, DNA damage and fibrosis. Food Chem Toxicol 2013; 59:339-55. [DOI: 10.1016/j.fct.2013.06.019] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 05/07/2013] [Accepted: 06/12/2013] [Indexed: 01/08/2023]
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The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids. Food Chem Toxicol 2013. [DOI: 10.1016/j.fct.2012.11.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Schaue D, Kachikwu EL, McBride WH. Cytokines in radiobiological responses: a review. Radiat Res 2012; 178:505-23. [PMID: 23106210 DOI: 10.1667/rr3031.1] [Citation(s) in RCA: 279] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great.
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Affiliation(s)
- Dörthe Schaue
- David Geffen School Medicine, University of California at Los Angeles, Los Angeles, California 90095-1714, USA.
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Kim JI, Cho SR, Lee CM, Park ES, Kim KN, Kim HC, Lee HY. Induction of ER Stress-Mediated Apoptosis by α-Lipoic Acid in A549 Cell Lines. THE KOREAN JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2012; 45:1-10. [PMID: 22363901 PMCID: PMC3283777 DOI: 10.5090/kjtcs.2012.45.1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 11/25/2011] [Accepted: 11/25/2011] [Indexed: 12/25/2022]
Abstract
Background α-Lipoic acid (α-LA) has been studied as an anticancer agent as well as a therapeutic agent for diabetes and obesity. We performed this study to evaluate the anticancer effects and mechanisms of α-LA in a lung cancer cell line, A549. Materials and Methods α-LA-induced apoptosis of A549 cells was detected by fluorescence-activated cell sorting analysis and a DNA fragmentation assay. Expression of apoptosis-related genes was analyzed by western blot and reverse transcription-polymerase chain reaction analyses. Results α-LA induced apoptosis and DNA fragmentation in A549 cells in a dose- and time-dependent manner. α-LA increased caspase activity and the degradation of poly (ADP-ribose) polymerase. It induced expression of endoplasmic reticulum (ER) stress-related genes, such as glucose-regulated protein 78, C/EBP-homologous protein, and the short form of X-box binding protein-1, and decreased expression of the anti-apoptotic protein, X-linked inhibitor of apoptosis protein. Reactive oxygen species (ROS) production was induced by α-LA, and the antioxidant N-acetyl-L-cysteine decreased the α-LA-induced increase in expression of apoptosis and ER stress-related proteins. Conclusion α-LA induced ER stress-mediated apoptosis in A549 cells via ROS. α-LA may therefore be clinically useful for treating lung cancer.
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Affiliation(s)
- Jong In Kim
- Department of Thoracic and Cardiovascular Surgery, Gospel Hospital, Kosin University College of Medicine, Korea
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Abstract
The palliative doctor gives the ‘touch of God’ as he/she takes care of the terminally ill patient. The oncologist encounters great difficulties in managing oral cavity problems of these patients. A trained dental doctor can help other doctors in dealing with these situations. But the general dental surgeon does not have enough idea about his part in these treatments. The community is also unaware of the role that a nearby dentist can play. Adequate training programs have to be conducted and awareness has to be created. A trained dentist will be a good team mate for the oncologist or radiotherapist or other doctors of the palliative care team. In this paper, a brief attempt is made to list a few areas in which a palliative care dentist can help other members of the palliative care team and also the patient in leading a better life.
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Affiliation(s)
- Rani P Mol
- Department of Oral Medicine and Radiology, Government Dental College, Thiruvananthapuram, India
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Abstract
Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful.
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Affiliation(s)
- Em Tazi
- Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco
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Silvério R, Laviano A, Rossi Fanelli F, Seelaender M. l-carnitine and cancer cachexia: Clinical and experimental aspects. J Cachexia Sarcopenia Muscle 2011; 2:37-44. [PMID: 21475677 PMCID: PMC3063878 DOI: 10.1007/s13539-011-0017-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 01/06/2011] [Indexed: 12/23/2022] Open
Abstract
Cancer cachexia is a multifaceted syndrome characterized, among many symptoms, by extensive muscle wasting. Chronic systemic inflammation, partly triggered and sustained by cytokines, as well as increased oxidative stress contributes to the pathogenesis of this complex metabolic disorder. l-carnitine plays a central role in the metabolism of fatty acids and shows important antioxidant and anti-inflammatory properties. Systemic carnitine depletion has been described in several diseases, and it is characterized by fatigue, muscle weakness, and decreased tolerance to metabolic stress. In cachectic cancer patients, low serum carnitine levels have been reported, and this change has been suggested to play an important contributory role in the development of cachexia. Based on these data, carnitine supplementation has been tested in preliminary studies concerning human cachexia, resulting in improved fatigue and quality of life. We present here a review of clinical and experimental evidence regarding the use of carnitine supplementation in the management of cancer cachexia.
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Affiliation(s)
- Renata Silvério
- Cancer Metabolism Research Group, Institute of Biomedical Sciences, Department of Cell and Developmental Biology University of São Paulo Av. Prof. Lineu Prestes, 1524 lab 434 CEP 08800-090 São Paulo SP
| | | | | | - Marília Seelaender
- Cancer Metabolism Research Group, Institute of Biomedical Sciences, Department of Cell and Developmental Biology University of São Paulo Av. Prof. Lineu Prestes, 1524 lab 434 CEP 08800-090 São Paulo SP
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Mantovani G, Macciò A, Madeddu C, Serpe R, Massa E, Dessì M, Panzone F, Contu P. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist 2010; 15:200-211. [PMID: 20156909 PMCID: PMC3227938 DOI: 10.1634/theoncologist.2009-0153] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Accepted: 01/05/2010] [Indexed: 12/29/2022] Open
Abstract
PURPOSE A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS AND METHODS Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.
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An Evaluation of the Stability and Pharmacokinetics of R-Lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Human Plasma from Healthy Subjects. ACTA ACUST UNITED AC 2009. [DOI: 10.1201/9781420045390.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Mantovani G, Madeddu C. Cancer cachexia: medical management. Support Care Cancer 2009; 18:1-9. [PMID: 19688225 DOI: 10.1007/s00520-009-0722-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Accepted: 08/03/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. MATERIALS AND METHODS The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. RESULTS Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). CONCLUSIONS To date, despite several years of co-ordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful.
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Affiliation(s)
- Giovanni Mantovani
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy.
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Differential regulation of Apak by various DNA damage signals. Mol Cell Biochem 2009; 333:181-7. [DOI: 10.1007/s11010-009-0218-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Accepted: 07/07/2009] [Indexed: 12/31/2022]
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Prieto González EA, Fuchs AG, Sánchez GS. Amifostine (WR2721) confers DNA protection to in vivo cisplatin-treated murine peripheral blood leukocytes. Dose Response 2009; 7:234-46. [PMID: 19809542 DOI: 10.2203/dose-response.08-026.prieto] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Amifostine [S-2-3-aminopropyl amino ethyl phosphorotioic acid], a modulator agent for antineoplastic drugs involved in free radicals generation has given controversial results in cisplatin treated leukocytes in vitro. We have evaluated the amifostine protection over leukocytes in vivo, using comet assay. Groups of five OF1 male mice were given one of three doses of amifostine (56, 105 and 200 mg/Kg) after a cisplatin single injection (10 mg/Kg). Serum malonyldialdehyde levels, catalase and superoxide dismutase activity were also evaluated. Amifostine showed significant DNA protection (p< 0.01) at the two lower doses evaluated. Malonyldialdehyde decreased in all amifostine treatments with respect to cisplatin while antioxidant enzyme activities remained unchanged. However, DNA migration increased with the highest amifostine dose; in fact highest dose of amifostine did no protect damage caused by cisplatin this result have implications on amifostine treatment schedules in clinical practice.
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Affiliation(s)
- E A Prieto González
- Centro de Altos Estudios en Ciencias de la Salud, Universidad Abierta Interamericana, Ave. Montes de Oca. No. 745, Buenos Aires Capital, Federal Argentina.
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Cyclooxygenase-2 inhibitors and antioxidants in the treatment of cachexia. Curr Opin Support Palliat Care 2009; 2:275-81. [PMID: 19069312 DOI: 10.1097/spc.0b013e32830f47e4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Cancer cachexia is increasingly becoming a critical component in the comprehensive approach to cancer patients influencing morbidity, mortality and quality of life. Therefore its pathophysiology and the main contributing factors have been investigated with the aim of developing effective therapies. Reported findings highlight the role of chronic inflammation and oxidative stress in the onset of cancer cachexia. RECENT FINDINGS Chronic inflammation, one of the main features of cancer cachexia, triggers the overproduction of proinflammatory cytokines playing a major role in the pathogenesis of systemic symptoms of cachexia; therefore, antiinflammatory drugs such as cyclooxygenase-2 inhibitors could break the 'vicious circle' leading to the onset and worsening of this devastating syndrome. Likewise, oxidative stress, almost always accompanying cancer cachexia, may be counteracted by effective antioxidant treatments. The most relevant recent clinical approaches addressing these targets are reported. SUMMARY Fairly advanced clinical data on efficacy of cyclooxygenase-2 inhibitors and antioxidants in advanced cancer patients are promising, but the best way to administer and combine them with other agents, the optimal dose and timing remain uncertain. However, because cachexia is a multifactorial syndrome, therapeutic approaches targeting a single contributing factor may be inadequate. A rational treatment should thus be multitargeted addressing all key contributing factors.
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Macciò A, Madeddu C, Panzone F, Mantovani G. Carbocysteine: clinical experience and new perspectives in the treatment of chronic inflammatory diseases. Expert Opin Pharmacother 2009; 10:693-703. [PMID: 19239402 DOI: 10.1517/14656560902758343] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Carbocysteine is a muco-active drug with free radical scavenging and anti-inflammatory properties. It is actually approved for clinical use as adjunctive therapy of respiratory tract disorders characterized by excessive, viscous mucus, including chronic obstructive airways disease (COPD). OBJECTIVE The intriguing antioxidant and anti-inflammatory properties of carbocysteine, beyond its known mucolytic activity, are described to explain its therapeutic efficacy and suggest new clinical uses. METHODS After reviewing physiology and preclinical studies, human studies on the use of carbocysteine in chronic inflammatory diseases, i.e., COPD and cancer cachexia, are reviewed. RESULTS/CONCLUSIONS Carbocysteine has been recently recognized as an effective and safe treatment for the long-term management of COPD, able to reduce the incidence of exacerbations and improve patient quality of life. Moreover, carbocysteine was effective in counteracting some symptoms associated with cancer cachexia. Preclinical and clinical studies have demonstrated that the antioxidant and anti-inflammatory properties of carbocysteine are more important than mucolysis itself for its therapeutic efficacy. Therefore, carbocysteine may be able to reverse the oxidative stress associated with several chronic inflammatory diseases, such as cardiovascular diseases and neurodegenerative disorders. Controlled, randomized studies in humans are warranted.
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Affiliation(s)
- Antonio Macciò
- Sirai Hospital, Department of Obstetrics and Gynecology, Carbonia, Italy.
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Vitamin C Enhances Phagocytosis of Necrotic Trophoblasts by Endothelial Cells and Protects the Phagocytosing Endothelial Cells from Activation. Placenta 2009; 30:163-8. [DOI: 10.1016/j.placenta.2008.11.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 11/11/2008] [Accepted: 11/12/2008] [Indexed: 11/21/2022]
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Mantovani G, Macciò A, Madeddu C, Gramignano G, Serpe R, Massa E, Dessì M, Tanca FM, Sanna E, Deiana L, Panzone F, Contu P, Floris C. Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. Nutrition 2008; 24:305-313. [PMID: 18262758 DOI: 10.1016/j.nut.2007.12.010] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2007] [Revised: 12/10/2007] [Accepted: 12/13/2007] [Indexed: 11/30/2022]
Abstract
OBJECTIVE In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.
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Affiliation(s)
- Giovanni Mantovani
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy.
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Abstract
Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, and have a significant economic impact. The pathogenesis of oral mucositis is multifactorial and complex. This review discusses the morbidity, economic impact, pathogenesis and clinical course of mucositis. Current clinical management of oral mucositis is largely focused on palliative measures such as pain management, nutritional support and maintenance of good oral hygiene. However, several promising therapeutic agents are in various stages of clinical development for the management of oral mucositis. These agents are discussed in the context of recently updated evidence-based clinical management guidelines.
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Affiliation(s)
- Rajesh V Lalla
- Division of Oral Medicine, Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center MC 1605, 263 Farmington Avenue, Farmington, CT 06030, USA.
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Antonello A, Tarozzi A, Morroni F, Cavalli A, Rosini M, Hrelia P, Bolognesi ML, Melchiorre C. Multitarget-directed drug design strategy: a novel molecule designed to block epidermal growth factor receptor (EGFR) and to exert proapoptotic effects. J Med Chem 2007; 49:6642-5. [PMID: 17154492 DOI: 10.1021/jm0608762] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The multifactorial mechanistic nature of cancer calls for the development of multifunctional therapeutic tools, i.e., single compounds able to interact with multiple altered pathogenetic pathways. Following this rationale, we designed compounds able to irreversibly block epidermal growth factor receptor (EGFR), and to induce apoptosis in tumor cell lines. The novel molecules were synthesized by combining the structural features of the EGFR inhibitor PD153035 (1) and lipoic acid, which among other therapeutic effects triggers apoptosis in human cancer cells.
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Affiliation(s)
- Alessandra Antonello
- Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
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Simbula G, Columbano A, Ledda-Columbano GM, Sanna L, Deidda M, Diana A, Pibiri M. Increased ROS generation and p53 activation in α-lipoic acid-induced apoptosis of hepatoma cells. Apoptosis 2006; 12:113-23. [PMID: 17136495 DOI: 10.1007/s10495-006-0487-9] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Alpha-lipoic acid (alpha-LA) is an antioxidant used for the treatment of a variety of diseases, including liver cirrhosis, heavy metal poisoining, and diabetic polyneuropathy. In addition to its protective effect against oxidative stress, alpha-LA induces apoptosis in different cancer cells types. However, whether alpha-LA acid induces apoptosis of hepatoma cells is unknown. Herein, we investigated whether alpha-LA induces apoptosis in two different hepatoma cell lines FaO and HepG2. The results showed that alpha-LA inhibits the growth of both cell lines as indicated by the reduction in cell number, the reduced expression of cyclin A and the increased levels of the cyclin/CDKs inhibitors, p27(Kip1) and p21(Cip1). Cell cycle arrest was associated with cell loss, and DNA laddering indicative of apoptosis. Apoptosis was preceded by increased generation of reactive oxygen species, and associated with p53 activation, increased expression of Bax, release of cytochrome c from mitochondria, caspases activation, decreased levels of survivin, induction of pro-apoptotic signaling (i.e JNK) and inhibition of anti-apoptotic signaling (i.e. PKB/Akt) pathways. In conclusion, this study provides evidence that alpha-LA induces apoptosis in hepatoma cells, describes a possible sequence of molecular events underlying its lethal effect, and suggests that it may prove useful in liver cancer therapy.
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Affiliation(s)
- G Simbula
- Department of Toxicology, Oncology and Molecular Pathology Unit, Italy
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Friel H, Lederman H. A nutritional supplement formula for influenza A (H5N1) infection in humans. Med Hypotheses 2006; 67:578-87. [PMID: 16624496 DOI: 10.1016/j.mehy.2006.02.040] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2006] [Revised: 02/27/2006] [Accepted: 02/27/2006] [Indexed: 11/23/2022]
Abstract
By early February 2006, the World Health Organization had reported 165 human cases of H5N1 influenza since December 2003, with 88 fatalities. However, the avian H5N1 influenza virus apparently is not yet efficiently transmitted between humans. Though a near-term possibility of a global H5N1 influenza pandemic remains, currently there is no vaccine or anti-viral drug that is proven to be safe and effective in preventing or treating H5N1 influenza in humans. There is thus a compelling public interest in developing alternative prophylaxis and treatment strategies for H5N1 influenza, which would need to address the complex pathogenesis of H5N1 influenza that is responsible for its apparently unusually high virulence. The authors present here a significant body of medical and scientific evidence to support the prophylactic use of a carefully designed nutritional supplement formulation that may antagonize the major pathogenic processes of H5N1 influenza in humans. Through several independently-mediated mechanisms, the formulations may: (a) degrade H5N1 virulence by directly affecting the virus itself, (b) inhibit H5N1 viral replication by maintaining cellular redox equilibrium in host cells, (c) inhibit H5N1 replication by a blockade of the nuclear-cytoplasmic translocation of the viral ribonucleoproteins and reduced expression of late viral proteins related to the inhibition of protein kinase C activity and its dependent pathways, (d) down-regulate activation and proliferation of proinflammatory cytokines in respiratory epithelial cells and macrophages that are implicated in the pathogenesis of H5N1 influenza, and (e) protect the lungs and other vital organs from virus- and cytokine-induced oxidative stress by supplying and maintaining sufficient levels of exogenous and endogenous antioxidants. Key mediators in these processes include selenium, vitamin E, NAC/glutathione, resveratrol, and quercetin. Taken prophylactically, and throughout the duration and recovery of an H5N1 infection, the nutritional supplement formula may aid humans infected with H5N1 influenza to survive with a reduced likelihood of major complications, and may provide a relatively low-cost strategy for individuals as well as government, public-health, medical, health-insurance, and corporate organizations to prepare more prudently for an H5N1 pandemic. Some evidence also indicates that the supplement formulation may be effective as an adjunctive to H5N1 vaccine and anti-viral treatments, and should be tested as such.
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Wenzel U, Nickel A, Daniel H. alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis 2005; 10:359-68. [PMID: 15843897 DOI: 10.1007/s10495-005-0810-x] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The antioxidant alpha-lipoic acid (ALA) has been shown to affect a variety of biological processes associated with oxidative stress including cancer. We determined in HT-29 human colon cancer cells whether ALA is able to affect apoptosis, as an important parameter disregulated in tumour development. Exposure of cells to ALA or its reduced form dihydrolipoic acid (DHLA) for 24 h dose dependently increased caspase-3-like activity and was associated with DNA-fragmentation. DHLA but not ALA was able to scavenge cytosolic O2-* in HT-29 cells whereas both compounds increased O2-*-generation inside mitochondria. Increased mitochondrial O2-*-production was preceded by an increased influx of lactate or pyruvate into mitochondria and resulted in the down-regulation of the anti-apoptotic protein bcl-X(L). Mitochondrial O2-*-generation and apoptosis induced by ALA and DHLA could be prevented by the O2-*-scavenger benzoquinone. Moreover, when the lactate/pyruvate transporter was inhibited by 5-nitro-2-(3-phenylpropylamino) benzoate, ALA- and DHLA-induced mitochondrial ROS-production and apoptosis were blocked. In contrast to HT-29 cells, no apoptosis was observed in non-transformed human colonocytes in response to ALA or DHLA addition. In conclusion, our study provides evidence that ALA and DHLA can effectively induce apoptosis in human colon cancer cells by a prooxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria.
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Affiliation(s)
- U Wenzel
- Molecular Nutrition Unit, Department of Food and Nutrition, Technical University of Munich, Hochfeldweg 2, D-85350, Freising, FRG.
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Skrzydlewska E, Sulkowska M, Koda M, Sulkowski S. Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J Gastroenterol 2005; 11:1251-66. [PMID: 15761961 PMCID: PMC4250670 DOI: 10.3748/wjg.v11.i9.1251] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g., cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
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Affiliation(s)
- Elzbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2, 15-230 Bialystok, Poland.
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Alves AA, Pereira da Silva L, Macedo DV, Kubota LT. Amperometric sensor for glutathione reductase activity determination in erythrocyte hemolysate. Anal Biochem 2003; 323:33-8. [PMID: 14622956 DOI: 10.1016/j.ab.2003.08.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The development of an amperometric sensor for glutathione reductase (GR) activity in erythrocyte hemolysate to contribute to oxidative stress evaluation is presented. In this assay, the reduced form of glutathione, the product of the GR reaction, reacts with 5,5(')-dithiobis(2-nitrobenzoic acid), producing GSTNB, which is easily reduced in the electrode surface. The current was recorded during 180 s after the sample addition, applying a potential of -300 mV. The sensor presented a suitable sensitivity, a good operational range, and precision. The effects of pH variations and specific uncompetitive inhibitor (safranin-O) in the enzyme activity were also evaluated. The GR activity determination in human erythrocyte hemolysate using this method has provided results that are statistically equal to those obtained by the classical spectrophotometric method, with 95% of confidence. The advantages of this method are the saved time, reagents, and samples and the possibility of its use in the field.
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Affiliation(s)
- A A Alves
- Labex, Laboratory of Biochemistry of Exercise, Departamento Bioquímica, IB-UNICAMP, Campinas, 13083-971 Sao Paulo, Brazil
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Mantovani G, Macciò A, Madeddu C, Mura L, Gramignano G, Lusso MR, Massa E, Mocci M, Serpe R. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med (Berl) 2003; 81:664-673. [PMID: 12928788 DOI: 10.1007/s00109-003-0476-1] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2003] [Accepted: 07/08/2003] [Indexed: 10/26/2022]
Abstract
This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
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Affiliation(s)
- Giovanni Mantovani
- Department of Medical Oncology, Policlinico Universitario, University of Cagliari, Strada Statale 554 bivio Sestu, 09042 Monserrato, Italy.
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Mantovani G, Madeddu C, Gramignano G, Lusso MR, Mocci M, Massa E, Ferreli L, Astara G, Macciò A, Serpe R. Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters. JOURNAL OF EXPERIMENTAL THERAPEUTICS AND ONCOLOGY 2003; 3:205-219. [PMID: 14567291 DOI: 10.1046/j.1359-4117.2003.01096.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.
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Affiliation(s)
- Giovanni Mantovani
- Department of Medical Oncology, University of Cagliari, Cagliari, Italy.
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