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1
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Rhi H, Choi HG, Kang JW. Impact of statin use in head and neck cancer: a nested case-control study. Eur Arch Otorhinolaryngol 2025; 282:1443-1457. [PMID: 39441362 DOI: 10.1007/s00405-024-09020-1] [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: 04/29/2024] [Accepted: 09/30/2024] [Indexed: 10/25/2024]
Abstract
PURPOSE Dyslipidemia and statin use are associated with an increased risk of various cancers. However, the association in head and neck cancer (HNC) remains unclear. Therefore, this study aimed to investigate the impact of dyslipidemia and statin use on the development of HNC. METHODS Using data from the Korean National Health Insurance Service-National Sample Cohort from 2002 to 2019, we compared two groups HNC patients (n = 1006) and matched control participants (n = 4024) after propensity score overlap weighted balancing. The odds ratios (ORs) for HNC development according to dyslipidemia and statin use duration were assessed using propensity score overlap-weighted multivariable logistic regression. RESULTS Individuals with untreated dyslipidemia had significantly lower odds of developing HNC than those of normal participants (OR 0.70, 95% confidence interval [CI] 0.59-0.82). Conversely, patients with dyslipidemia who received statin therapy (< 60 days) showed a nearly two-fold increase in the odds of HNC (OR 1.94, 95% CI 1.29-2.90). Long-term statin use (≥ 60 days) aligned the odds with those of normal participants (OR 0.89, 95% CI 0.76-1.04). CONCLUSIONS The adverse effect of short-term statin use on HNC development requires further study, and long-term statin use for dyslipidemia treatment does not increase the odds of HNC.
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Affiliation(s)
- Haewon Rhi
- Department of Otorhinolaryngology-Head & Neck Surgery, Hallym University Sacred Heart Hospital, Anyang, 14068, Republic of Korea
| | - Hyo Geun Choi
- Suseo Seoul ENT Clinic and MD Analytics, 10, Bamgogae-ro 1-gil, Gangnam-gu, Seoul, 06349, Republic of Korea
| | - Jeong Wook Kang
- Department of Otorhinolaryngology-Head & Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, #22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang, 14068, Republic of Korea.
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2
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Millar JE, Reddy K, Bos LDJ. Future Directions in Therapies for Acute Respiratory Distress Syndrome. Clin Chest Med 2024; 45:943-951. [PMID: 39443010 DOI: 10.1016/j.ccm.2024.08.014] [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] [Indexed: 10/25/2024]
Abstract
Acute respiratory distress syndrome (ARDS) is caused by a complex interplay among hyperinflammation, endothelial dysfunction, and alveolar epithelial injury. Targeted treatments toward the underlying pathways have been unsuccessful in unselected patient populations. The first reliable biological subphenotypes reflective of these biological disease states have been identified in the past decade. Subphenotype targeted intervention studies are needed to advance the pharmacologic treatment of ARDS.
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Affiliation(s)
- Jonathan E Millar
- Baillie-Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Repair and Regeneration, University of Edinburgh, The Roslin Institute, Easter Bush Campus, Midlothian, Edinburgh EH25 9RG, UK; Department of Critical Care, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kiran Reddy
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, University Road, Belfast BT7 1NN, UK
| | - Lieuwe D J Bos
- Intensive Care Department, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands.
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3
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Singh MK, Han S, Kim S, Kang I. Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment. Int J Mol Sci 2024; 25:11185. [PMID: 39456967 PMCID: PMC11508222 DOI: 10.3390/ijms252011185] [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: 09/06/2024] [Revised: 10/14/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.
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Affiliation(s)
- Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sungsoo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (M.K.S.); (S.H.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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4
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Cheung KS. Big data approach in the field of gastric and colorectal cancer research. J Gastroenterol Hepatol 2024; 39:1027-1032. [PMID: 38413187 DOI: 10.1111/jgh.16527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 02/07/2024] [Indexed: 02/29/2024]
Abstract
Big data is characterized by three attributes: volume, variety,, and velocity. In healthcare setting, big data refers to vast dataset that is electronically stored and managed in an automated manner and has the potential to enhance human health and healthcare system. In this review, gastric cancer (GC) and postcolonoscopy colorectal cancer (PCCRC) will be used to illustrate application of big data approach in the field of gastrointestinal cancer research. Helicobacter pylori (HP) eradication only reduces GC risk by 46% due to preexisting precancerous lesions. Apart from endoscopy surveillance, identifying medications that modify GC risk is another strategy. Population-based cohort studies showed that long-term use of proton pump inhibitors (PPIs) associated with higher GC risk after HP eradication, while aspirin and statins associated with lower risk. While diabetes mellitus conferred 73% higher GC risk, metformin use associated with 51% lower risk, effect of which was independent of glycemic control. Nonetheless, nonsteroidal anti-inflammatory drugs (NA-NSAIDs) are not associated with lower GC risk. CRC can still occur after initial colonoscopy in which no cancer was detected (i.e. PCCRC). Between 2005 and 2013, the rate of interval-type PCCRC-3y (defined as CRC diagnosed between 6 and 36 months of index colonoscopy which was negative for CRC) was 7.9% in Hong Kong, with >80% being distal cancers and higher cancer-specific mortality compared with detected CRC. Certain clinical and endoscopy-related factors were associated with PCCRC-3 risk. Medications shown to have chemopreventive effects on PCCRC include statins, NA-NSAIDs, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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5
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Gupta A, Das D, Taneja R. Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors. Cancers (Basel) 2024; 16:1313. [PMID: 38610991 PMCID: PMC11010992 DOI: 10.3390/cancers16071313] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.
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Affiliation(s)
| | | | - Reshma Taneja
- Department of Physiology, Healthy Longevity and NUS Centre for Cancer Research Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore 117593, Singapore
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Krishnappa S, Karthik Y, Pratap GK, Shantaram M, Umarajashekhar A, Soumya J, Bhatt B, Sayed SM, Alhelaify SS, Aharthy OM, Mushtaq M. Exploration of bioactive compounds from Olea dioica in Western Ghats of Karnataka using GC-MS. 3 Biotech 2024; 14:63. [PMID: 38344286 PMCID: PMC10853147 DOI: 10.1007/s13205-023-03888-2] [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: 03/11/2023] [Accepted: 12/06/2023] [Indexed: 03/10/2024] Open
Abstract
Bioactive compounds in plants are essential for the formation of novel chemotherapeutic drugs, which have been used in Ayurveda to treat a variety of illnesses. Indian medicinal herbs have been used for thousands of years to treat a variety of illnesses, such as fever, cancer, snake bites, rheumatism, skin problems, and neurodegenerative diseases. GC-MS was used to locate and categorize bioactive components in Olea dioica leaves. The results showed that presence of octanoic acid, methyl ester, decanoic acid, methyl ester, desulphosinigrin, l-gala-l-ido-octose, methyl tetradecanoate, Tetradecanoic acid, 6-benzoxazolesulfonamide, N-(2-hydroxyethyl)-2-methyl-, 10-chloro-5-methoxy-5H-dibenzo[a,d][7]annulene, pentadecanoic acid, oleic acid, n-hexadecanoic acid, hexanedioic acid, dioctyl ester, and squalene. The methanol extract of Olea dioica was effective against a wide spectrum of pathogenic bacteria at four different concentrations, with the highest activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Xanthomonas campestris, and Salmonella typhimurium. It also showed moderate activity against Agrobacterium tumefaciens, Pseudomonas aeruginosa, Streptomyces pneumonia, and Pseudomonas syringae. The pharmacological properties of O. dioica, as well as their variety and comprehensive phytochemistry, could be exploited as a potent antimicrobial agent for future therapeutics.
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Affiliation(s)
- Srinivasa Krishnappa
- Department of Studies and Research in Biochemistry, Mangalore University, Jnana Kaveri, Chikka Aluvara, Kodagu, Karnataka India
| | - Yalpi Karthik
- Department of Studies and Research in Microbiology, Mangalore University, Jnana Kaveri, Chikka Aluvara, Kodagu, Karnataka India
| | - G. K. Pratap
- Department of Studies and Research in Biochemistry, Mangalore University, Jnana Kaveri, Chikka Aluvara, Kodagu, Karnataka India
| | - Manjula Shantaram
- Department of Studies and Research in Biochemistry, Mangalore University, Jnana Kaveri, Chikka Aluvara, Kodagu, Karnataka India
| | - Alavala Umarajashekhar
- Department of Agricultural Microbiology and Bio-Energy Agricultural College JilleleSircilla, Professor Jayashankar Telangana State Agriculture University, Rajendranagar, Hyderabad, India
| | - J. Soumya
- Department of Microbiology, Government Degree College, Bodhan, Kakatiya University, Warangal, India
| | - Bhagyashree Bhatt
- MS Swaminathan School of Agriculture, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229 India
| | - Samy M. Sayed
- Department of Science and Technology, University College-Ranyah, Taif University, B.O. Box 11099, 21944 Taif, Saudi Arabia
| | - Seham Sater Alhelaify
- Department of Biotechnology, Faculty of Science, Taif University, P.O. Box 11099, 21944 Taif, Saudi Arabia
| | - Ohud Muslat Aharthy
- Department of Biotechnology, Faculty of Science, Taif University, P.O. Box 11099, 21944 Taif, Saudi Arabia
| | - Muntazir Mushtaq
- MS Swaminathan School of Agriculture, Shoolini University of Biotechnology and Management Sciences, Bajhol, Solan, Himachal Pradesh 173229 India
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Nie G, Chen S, Song Q, Zou D, Li M, Tang X, Deng Y, Huang B, Yang M, Lv G, Zhang Y. DHX33 mediates p53 to regulate mevalonate pathway gene transcription in human cancers. Biochim Biophys Acta Gen Subj 2024; 1868:130547. [PMID: 38143011 DOI: 10.1016/j.bbagen.2023.130547] [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: 08/06/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 12/26/2023]
Abstract
Tumor suppressor p53 is frequently null or mutated in human cancers. Here in this study, DHX33 protein was found to be induced in p53 null cells in vitro, and in p53 mutant lung tumorigenesis in vivo. Cholesterol metabolism through mevalonate pathway is pivotal for cell proliferation and is frequently altered in human cancers. Mice carrying mutant p53 and KrasG12D alleles showed upregulation of mevalonate pathway gene expression. However upon DHX33 loss, their upregulation was significantly debilitated. Additionally, in many human cancer cells, DHX33 knockdown caused inhibition of mavelonate pathway gene transcription. We propose DHX33 locates downstream of mutant p53 and Ras to regulate mevalonate pathway gene transcription and thereby supports cancer development in vivo.
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Affiliation(s)
- Guangli Nie
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Shiyun Chen
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China; Southern University of Science and Technology, Shenzhen, China
| | - Qingzhi Song
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, China
| | - Dongxu Zou
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Maggie Li
- Shenzhen College of International Education, Shenzhen, China
| | - Xiyu Tang
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Yuanlian Deng
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Bizhou Huang
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Mengxia Yang
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China
| | - Guoqing Lv
- Shenzhen College of International Education, Shenzhen, China.
| | - Yandong Zhang
- Shenzhen KeYe Life Technologies Co., Ltd, Shenzhen, Guangdong 518000, China; Southern University of Science and Technology, Shenzhen, China.
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Lu J, Chen S, Bai X, Liao M, Qiu Y, Zheng LL, Yu H. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications. Biochem Pharmacol 2023; 218:115907. [PMID: 37931664 DOI: 10.1016/j.bcp.2023.115907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023]
Abstract
Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.
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Affiliation(s)
- Jia Lu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Siwei Chen
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xuejiao Bai
- Department of Anesthesiology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minru Liao
- Department of Anesthesiology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuling Qiu
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
| | - Ling-Li Zheng
- Department of Pharmacy, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Jeon D, Cha HR, Chung SW, Choi J, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Lee SW, Choi WM. Association between statin use and the prognosis of hepatocellular carcinoma after resection: a nationwide cohort study. EClinicalMedicine 2023; 65:102300. [PMID: 37965429 PMCID: PMC10641481 DOI: 10.1016/j.eclinm.2023.102300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 11/16/2023] Open
Abstract
Background The majority of patients with hepatocellular carcinoma (HCC) following hepatic resection experience tumor recurrence. Statin use is associated with a reduced risk of HCC development; however, the association between statin use and the prognosis of HCC after resection remains unclear. We aimed to investigate the effect of statin use on the prognosis after hepatic resection among patients with HCC. Methods A nationwide cohort study was performed with data from the National Health Insurance Service Database in Korea. Among 65,101 HCC patients who underwent hepatic resection between January 2002 and December 2017, we included 21,470 patients. For validation, a hospital-based cohort of 3366 patients with very early or early-stage HCC who received curative-intent hepatic resection between January 2010 and December 2018 was analyzed. Recurrence-free survival (RFS) and overall survival (OS) was compared between statin users and non-users. Findings Among the nationwide cohort of 21,470 patients, 2399 (11.2%) used statins and 19,071 (88.8%) did not. Among the hospital cohort of 3366 patients, 363 (10.8%) used statins and 3003 (89.2%) did not. In the propensity score-matched nationwide cohort, statin users had better RFS (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.56-0.64; P < 0.001) and OS (HR, 0.49; 95% CI, 0.45-0.53; P < 0.001), with a duration-response relationship. In the propensity score-matched validation hospital cohort, statin treatment was significantly associated with better RFS (HR, 0.73; 95% CI, 0.59-0.90; P = 0.003) and OS (HR, 0.48; 95% CI, 0.32-0.72; P < 0.001). The beneficial effects of statins were more prominent in non-cirrhotics, tumors sized ≥3 cm, tumors with microscopic vascular invasion, or early HCC recurrence (<2 years after resection). Interpretation Statin use was associated with a better prognosis in a population-based cohort of patients with HCC after hepatic resection, which was further validated in a large hospital-based cohort. Funding Asan Institute for Life Sciences and Corporate Relations; Korean Association for the Study of the Liver.
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Affiliation(s)
- Dongsub Jeon
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Ryeong Cha
- Department of Computer Science and Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
| | - Sung Won Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Schelz Z, Muddather HF, Zupkó I. Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance. Antibiotics (Basel) 2023; 12:1468. [PMID: 37760764 PMCID: PMC10525194 DOI: 10.3390/antibiotics12091468] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Efflux pump (EP)-mediated multidrug resistance (MDR) seems ubiquitous in bacterial infections and neoplastic diseases. The diversity and lack of specificity of these efflux mechanisms raise a great obstacle in developing drugs that modulate efflux pumps. Since developing novel chemotherapeutic drugs requires large investments, drug repurposing offers a new approach that can provide alternatives as adjuvants in treating resistant microbial infections and progressive cancerous diseases. Hydroxy-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, also known as statins, are promising agents in this respect. Originally, statins were used in the therapy of dyslipidemia and for the prevention of cardiovascular diseases; however, extensive research has recently been performed to elucidate the functions of statins in bacterial infections and cancers. The mevalonate pathway is essential in the posttranslational modification of proteins related to vital eukaryotic cell functions. In this article, a comparative review is given about the possible role of HMG-CoA reductase inhibitors in managing diseases of bacterial and neoplastic origin. Molecular research and clinical studies have proven the justification of statins in this field. Further well-designed clinical trials are urged to clarify the significance of the contribution of statins to the lower risk of disease progression in bacterial infections and cancerous diseases.
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Affiliation(s)
| | | | - István Zupkó
- Institute of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary; (Z.S.); (H.F.M.)
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11
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Wu B, Shen W, Wang X, Wang J, Zhong Z, Zhou Z, Chen X. Plasma lipid levels are associated with the CD8+ T-cell infiltration and prognosis of patients with pancreatic cancer. Cancer Med 2023. [PMID: 37184113 DOI: 10.1002/cam4.6080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 04/15/2023] [Accepted: 05/04/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Recently, researchers have found that the tumour microenvironment plays an important role in tumours. We aimed to investigate the effects of plasma lipids on the prognosis of patients with pancreatic cancer and the infiltration of CD8+ T lymphocytes in tumour tissue. METHODS We enrolled patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreatic surgery between 2012 and 2021. Clinical pathological data were recorded; total cholesterol (TC) and triglyceride (TG) levels were measured; and tissue samples were collected. A tissue microarray was generated using collected tissue samples, and CD8 staining was performed to determine immunoreactive scores (IRSs). The correlations of TC and TG levels with clinicopathological characteristics and prognosis were analysed. Finally, the correlations of TC and TG levels with CD8+ T-cell infiltration were analysed. RESULTS A total of 90 eligible PDAC patients were included. TC levels were significantly correlated with tumour grade and lymph node metastasis, and TG levels were significantly correlated with perineural invasion. The Kaplan-Meier survival analysis results indicated that the prognosis in the high TC group was significantly worse than that in the low TC group, and the prognosis in the high TG group was significantly worse than that in the low TG group. Cox multivariate analysis indicated that TC was an independent indicator of poor prognosis of pancreatic cancer patients after surgery. Spearman correlation analysis indicated that there were significant negative correlations between CD8 IRS and TC and between CD8 IRS and TG. CONCLUSIONS TC and TG levels are significantly related to the prognosis of pancreatic cancer patients. They may be associated with tumour progression to higher grades, lymph node metastasis and/or nerve invasion. More importantly, TC and TG may reduce CD8+ T lymphocyte infiltration into pancreatic cancer tissue, affecting antitumour immune functions and immunotherapy efficacy.
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Affiliation(s)
- Bin Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Weiai Shen
- Medical College of Ningbo University, Ningbo, China
| | - Xiaoguang Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jing Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Zhengxiang Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Zhongchen Zhou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Xujian Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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12
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Su CH, Islam MM, Jia G, Wu CC. Statins and the Risk of Gastric Cancer: A Systematic Review and Meta-Analysis. J Clin Med 2022; 11:jcm11237180. [PMID: 36498753 PMCID: PMC9739712 DOI: 10.3390/jcm11237180] [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: 10/20/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Previous epidemiological studies have reported that the use of statins is associated with a decreased risk of gastric cancer, although the beneficial effects of statins on the reduction of gastric cancer remain unclear. Therefore, we conducted a systematic review and meta-analysis to investigate the association between the use of statins and the risk of gastric cancer. Electronic databases such as PubMed, EMBASE, Scopus, and Web of Science were searched between 1 January 2000 and 31 August 2022. Two authors used predefined selection criteria to independently screen all titles, abstracts, and potential full texts. Observational studies (cohort and case-control) or randomized control trials that assessed the association between statins and gastric cancer were included in the primary and secondary analyses. The pooled effect sizes were calculated using the random-effects model. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed to conduct this study. The total sample size across the 20 included studies was 11,870,553. The use of statins was associated with a reduced risk of gastric cancer (RRadjusted: 0.72; 95%CI: 0.64−0.81, p < 0.001). However, the effect size of statin use on the risk of gastric cancer was lower in Asian studies compared to Western studies (RRAsian: 0.62; 95%CI: 0.53−0.73 vs. RRwestern: 0.88; 95%CI: 0.79−0.99). These findings suggest that the use of statins is associated with a reduced risk of gastric cancer. This reverse association was even stronger among Asian people than Western individuals.
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Affiliation(s)
- Chun-Hsien Su
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei 111396, Taiwan
- Graduate Institute of Sports Coaching Science, College of Kinesiology and Health, Chinese Culture University, Taipei 111396, Taiwan
| | - Md. Mohaimenul Islam
- International Center for Health Information Technology (ICHIT), Taipei Medical University, Taipei 111396, Taiwan
| | - Guhua Jia
- Sports Teaching Department, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
| | - Chieh-Chen Wu
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei 111396, Taiwan
- Correspondence:
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13
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Patel KK, Sehgal VS, Kashfi K. Molecular targets of statins and their potential side effects: Not all the glitter is gold. Eur J Pharmacol 2022; 922:174906. [PMID: 35321818 PMCID: PMC9007885 DOI: 10.1016/j.ejphar.2022.174906] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/12/2022] [Accepted: 03/17/2022] [Indexed: 12/11/2022]
Abstract
Statins are a class of drugs widely used worldwide to manage hypercholesterolemia and the prevention of secondary heart attacks. Currently, available statins vary in terms of their pharmacokinetic and pharmacodynamic profiles. Although the primary target of statins is the inhibition of HMG-CoA reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis, statins exhibit many pleiotropic effects downstream of the mevalonate pathway. These pleiotropic effects include the ability to reduce myocardial fibrosis, pathologic cardiac disease states, hypertension, promote bone differentiation, anti-inflammatory, and antitumor effects through multiple mechanisms. Although these pleiotropic effects of statins may be a cause for enthusiasm, there are many adverse effects that, for the most part, are unappreciated and need to be highlighted. These adverse effects include myopathy, new-onset type 2 diabetes, renal and hepatic dysfunction. Although these adverse effects may be relatively uncommon, considering the number of people worldwide who use statins daily, the actual number of people affected becomes quite large. Also, co-administration of statins with several other medications, herbal agents, and foods, which interact through common enzymatic pathways, can have untoward clinical consequences. In this review, we address these concerns.
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Affiliation(s)
- Kush K Patel
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Viren S Sehgal
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, USA.
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14
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Deng CF, Zhu N, Zhao TJ, Li HF, Gu J, Liao DF, Qin L. Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential. Front Oncol 2022; 12:803473. [PMID: 35251975 PMCID: PMC8889620 DOI: 10.3389/fonc.2022.803473] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/12/2022] [Indexed: 01/17/2023] Open
Abstract
Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation.
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Affiliation(s)
- Chang-Feng Deng
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Tan-Jun Zhao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Hong-Fang Li
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Jia Gu
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Li Qin,
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15
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Patel KK, Kashfi K. Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs. Biochem Pharmacol 2022; 196:114654. [PMID: 34129857 PMCID: PMC8665945 DOI: 10.1016/j.bcp.2021.114654] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 02/03/2023]
Abstract
Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.
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Affiliation(s)
- Kush K Patel
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, NY, USA.
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16
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Uemura N, Hayashi H, Baba H. Statin as a therapeutic agent in gastroenterological cancer. World J Gastrointest Oncol 2022; 14:110-123. [PMID: 35116106 PMCID: PMC8790423 DOI: 10.4251/wjgo.v14.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
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Affiliation(s)
- Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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17
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Van Vo G, Guest PC, Nguyen NH. Evaluation of Antimicrobial and Anticancer Activities of Bouea macrophylla Ethanol Extract. Methods Mol Biol 2021; 2343:215-228. [PMID: 34473325 DOI: 10.1007/978-1-0716-1558-4_14] [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] [Indexed: 03/14/2023]
Abstract
The Bouea macrophylla (B. macrophylla) tree is widely grown throughout South East Asia and has been used as a traditional medicine for the treatment of various illnesses. This chapter presents a protocol for preparation of ethanol extracts of B. macrophylla leaves and evaluation of the potential antimicrobial and anticancer activities in vitro. The extract displayed antibacterial activity against nine out of the ten target microorganisms tested. In addition, the extract was capable of inhibiting the proliferation of HeLa and HCT116 cells, thus demonstrating some anticancer activity.
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Affiliation(s)
- Giau Van Vo
- Department of Biomedical Engineering, School of Medicine, Vietnam National University - Ho Chi Minh City (VNU-HCM), Ho Chi Minh City, Vietnam.
- Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University - Ho Chi Minh City (VNU-HCM), Ho Chi Minh City, Vietnam.
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Ngoc Hong Nguyen
- CirTech Institute, Ho Chi Minh City University of Technology (HUTECH), Ho Chi Minh City, Vietnam.
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18
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Huang CT, Liang YJ. Anti-tumor effect of statin on pancreatic adenocarcinoma: From concept to precision medicine. World J Clin Cases 2021; 9:4500-4505. [PMID: 34222418 PMCID: PMC8223840 DOI: 10.12998/wjcc.v9.i18.4500] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/11/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
A statin is a cholesterol-lowering agent, which inhibits HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase and subsequently reduces the cholesterol precursor, and was first used commercially in 1987. The concept of cholesterol restriction leading to cancer cell dysfunction was proposed in 1992. The interruption of different signaling pathways has been proved in preclinical experiments to elucidate the anti-tumor mechanism of statins in pancreatic adenocarcinoma. Observational studies have shown that the clinical use of statins is beneficial in patients with pancreatic adenocarcinoma, including a chemoprevention effect, post-surgical resection follow-up and therapeutic prognosis of advanced cancer stage. Arrest of the cancer cell cycle by the combined use of gemcitabine and statin was observed in a cell line study. The effect of microbiota on the tumor microenvironment of pancreatic adenocarcinoma is a new therapeutic approach as statins can modulate the gut microbiota. Hence, further randomized trials of statins in pancreatic adenocarcinoma treatment will be warranted with application of precision medicine from microbiota-derived, cell cycle-based and signaling pathway-targeted research.
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Affiliation(s)
- Chung-Tsui Huang
- Department of Gastroenterology and Hepatology, Far Eastern Memorial Hospital, New Taipei 220, Taiwan
| | - Yao-Jen Liang
- Graduate Institute of Applied Science and Engineering, Department and Institute of Life Science, Fu-Jen University, New Taipei 242, Taiwan
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19
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Cheung KS, Chung KL, Leung WK. Chemopreventive Effect of Metformin on Gastric Cancer Development. Gut Liver 2021; 16:147-156. [PMID: 34158423 PMCID: PMC8924804 DOI: 10.5009/gnl210132] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/17/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Although Helicobacterpylori infection is the most important causative factor for gastric cancer (GC), H. pylori eradication alone does not completely eliminate the GC risk. In addition to H. pylori eradication, other risk factors for GC should be identified and targeted. Diabetes mellitus (DM) confers a 20% increased risk of GC, which could be mediated via several biological mechanisms including the stimulation of cell proliferation via hyperinsulinemia and increased insulin-growth factor production, the promotion of angiogenesis, and DNA damage. With a current global prevalence of 9.3% and a predicted rise to 10.2% by 2030, DM could contribute substantially to the burden of GC cases worldwide. Emerging evidence showed that metformin possesses chemopreventive effects via both direct (e.g., adenosine monophosphate-activated protein kinase activation and subsequent inhibition of the mammalian target of rapamycin pathway) and indirect (e.g., modulation of the interaction between tumor cells and their microenvironment and gut microbiota) pathways. A recent meta-analysis of observational studies showed that metformin use was associated with 24% lower GC risk. However, many available observational studies related to metformin effects suffered from biases including the failure to adjust for the H. pylori infection status and serial glycemic control and time-related biases. Future prospective studies addressing these pitfalls are needed.
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Affiliation(s)
- Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Kit Lam Chung
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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20
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Targeting nutrient metabolism with FDA-approved drugs for cancer chemoprevention: Drugs and mechanisms. Cancer Lett 2021; 510:1-12. [PMID: 33857528 DOI: 10.1016/j.canlet.2021.03.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/21/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022]
Abstract
Proliferating cancer cells exhibit metabolic alterations and specific nutritional needs for adapting to their rapid growth. These changes include using aerobic glycolysis, lipid metabolic disorder, and irregular protein degradation. It may be useful to target metabolic abnormalities for cancer chemoprevention. Epidemiological and mechanism-related studies have indicated that many FDA-approved anti-metabolic drugs decrease tumor risk, inhibit tumor growth, or enhance the effect of chemotherapeutic drugs. Drugs targeting nutrient metabolism have fewer side effects with long-term use compared to chemotherapeutic drugs. The characteristics of these drugs make them promising candidates for cancer chemoprevention. Here, we summarize recent discoveries of the chemo-preventive effects of drugs targeting nutrient metabolic pathways and discuss future applications and challenges. Understanding the effects and mechanisms of anti-metabolic drugs in cancer has important implications for exploring strategies for cancer chemoprevention.
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21
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Amin F, Fathi F, Reiner Ž, Banach M, Sahebkar A. The role of statins in lung cancer. Arch Med Sci 2021; 18:141-152. [PMID: 35154535 PMCID: PMC8826694 DOI: 10.5114/aoms/123225] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023] Open
Abstract
Lung cancer is one of the most common causes of cancer-related mortality in the 21st century. Statins as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase not only reduce the cholesterol levels in the blood and decrease the risk of cardiovascular disease but may also play an important role in the prevention and treatment of lung cancer. Statins have several antitumor properties including the ability to reduce cell proliferation and angiogenesis, decrease invasion and synergistic suppression of lung cancer progression. Statins induce tumor cell apoptosis by inhibition of downstream products such as small GTP-binding proteins, Rho, Ras and Rac, which are dependent on isoprenylation. Statins reduce angiogenesis in tumors by down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor. In this review, the feasibility and efficacy of statins in the prevention and treatment of lung cancer are discussed.
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Affiliation(s)
- Fatemeh Amin
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Farzaneh Fathi
- Pharmaceutical Sciences Research Center, Biosensor and Bioelectronic Department, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Lodz, Lodz, Poland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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22
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Ahmadi M, Amiri S, Pecic S, Machaj F, Rosik J, Łos MJ, Alizadeh J, Mahdian R, da Silva Rosa SC, Schaafsma D, Shojaei S, Madrakian T, Zeki AA, Ghavami S. Pleiotropic effects of statins: A focus on cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165968. [PMID: 32927022 DOI: 10.1016/j.bbadis.2020.165968] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/21/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
The statin drugs ('statins') potently inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease de novo cholesterol biosynthesis and thereby reduce plasma cholesterol levels. Statins exhibit "pleiotropic" properties that are independent of their lipid-lowering effects. For example, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. Furthermore, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling. However, whether statins have clinically meaningful anti-cancer effects remains an area of active investigation. Both preclinical and clinical studies on the potential mechanisms of action of statins in several cancers have been reviewed in the literature. Considering the contradictory data on their efficacy, we present an up-to-date summary of the pleiotropic effects of statins in cancer therapy and review their impact on different malignancies. We also discuss the synergistic anti-cancer effects of statins when combined with other more conventional anti-cancer drugs to highlight areas of potential therapeutic development.
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Affiliation(s)
- Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Shayan Amiri
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, R4046 - 351 Taché Ave, Winnipeg, Manitoba R2H 2A6, Canada; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - Stevan Pecic
- Department of Chemistry and Biochemistry, California State University Fullerton, CA, USA
| | - Filip Machaj
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Department of Pathology, Pomeranian Medical University in Szczecin, Poland
| | - Jakub Rosik
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Department of Pathology, Pomeranian Medical University in Szczecin, Poland
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, Gliwice, Poland
| | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
| | - Reza Mahdian
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | | | - Shahla Shojaei
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Amir A Zeki
- University of California, Davis School of Medicine. Division of Pulmonary, Critical Care, and Sleep Medicine. U.C. Davis Lung Center, Davis, California, USA; Veterans Affairs Medical Center, Mather, California, USA
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, 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, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada.
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23
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Thomas JP, Loke YK, Alexandre L. Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials. Eur J Clin Pharmacol 2020; 76:1639-1651. [PMID: 32719919 PMCID: PMC7661422 DOI: 10.1007/s00228-020-02967-0] [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: 04/25/2020] [Accepted: 07/16/2020] [Indexed: 01/14/2023]
Abstract
PURPOSE A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. METHODS Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). RESULTS Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. CONCLUSION The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.
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Affiliation(s)
- John P Thomas
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK
| | - Yoon K Loke
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
| | - Leo Alexandre
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK.
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR47UY, UK.
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24
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Gachpazan M, Kashani H, Khazaei M, Hassanian SM, Rezayi M, Asgharzadeh F, Ghayour-Mobarhan M, Ferns GA, Avan A. The Impact of Statin Therapy on the Survival of Patients with Gastrointestinal Cancer. Curr Drug Targets 2020; 20:738-747. [PMID: 30539694 DOI: 10.2174/1389450120666181211165449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/25/2018] [Accepted: 12/05/2018] [Indexed: 12/13/2022]
Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins affect several potential pathways, including cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website clinicaltrials.gov. Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting. However, randomized controlled trials on specific cancer types in relation to statin use, as well as studies on populations without a clinical indication for using statins, have elucidated some potential underlying biological mechanisms, and the investigation of different statins is probably warranted. It would be useful for these trials to incorporate the assessment of tumour biomarkers predictive of statin response in their design. This review summarizes the recent preclinical and clinical studies that assess the application of statins in the treatment of gastrointestinal cancers with particular emphasize on their association with cancer risk.
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Affiliation(s)
- Meysam Gachpazan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hoda Kashani
- Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Rezayi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fereshteh Asgharzadeh
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, United Kingdom
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies; Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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25
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Oni TE, Biffi G, Baker LA, Hao Y, Tonelli C, Somerville TD, Deschênes A, Belleau P, Hwang CI, Sánchez-Rivera FJ, Cox H, Brosnan E, Doshi A, Lumia RP, Khaledi K, Park Y, Trotman LC, Lowe SW, Krasnitz A, Vakoc CR, Tuveson DA. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med 2020; 217:151922. [PMID: 32633781 PMCID: PMC7478739 DOI: 10.1084/jem.20192389] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/28/2020] [Accepted: 05/12/2020] [Indexed: 12/31/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
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Affiliation(s)
- Tobiloba E. Oni
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY
| | - Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Lindsey A. Baker
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Yuan Hao
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Claudia Tonelli
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Astrid Deschênes
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Chang-il Hwang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA
| | | | - Hilary Cox
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Erin Brosnan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Abhishek Doshi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Rebecca P. Lumia
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Kimia Khaledi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Youngkyu Park
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Scott W. Lowe
- Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY,Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | | | | | - David A. Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Correspondence to David A. Tuveson:
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26
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Meng Z, Yuan Q, Zhao J, Wang B, Li S, Offringa R, Jin X, Wu H. The m 6A-Related mRNA Signature Predicts the Prognosis of Pancreatic Cancer Patients. Mol Ther Oncolytics 2020; 17:460-470. [PMID: 32490170 PMCID: PMC7256444 DOI: 10.1016/j.omto.2020.04.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 04/23/2020] [Indexed: 12/19/2022] Open
Abstract
N6-methyladenosine (m6A) has an important epitranscriptomic modification that controls cancer self-renewal and cell fate. The addition of m6A to mRNA is a reversible modification. The deposition of m6A is encoded by a methyltransferase complex involving three homologous factors, jargonized as "writers," "erasers," and "readers." However, their roles in pancreatic adenocarcinoma (PAAD) are underexploited. With the use of The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we provided an mRNA signature that may improve the prognostic prediction of PAAD patients based on the genetic status of m6A regulators. PAAD patients with genetic alteration of m6A regulators had worse disease-free and overall survival. After comparing PAAD groups with/without genetic alteration of m6A regulators, we identified 196 differentially expressed genes (DEGs). Then, we generated a 16-mRNA signature score system through least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Multivariate cox regression analysis demonstrated that a high-risk score significantly correlates with poor prognosis. Moreover, time-dependent receiver operating characteristic (ROC) curves revealed it was effective in predicting the overall survival in both training and validation sets. PAH, ZPLD1, PPFIA3, and TNNT1 from our signature also exhibited an independent prognostic value. Collectively, these findings can improve the understanding of m6A modifications in PAAD and potentially guide therapies in PAAD patients.
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Affiliation(s)
- Zibo Meng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qingchen Yuan
- Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jingyuan Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shoukang Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rienk Offringa
- Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Xin Jin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Shen Y, Li M, Sun F, Zhang Y, Qu C, Zhou M, Shen F, Xu L. Low-dose photodynamic therapy-induced increase in the metastatic potential of pancreatic tumor cells and its blockade by simvastatin. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2020; 207:111889. [DOI: 10.1016/j.jphotobiol.2020.111889] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 04/03/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023]
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28
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Elsayed I, El-Dahmy RM, El-Emam SZ, Elshafeey AH, El Gawad NAA, El-Gazayerly ON. Response surface optimization of biocompatible elastic nanovesicles loaded with rosuvastatin calcium: enhanced bioavailability and anticancer efficacy. Drug Deliv Transl Res 2020; 10:1459-1475. [PMID: 32394333 DOI: 10.1007/s13346-020-00761-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Statins are mainly used for the treatment of hyperlipidemia, but recently, their anticancer role was extremely investigated. The goal of this study was to statistically optimize novel elastic nanovesicles containing rosuvastatin calcium to improve its transdermal permeability, bioavailability, and anticancer effect. The elastic nanovesicles were composed of Tween® 80, cetyl alcohol, and clove oil. The nanodispersions were investigated for their entrapment efficiency, particle size, zeta potential, polydispersity index, and elasticity. The optimized elastic nanovesicular dispersion is composed of 20% cetyl alcohol, 53.47% Tween 80, and 26.53% clove oil. Carboxy methylcellulose was utilized to convert the optimized elastic nanovesicular dispersion into elastic nanovesicular gels. Both the optimized dispersion and the optimized gel (containing 2% w/v carboxymethylcellulose) were subjected to in vitro release study, scanning and transmission electron microscopy, histopathological evaluation, and ex vivo permeation. The cell viability assay of the optimized gel on MCF-7 and Hela cell lines showed significant antiproliferative and potent cytotoxic effects when compared to the drug gel. Moreover, the optimized gel accomplished a significant increase in rosuvastatin bioavailability upon comparison with the drug gel. The optimized gel could be considered as a promising nanocarrier for statins transdermal delivery to increase their systemic bioavailability and anticancer effect. Graphical abstract.
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Potential Antimicrobial and Anticancer Activities of an Ethanol Extract from Bouea macrophylla. Molecules 2020; 25:molecules25081996. [PMID: 32344601 PMCID: PMC7221966 DOI: 10.3390/molecules25081996] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/18/2020] [Accepted: 04/19/2020] [Indexed: 12/31/2022] Open
Abstract
Bouea macrophylla is a tree widely grown throughout South East Asia. It is used in folk medicine for the treatment of various illnesses. The present study aimed to identify the chemical constituents and to test the antimicrobial and anticancer activities of an ethanol extract from B. macrophylla leaves. The extract exhibited excellent antibacterial properties against 9 out of 10 target microorganisms. including four Gram-negative bacteria (Escherichia coli, Shigella flexneri, Vibrio cholera, and Pseudomonas aeruginosa) and four Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, and Bacillus cereus), as well as a fungus (Candida albicans). In addition, the extract was also tested on HeLa and human colorectal carcinoma (HCT116) cells to evaluate its cytostatic effects. The ethanol extract was able to inhibit the proliferation of HeLa and HCT116 cells, showing IC50 = 24 ± 0.8 and 28 ± 0.9 µg/mL, respectively, whereas the IC50 values of doxorubicin (standard) were 13.6 ± 1.3 and 15.8 ± 1.1 µg/mL respectively. Also, we identified various bioactive compounds in the extract such as polyphenols, flavonoids, caryophyllene, phytol, and trans-geranylgeraniol by GC-MS, which could contribute to the extract's biological activities. Therefore, our findings strongly indicate that the constituents of the B. macrophylla ethanol extract could be active against the tested bacteria and fungi as well as cancer cells. Further investigation is needed to understand the mechanisms mediating the antimicrobial and anticancer effects and identify signaling pathways that could be targeted for therapeutic application.
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30
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Zhao Y, Wu TY, Zhao MF, Li CJ. The balance of protein farnesylation and geranylgeranylation during the progression of nonalcoholic fatty liver disease. J Biol Chem 2020; 295:5152-5162. [PMID: 32139507 DOI: 10.1074/jbc.rev119.008897] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Protein prenylation is an essential posttranslational modification and includes protein farnesylation and geranylgeranylation using farnesyl diphosphate or geranylgeranyl diphosphate as substrates, respectively. Geranylgeranyl diphosphate synthase is a branch point enzyme in the mevalonate pathway that affects the ratio of farnesyl diphosphate to geranylgeranyl diphosphate. Abnormal geranylgeranyl diphosphate synthase expression and activity can therefore disrupt the balance of farnesylation and geranylgeranylation and alter the ratio between farnesylated and geranylgeranylated proteins. This change is associated with the progression of nonalcoholic fatty liver disease (NAFLD), a condition characterized by hepatic fat overload. Of note, differential accumulation of farnesylated and geranylgeranylated proteins has been associated with differential stages of NAFLD and NAFLD-associated liver fibrosis. In this review, we summarize key aspects of protein prenylation as well as advances that have uncovered the regulation of associated metabolic patterns and signaling pathways, such as Ras GTPase signaling, involved in NAFLD progression. Additionally, we discuss unique opportunities for targeting prenylation in NAFLD/hepatocellular carcinoma with agents such as statins and bisphosphonates to improve clinical outcomes.
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Affiliation(s)
- Yue Zhao
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China.,MOE Key Laboratory of Model Animal for Disease Study, Model Animals Research Center, Nanjing University, Nanjing 210093, China
| | - Tian-Yu Wu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Meng-Fei Zhao
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Chao-Jun Li
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China .,MOE Key Laboratory of Model Animal for Disease Study, Model Animals Research Center, Nanjing University, Nanjing 210093, China
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31
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Han S, Li X, Xia Y, Yu Z, Cai N, Malwal SR, Han X, Oldfield E, Zhang Y. Farnesyl Pyrophosphate Synthase as a Target for Drug Development: Discovery of Natural-Product-Derived Inhibitors and Their Activity in Pancreatic Cancer Cells. J Med Chem 2019; 62:10867-10896. [DOI: 10.1021/acs.jmedchem.9b01405] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Shuai Han
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
| | - Xin Li
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
- Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China
| | - Yun Xia
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
- Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China
| | - Zhengsen Yu
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
| | - Ningning Cai
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
- Collaborative Innovation Center for Biotherapy, Sichuan University, 610041 Chengdu, Sichuan, China
| | - Satish R. Malwal
- Department of Chemistry, University of Illinois at Urbana—Champaign, Urbana, Illinois 61801, United States
| | - Xu Han
- Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 300308 Tianjin, China
| | - Eric Oldfield
- Department of Chemistry, University of Illinois at Urbana—Champaign, Urbana, Illinois 61801, United States
| | - Yonghui Zhang
- School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, 100084 Beijing, China
- Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, 100084 Beijing, China
- Collaborative Innovation Center for Biotherapy, Sichuan University, 610041 Chengdu, Sichuan, China
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Cheung KS, Chen L, Chan EW, Seto WK, Wong ICK, Leung WK. Statins reduce the progression of non-advanced adenomas to colorectal cancer: a postcolonoscopy study in 187 897 patients. Gut 2019; 68:1979-1985. [PMID: 30808646 DOI: 10.1136/gutjnl-2018-317714] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 02/02/2019] [Accepted: 02/10/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Postcolonoscopy colorectal cancer (PCCRC) accounts for up to 9% of all CRCs. Statins have been shown to be associated with a lower CRC risk. We aimed to investigate whether PCCRC risk was also lower among statin users. METHODS This is a retrospective cohort study using a territory-wide electronic healthcare database in Hong Kong including patients aged 40 years or above who had undergone colonoscopies between 2005 and 2013. Exclusion criteria included prior colorectal cancer (CRC), inflammatory bowel disease, prior colectomy and CRC detected within 6 months of index colonoscopy. We defined statin use as at least 90-day use before index colonoscopy. Medication use was traced up to 5 years before index colonoscopy. PCCRC-3y was defined as cancer diagnosed between 6 and 36 months after index colonoscopy. Sites of CRC were categorised as proximal (proximal to splenic flexure) and distal cancer. The subdistribution HR (SHR) of PCCRC-3y with statin use was derived by propensity score matching based on covariates (including patient factors, concurrent medication use and endoscopy centre's performance). RESULTS Of 187 897 eligible subjects, 854 (0.45%) were diagnosed with PCCRC-3y. Statin use was associated with a lower PCCRC-3y risk (SHR: 0.72; 95% CI 0.55 to 0.95; p=0.018). Subgroup analysis shows that SHRs were 0.50 (95% CI 0.28 to 0.91; p=0.022) for proximal and 0.80 (95% CI 0.59 to 1.09; p=0.160) for distal cancer. Older (>60 years) patients, women and those without diabetes mellitus or polyps appeared to benefit more from statins. CONCLUSIONS Statins were associated with a lower PCCRC risk, particularly for proximal cancer.
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Affiliation(s)
- Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lijia Chen
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Esther W Chan
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ian C K Wong
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Hong Kong.,UCL School of Pharmacy, UCL, London, UK
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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Beyond the boundaries of cardiology: Still untapped anticancer properties of the cardiovascular system-related drugs. Pharmacol Res 2019; 147:104326. [DOI: 10.1016/j.phrs.2019.104326] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023]
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Statin Use After Diagnosis of Hepatocellular Carcinoma Is Associated With Decreased Mortality. Clin Gastroenterol Hepatol 2019; 17:2117-2125.e3. [PMID: 30625400 PMCID: PMC6612541 DOI: 10.1016/j.cgh.2018.12.046] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/19/2018] [Accepted: 12/23/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Statin use is associated with a lower risk of developing hepatocellular carcinoma (HCC). However, it is unclear whether postdiagnosis statin use is associated with a reduced risk of death in patients with HCC. METHODS We performed a retrospective analysis of data from 15,422 patients with HCC in the Veterans Administration Central Cancer Registry, diagnosed from 2002 through 2016. We identified statin prescriptions that were filled before and after the cancer diagnosis and used time-dependent Cox regression models to calculate adjusted hazard ratios (HRs) and 95% CIs for risk of death. We used a time-varying exposure to avoid immortal time bias, and a 3-month lag (following up patients from 3 months after the cancer diagnosis) to reduce reverse causation. A sensitivity analysis was conducted varying the lag duration between date of cancer diagnosis and start of follow-up evaluation. RESULTS Statin use after diagnosis was recorded for 14.9% of patients with HCC. We found that postdiagnosis statin use was associated with a decreased risk of cancer-specific death (adjusted HR, 0.85; 95% CI, 0.77-0.93) and all-cause mortality (HR, 0.89; 95% CI, 0.83-0.95). The magnitudes of these inverse associations were consistent for patients who used high or low doses of statins, and the inverse associations remained across a range of lag periods (from 0 months to 12 months after HCC diagnosis). We found no evidence for effect modification by prediagnosis statin use, or by presentation- or treatment-related factors, and no independent association with prediagnosis statin use. CONCLUSIONS In a retrospective analysis of data from veterans with HCC, use of statins (high or low doses) after a diagnosis of HCC was associated with reduced mortality.
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Kirkegård J, Lund JL, Mortensen FV, Cronin-Fenton D. Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population-based cohort study. Int J Cancer 2019; 146:610-616. [PMID: 30861115 DOI: 10.1002/ijc.32264] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 02/07/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022]
Abstract
Statins (HMG-CoA reductase inhibitors) have antiinflammatory and possibly anticancer properties. We hypothesized that statin use is associated with lower risk of pancreatic cancer in patients with chronic pancreatitis. This nationwide population-based cohort study included all Danish patients diagnosed with incident chronic pancreatitis from 1 January 1996 to 31 December 2012. We used the Danish National Prescription Registry to ascertain information on statin prescriptions for members of the study population before and after their pancreatitis diagnosis. We computed crude incidence rates, incidence rate ratios (IRRs) and adjusted hazard ratios (HRs) with associated 95% confidence intervals (CIs) for pancreatic cancer, comparing statin users with nonusers. We computed HRs using Cox proportional hazards regression with statins treated as a time-varying exposure lagged by 1 year, adjusting for age, sex, socioeconomic status and individual comorbidities. The study included 8,311 chronic pancreatitis patients with a median age of 54 years. We observed 153 pancreatic cancers during 60,365 person-years of follow-up. The unadjusted IRR comparing statin users with nonusers was 1.00 (95% CI: 0.60-1.60). Adjustment for potential confounders only had a small impact on the estimate (adjusted HR: 0.90; 95% CI: 0.56-1.44). Our findings suggest that statin use is not associated with pancreatic cancer risk in patients with chronic pancreatitis.
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Affiliation(s)
- Jakob Kirkegård
- Department of Surgery, Section for Hepato-Pancreato-Biliary Surgery, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Jennifer L Lund
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.,Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Frank Viborg Mortensen
- Department of Surgery, Section for Hepato-Pancreato-Biliary Surgery, Aarhus University Hospital, Aarhus, Denmark
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Notarnicola M, Caruso MG, Tutino V, De Nunzio V, Gigante I, De Leonardis G, Veronese N, Rotolo O, Reddavide R, Stasi E, Miraglia C, Nouvenne A, Meschi T, De' Angelis GL, Di Mario F, Leandro G. Nutrition and lipidomic profile in colorectal cancers. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:87-96. [PMID: 30561400 PMCID: PMC6502197 DOI: 10.23750/abm.v89i9-s.7955] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Adherence to a healthy diet has been reported to be essential for the primary prevention of colorectal cancer, through a reduction of tissue inflammation, a low concentration of circulating lipoproteins and lower levels of serum cholesterol. Since an altered expression of the fatty acids pattern has been demonstrated to be a crucial event in colorectal carcinogenesis, lipidomic analysis is considered able to identify early diagnostic and prognostic biomarkers of complex diseases such as colorectal cancer. METHODS cell membrane fatty acid profile and serum lipoproteins pattern were evaluated by gas chromatography and electrophoresis method respectively. RESULTS There is a close association between diet and lipidomic profile in colorectal cancer, both in pre-clinical and clinical studies. A modified serum lipoproteins pattern has been demonstrated to be predominant in intestinal tumors. CONCLUSIONS The study of fatty acids profile in cell membrane and the evaluation of serum lipoproteins subfractions could be useful to have an integrate vision on the interactions between lipids and the pathogenesis of colorectal cancer and to understand the mechanisms of action and the consequences of these interactions on human health status.
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Affiliation(s)
- Maria Notarnicola
- National Institute of Gastroenterology "S. De Bellis" Research Hospital, Castellana Grotte, Italy.
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Cytotoxic Activity and Kinetic Release Study of Lovastatin-Loaded Ph-Sensitive Polymersomes. Pharm Chem J 2018. [DOI: 10.1007/s11094-018-1888-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Li J, Liu R, Sun Z, Tang S, Wang L, Liu C, Zhao W, Yao Y, Sun C. The association between statin use and endometrial cancer survival outcome: A meta-analysis. Medicine (Baltimore) 2018; 97:e13264. [PMID: 30461633 PMCID: PMC6393075 DOI: 10.1097/md.0000000000013264] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous studies on the association between statin use and survival outcomes in gynecologic cancers have presented conflicting results. No independent studies to elucidate the association between statin use and survival outcomes of endometrial cancer (EC) have been conducted. METHODS To gather updated evidence, we carried out an extensive literature search on Medline (PubMed and OvidSP), Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), wanfang data, and Vip network to identify all potential studies on the effect of statins on the prognosis of endometrial carcinoma. The design and quality of all studies were evaluated, and a fixed-effects model was used to calculate pooled hazard ratios (HRs) for overall survival (OS) and disease-specific survival (DSS). RESULTS Of the 219 articles screened, 9 articles were eligible, including 8 articles and 1 abstract. A total of 5923 patients with endometrial cancer who used statins were identified. Statin use was related to increased overall survival (HR, 0.80; 95% confidence interval [CI], 0.66-0.95, without significant heterogeneity, I = 52%, P = .080). Statin users also had increased disease-specific survival (HR, 0.69; 95% CI, 0.61-0.79, I = 0.0%). CONCLUSION Statins are beneficial to the survival outcome of patients with endometrial cancer. The selection of statins as a 1st-line agent seems justified for endometrial carcinoma.
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Affiliation(s)
- Jia Li
- Weifang Medical University
| | - Ruijuan Liu
- Weifang Traditional Chinese Hospital, Weifang City
| | - Zhengdi Sun
- Weifang Traditional Chinese Hospital, Weifang City
| | - Shifeng Tang
- Weifang Traditional Chinese Hospital, Weifang City
| | - Lu Wang
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | - Cun Liu
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
| | | | | | - Changgang Sun
- Shandong University of Traditional Chinese Medicine, Jinan City, Shandong Province, China
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Macchini M, Chiaravalli M, Zanon S, Peretti U, Mazza E, Gianni L, Reni M. Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. Cancer Treat Rev 2018; 72:1-6. [PMID: 30414985 DOI: 10.1016/j.ctrv.2018.10.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/27/2018] [Indexed: 12/27/2022]
Abstract
By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.
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Affiliation(s)
- Marina Macchini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Marta Chiaravalli
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Silvia Zanon
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Umberto Peretti
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Elena Mazza
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Luca Gianni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
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40
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Jian-Yu E, Graber JM, Lu SE, Lin Y, Lu-Yao G, Tan XL. Effect of Metformin and Statin Use on Survival in Pancreatic Cancer Patients: a Systematic Literature Review and Meta-analysis. Curr Med Chem 2018; 25:2595-2607. [PMID: 28403788 DOI: 10.2174/0929867324666170412145232] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 01/05/2017] [Accepted: 01/06/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVE Current epidemiological studies report conflicting results for the effect of statin or metformin on pancreatic cancer overall survival. This literature review and meta-analysis summarize the studies reporting an association between statin or metformin use and overall survival of pancreatic cancer patients. METHODS We systematically searched for studies about the association between statin or metformin use and pancreatic cancer overall survival in electronic databases (PubMed, ISI Web of Science, MEDLINE, Cochrane, Scopus, Google Scholar). A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses were conducted to assess the robustness of the findings. RESULTS Of 116 statin-related articles identified, 6 retrospective cohort studies representing 12,057 patients were included. There was significant heterogeneity between studies. Statin use was associated with improved survival among pancreatic cancer patients (meta-HR = 0.75; 95% CI: 0.59, 0.90; P < 0.001). Of 311 metformin-related articles, 8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified. Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95% CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between studies. CONCLUSION Our findings suggest that the improved survival time of pancreatic cancer patients are associated with statin or metformin use. Due to the multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed with larger prospective individual-level studies.
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Affiliation(s)
- Jian-Yu E
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Judith M Graber
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.,Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, United States
| | - Shou-En Lu
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Yong Lin
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States
| | - Grace Lu-Yao
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States
| | - Xiang-Lin Tan
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States.,Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States.,Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08904, United States
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41
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Hamidreza Kheiri M, Alimohammadi N, Danafar H. Preparation of biocompatible copolymeric micelles as a carrier of atorvastatin and rosuvastatin for potential anticancer activity study. Pharm Dev Technol 2018; 24:303-313. [PMID: 29741465 DOI: 10.1080/10837450.2018.1474221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on investigational breast cancer. Thus, in this study, biodegradable polymeric micelles as carrier of statins were prepared using biodegradable copolymers (PCL-PEG-PCL). These nanoparticles were prepared with two statins (atorvastatin and rosuvastatin) and drug loading, release, kinetic release, and anti-cancer activity of these drugs were studied. The triblock copolymer PCL-PEG-PCL was synthesized by a ring opening polymerization of e-caprolactone in the presence of PEG as the initiator and Sn(oct)2 as the catalyst. The synthesized copolymers and nanoparticles were characterized by FTIR, HNMR, GPC, DLS, and AFM analyses. The drug loading and release of drugs were studied by UV-Vis. Additionally, MTT assays on HFF-2 cell lines were performed for determination of biocompatibility of micelles. Finally, the anticancer activity of micelles was studied on MCF-7 breast cancer cell lines. The results showed that the average diameter of nanoparticles was less than 45 nm. The loading capacity of atorvastatin and rosuvastatin was 20.0 ± 1.01% and 13.21 ± 1.18%, respectively, and encapsulation efficiency of atorvastatin and rosuvastatin was 88.19 ± 1.11% and 69.32 ± 0.23%, respectively. The results showed strong and dose-dependent inhibition of cell (MCF-7line) growth by the nanoparticles compared with statins. The result of cell viability assay on the MCF-7 cell line verified that the bare nanoparticles showed little inherent cytotoxicity whereas the statins-loaded nanoparticles were cytotoxic.
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Affiliation(s)
- Manjili Hamidreza Kheiri
- a Zanjan Pharmaceutical Biotechnology Research Center , Zanjan University of Medical Sciences , Zanjan , Iran.,b Cancer Gene Therapy Research Center , Zanjan University of Medical Sciences , Zanjan , Iran
| | - Niusha Alimohammadi
- a Zanjan Pharmaceutical Biotechnology Research Center , Zanjan University of Medical Sciences , Zanjan , Iran.,b Cancer Gene Therapy Research Center , Zanjan University of Medical Sciences , Zanjan , Iran
| | - Hossein Danafar
- b Cancer Gene Therapy Research Center , Zanjan University of Medical Sciences , Zanjan , Iran.,c Zanjan Applied Pharmacology Research Center , Zanjan University of Medical Sciences , Zanjan , Iran.,d Zanjan Pharmaceutical Nanotechnology Research Center , Zanjan University of Medical Sciences , Zanjan , Iran.,e Department of Pharmaceutical Nanotechnology, School of Pharmacy , Zanjan University of Medical Sciences , Zanjan , Iran
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Cheung KS, Leung WK. Risk of gastric cancer development after eradication of Helicobacter pylori. World J Gastrointest Oncol 2018; 10:115-123. [PMID: 29770171 PMCID: PMC5952268 DOI: 10.4251/wjgo.v10.i5.115] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/23/2018] [Accepted: 04/16/2018] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is the most important risk factor for gastric cancer (GC) development through the Correa’s gastric carcinogenesis cascade. However, H. pylori eradication alone does not eliminate GC, as pre-neoplastic lesions (atrophic gastritis, intestinal metaplasia and dysplasia) may have already developed in some patients. It is therefore necessary to identify patients at high-risk for gastric cancer after H. pylori eradication to streamline the management plan. If the patients have not undergone endoscopy with histologic assessment, the identification of certain clinical risk factors and non-invasive testing (serum pepsinogen) can predict the risk of atrophic gastritis. For those with suspected atrophic gastritis, further risk stratification by endoscopy with histologic assessment according to validated histologic staging systems would be advisable. Patients with higher stages may require long-term endoscopic surveillance. Apart from secondary prevention to reduce deaths by diagnosing GC at an early stage, identifying medications that could potentially modify the GC risk would be desirable. The potential roles of a number of medications have been suggested by various studies, including proton pump inhibitors (PPIs), aspirin, statins and metformin. However, there are currently no randomized clinical trials to address the impact of these medications on GC risk after H. pylori eradication. In addition, most of these studies failed to adjust for the effect of concurrent medications on GC risk. Recently, large population-based retrospective cohort studies have shown that PPIs were associated with an increased GC risk after H. pylori eradication, while aspirin was associated with a lower risk. The roles of other agents in reducing GC risk after H. pylori eradication remain to be determined.
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Affiliation(s)
- Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Wai K Leung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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Kashfi K. The dichotomous role of H 2S in cancer cell biology? Déjà vu all over again. Biochem Pharmacol 2018; 149:205-223. [PMID: 29397935 PMCID: PMC5866221 DOI: 10.1016/j.bcp.2018.01.042] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/17/2018] [Indexed: 02/09/2023]
Abstract
Nitric oxide (NO) a gaseous free radical is one of the ten smallest molecules found in nature, while hydrogen sulfide (H2S) is a gas that bears the pungent smell of rotten eggs. Both are toxic yet they are gasotransmitters of physiological relevance. There appears to be an uncanny resemblance between the general actions of these two gasotransmitters in health and disease. The role of NO and H2S in cancer has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and antiinflammatory properties have been described. These paradoxes have been explained for both gasotransmitters in terms of each having a dual or biphasic effect that is dependent on the local flux of each gas. In this review/commentary, I have discussed the major roles of NO and H2S in carcinogenesis, evaluating their dual nature, focusing on the enzymes that contribute to this paradox and evaluate the pros and cons of inhibiting or inducing each of these enzymes.
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Affiliation(s)
- Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, NY, USA.
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44
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Alarcon Martinez T, Zeybek ND, Müftüoğlu S. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on MCF-7 Breast Cancer Cells. Balkan Med J 2018; 35:256-262. [PMID: 29485098 PMCID: PMC5981123 DOI: 10.4274/balkanmedj.2017.0604] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background: Recently, cytotoxic effects of statins on breast cancer cells have been reported. However, the mechanism of anti-proliferative effects is currently unknown. Autophagy is non-apoptotic programmed cell death, which is characterized by degradation of cytoplasmic components and as having a role in cancer pathogenesis. Aims: To investigate the anti-proliferative effects of atorvastatin on MCF-7 human breast adenocarcinoma cells with respect to both autophagy and apoptosis. Study Design: Cell culture study. Methods: Cell viability was analyzed using WST-1 cell proliferation assay. Apoptosis was determined by the TUNEL method, whereas autophagy was assessed by Beclin-1 and LC3B immunofluorescence staining. Ultrastructural analysis of cells was performed by electron microscopy. Results: Atorvastatin reduced MCF-7 cell proliferation in a dose- and time-dependent manner inducing TUNEL-, Beclin-1-, and LC3B-positive cells. Moreover, ultrastructural analysis showed apoptotic, autophagic, and necrotic morphological changes in treatment groups. A statistically significant increase in the apoptotic index was detected with higher concentrations of atorvastatin at 24 h and 48 h (p<0.05). Conclusion: The anti-proliferative effects of atorvastatin on breast cancer cells is mediated by the induction of both apoptosis and autophagy which shows statins as a potential treatment option for breast cancer.
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Affiliation(s)
- Tuğba Alarcon Martinez
- Department of Histology and Embryology, Hacettepe University School of Medicine, Ankara, Turkey,Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey
| | - Naciye Dilara Zeybek
- Department of Histology and Embryology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Sevda Müftüoğlu
- Department of Histology and Embryology, Hacettepe University School of Medicine, Ankara, Turkey
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Long-term statin use in patients with lung cancer and dyslipidemia reduces the risk of death. Oncotarget 2018; 7:42208-42215. [PMID: 27283991 PMCID: PMC5173128 DOI: 10.18632/oncotarget.9906] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/20/2016] [Indexed: 12/02/2022] Open
Abstract
Background Clinical studies have obtained inconsistent results of statin use on cancer outcomes. This study investigated the association between statin use and lung cancer mortality. Results The use of statin decreased mortality (hazard ratio = 0.91; 95% confidence interval: 0.86–0.96; P < .01). The patients with a high cumulative defined daily dose of statin use before lung cancer diagnosis exhibited a low risk of mortality. Materials and Methods We conducted a population-based case-control study of patients with dyslipidemia. Among them, 6270 had used statins for at least 3 months before lung cancer diagnosis, and 6270 had never used statins. Conclusions We found that statin use can reduce lung cancer mortality. A further prospective study is necessary to confirm these findings.
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Chang FM, Wang YP, Lang HC, Tsai CF, Hou MC, Lee FY, Lu CL. Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: A population-based study. Hepatology 2017; 66:896-907. [PMID: 28318053 DOI: 10.1002/hep.29172] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 02/22/2017] [Accepted: 03/16/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED Statin use decreases the risk of decompensation and mortality in patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in the general population or cirrhosis due to other causes, such as hepatitis B virus (HBV) infection or alcohol, remains unknown. Statin use also decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV and HCV infection. It is unclear whether the effect can be observed in patients with pre-existing cirrhosis. The goal of this study was to determine the effect of statin use on rates of decompensation, mortality, and HCC in HBV-, HCV-, and alcohol-related cirrhosis. Patients with cirrhosis were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000 to 2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≥28, were selected and served as the case cohort. Statin nonusers (<28 cDDD) were matched through propensity scores. The association between statin use and risk of decompensation, mortality, and HCC were estimated. A total of 1350 patients with cirrhosis were enrolled. Among patients with cirrhosis, statin use decreased the risk of decompensation, mortality, and HCC in a dose-dependent manner (P for trend <0.0001, <0.0001, and 0.009, respectively). Regression analysis revealed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.25-0.62) or HCV infection (HR, 0.51; 95% CI, 0.29-0.93). The lowered risk of decompensation was of borderline significance among statin users with alcohol-related cirrhosis (HR, 0.69; 95% CI, 0.45-1.07). CONCLUSION Statin use decreases the decompensation rate in both HBV- and HCV-related cirrhosis. Of borderline significance is a decreased decompensation rate in alcohol-related cirrhosis. (Hepatology 2017;66:896-907).
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Affiliation(s)
- Fu-Ming Chang
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Yuanshan Branch, Taipei Veterans General Hospital, I-Lan, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yen-Po Wang
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Hui-Chu Lang
- Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan
| | - Chia-Fen Tsai
- Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ching-Liang Lu
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
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Buranrat B, Suwannaloet W, Naowaboot J. Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells. Oncol Lett 2017; 14:6243-6250. [PMID: 29113274 DOI: 10.3892/ol.2017.6783] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 02/07/2017] [Indexed: 01/01/2023] Open
Abstract
Simvastatin is a low density lipoprotein-lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF-7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF-7 cells was evaluated by a sulforhodamine B and colony formation assay. To delineate the mechanisms of cell death, the following parameters were measured: Reactive oxygen species (ROS) production using the fluorescence probe dihydroethidium; caspase 3 activity by the fluorometry method; gene expression by quantitative polymerase chain reaction; and apoptotic- and proliferative-related protein levels by western blotting. MCF-7 cell proliferation was significantly suppressed by 24-48 h treatment with simvastatin alone. Doses of 10-50 µM simvastatin also enhanced the cytotoxicity of doxorubicin against MCF-7 cells in a dose-dependent manner, and decreased the colony-forming ability of MCF-7 cells. Simvastatin alone or in combination with doxorubicin significantly increased ROS levels. Combination treatment significantly decreased expression of the cell cycle regulatory protein Ras-related C3 botulinum toxin substrate 1 and numerous downstream proteins including cyclin-dependent kinase (Cdk) 2, Cdk4 and Cdk6. Additionally, simvastatin in combination with doxorubicin significantly induced expression of the cyclin-dependent kinase inhibitor p21, increased cytochrome c and caspase 3 expression and reduced cyclin D1 expression. In conclusion, simvastatin acts synergistically with the anticancer drug doxorubicin against MCF-7 cells, possibly through a downregulation of the cell cycle or induction of apoptosis. Although additional studies are required, simvastatin and doxorubicin combination may be a reasonable regimen for the treatment of breast cancer.
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Affiliation(s)
- Benjaporn Buranrat
- Faculty of Medicine, Mahasarakham University, Talad, Maha Sarakham 44000, Thailand
| | - Wanwisa Suwannaloet
- College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, Warin chamrap, Ubon Ratchathani 34190, Thailand
| | - Jarinyaporn Naowaboot
- Division of Pharmacology, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Rangsit, Pathum Thani 12120, Thailand
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48
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E JY, Lu SE, Lin Y, Graber JM, Rotter D, Zhang L, Petersen GM, Demissie K, Lu-Yao G, Tan XL. Differential and Joint Effects of Metformin and Statins on Overall Survival of Elderly Patients with Pancreatic Adenocarcinoma: A Large Population-Based Study. Cancer Epidemiol Biomarkers Prev 2017; 26:1225-1232. [PMID: 28619830 PMCID: PMC5540782 DOI: 10.1158/1055-9965.epi-17-0227] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 04/19/2017] [Accepted: 05/17/2017] [Indexed: 12/18/2022] Open
Abstract
Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive.Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders.Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90-0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56-0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94-1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95-1.05).Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer.Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225-32. ©2017 AACR.
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Affiliation(s)
- Jian-Yu E
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Shou-En Lu
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Yong Lin
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Biostatistics, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Judith M Graber
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - David Rotter
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Lanjing Zhang
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Pathology, University Medical Center of Princeton, Plainsboro, New Jersey
- Department of Biological Sciences, Rutgers, The State University of New Jersey, Newark, New Jersey
| | - Gloria M Petersen
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Kitaw Demissie
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
- Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Grace Lu-Yao
- Department of Medical Oncology, Sidney Kimmel Cancer Center at Jefferson, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
- Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania
- Jefferson College of Population Health, Philadelphia, Pennsylvania
| | - Xiang-Lin Tan
- Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
- Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, New Jersey
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
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49
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Statin use and endometrial cancer risk: a meta-analysis. Oncotarget 2017; 8:62425-62434. [PMID: 28977956 PMCID: PMC5617516 DOI: 10.18632/oncotarget.18658] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 05/04/2017] [Indexed: 02/07/2023] Open
Abstract
Several studies have evaluated the association between statin use and endometrial cancer risk. We carried out a meta-analysis of randomized controlled trials (RCTs) and non-randomized studies to evaluate the effect of statins on endometrial cancer risk. A comprehensive search of electronic databases, conference abstracts and clinical trial registers was conducted for published and unpublished results. Studies that evaluated exposure to statins and endometrial cancer risk were considered. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using either a fixed-effects or a random-effects model. Two RCTs and eleven non-randomized studies (four cohort and seven case-control studies) involving 9,517 cases of endometrial cancer were included in the analysis. There was no evidence of an association between statin use and endometrial cancer risk either among RCTs (RR, 0.72; 95% CI, 0.19 to 2.67) or among non-randomized studies (RR, 0.94; 95% CI, 0.82 to 1.07). Combined analysis of all included studies also showed that statin use did not significantly affect endometrial cancer risk (RR, 0.94; 95% CI, 0.82 to 1.07). The sensitivity analysis confirmed the stability of our results. Our findings do not support a protective effect of statins against endometrial cancer at the population level.
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Xie W, Ning L, Huang Y, Liu Y, Zhang W, Hu Y, Lang J, Yang J. Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis. Oncotarget 2017; 8:41508-41517. [PMID: 28489569 PMCID: PMC5522329 DOI: 10.18632/oncotarget.17242] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 04/11/2017] [Indexed: 01/02/2023] Open
Abstract
Previous studies investigating the association between statin use and survival outcomes in gynecologic cancers have yielded controversial results. We conducted a systematic review and meta-analysis to evaluate the association based on available evidence. We searched the databases of the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from inception to January 2017. Studies that evaluated the association between statin use and survival outcomes in gynecologic cancers were included. Pooled hazard ratios (HRs) for overall survival, disease-specific survival and progression-free survival were calculated using a fixed-effects model. A total of 11 studies involving more than 6,920 patients with endocrine-related gynecologic cancers were identified. In a meta-analysis of 7 studies involving 5,449 patients with endocrine-related gynecologic cancers, statin use was linked to improved overall survival (HR, 0.71; 95% confidence interval [CI], 0.63 to 0.80) without significant heterogeneity (I2 = 33.3%). Statin users also had improved disease-specific survival (3 studies, HR, 0.72; 95% CI, 0.58 to 0.90, I2 = 35.1%) and progression-free survival (3 studies, HR, 0.68; 95% CI, 0.49 to 0.93, I2 = 33.6%) in endocrine-related gynecologic cancers. Our findings support that statin use has potential survival benefits for patients with endocrine-related gynecologic cancers. Further large-scale prospective studies are required to validate our findings.
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Affiliation(s)
- Weimin Xie
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Ning
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuenan Huang
- Department of General Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yan Liu
- Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Wen Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingchao Hu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinghe Lang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiaxin Yang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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