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Zarif Attalla K, Hassan DH, Teaima MH, Yousry C, El-Nabarawi MA, Said MA, Elhabal SF. Enhanced Intranasal Delivery of Atorvastatin via Superparamagnetic Iron-Oxide-Loaded Nanocarriers: Cytotoxicity and Inflammation Evaluation and In Vivo, In Silico, and Network Pharmacology Study for Targeting Glioblastoma Management. Pharmaceuticals (Basel) 2025; 18:421. [PMID: 40143197 PMCID: PMC11944838 DOI: 10.3390/ph18030421] [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: 02/15/2025] [Revised: 03/06/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
Objective: This study aims to develop an intranasal (IN) delivery system for glioblastoma multiforme (GBM) management using repurposed superparamagnetic iron-oxide (SPION) loaded with atorvastatin (ATO)-nanostructured lipid carrier (NLC). Methods: Emulsification and ultrasonication were used to formulate ATO-NLCs, and the best formula was loaded with SPION to make the final atorvastatin/superparamagnetic iron oxide-loaded nanostructured lipid carrier (ASN) formulation. Entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and drug release after 6 h (Q6h) were evaluated for NLCs. ASN was tested for cytotoxicity on T98G cancer cells, and the cell cycle was examined to determine cell death. Furthermore, the ability of the optimal formulation to suppress the levels of inflammatory biomarkers was investigated in Lipopolysaccharide (LPS)-induced inflammation. The brain-targeting behavior of IN-ASN was visualized in rabbits via confocal laser scanning microscopy (CLSM). Results: The optimum NLC exhibited a spherical shape, EE% of 84.0 ± 0.67%, PS of 282.50 ± 0.51 nm, ZP of -18.40 ± 0.15 mV, and Q6h of 89.23%. The cytotoxicity of ASN against cancer cells was 4.4-fold higher than ATO suspension, with a 1.3-fold increment in cell apoptosis. ASN showed significantly reduced pro-inflammatory biomarkers (IL-β, IL-6, TNF-α, TLR4, NF-қB), whereas CLSM revealed enhanced brain delivery with no observed histopathological nasal irritation. The in silico analysis demonstrated enhanced ATO-ADME (absorption, distribution, metabolism, and excretion) properties, while the network pharmacology study identified 10 target GBM genes, among which MAPK3 was the most prominent with a good binding score as elucidated by the simulated docking study. Conclusions: These findings may present ATO/SPION-NLCs as significant evidence for repurposing atorvastatin in the treatment of glioblastoma multiforme.
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Affiliation(s)
- Kristina Zarif Attalla
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza 12566, Egypt;
| | - Doaa H. Hassan
- Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza 12566, Egypt;
| | - Mahmoud H. Teaima
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (M.H.T.); (C.Y.); (M.A.E.-N.)
| | - Carol Yousry
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (M.H.T.); (C.Y.); (M.A.E.-N.)
- Department of Pharmaceutics and Industrial Pharmacy, School of Pharmacy, Newgiza University, km. 22 Cairo-Alex Road, Giza P.O. Box 12577, Egypt
| | - Mohamed A. El-Nabarawi
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (M.H.T.); (C.Y.); (M.A.E.-N.)
| | - Mohamed A. Said
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;
| | - Sammar Fathy Elhabal
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt
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Castanon A, Duffield S, Ramagopalan S, Reynolds R. Why is target trial emulation not being used in health technology assessment real-world data submissions? J Comp Eff Res 2024; 13:e240091. [PMID: 38850128 PMCID: PMC11284816 DOI: 10.57264/cer-2024-0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 05/24/2024] [Indexed: 06/09/2024] Open
Affiliation(s)
| | - Stephen Duffield
- National Institute of Health & Care Excellence, Manchester, M1 4BT, UK
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Xu W, Chan L, Danaei G, Lu Y, Wan EYF. Long-term statin use and risk of cancers: a target trial emulation study. J Clin Epidemiol 2024; 172:111425. [PMID: 38880437 DOI: 10.1016/j.jclinepi.2024.111425] [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: 01/19/2024] [Revised: 03/13/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND AND OBJECTIVES Controversy exists regarding potential cancer risks associated with long-term statin use. This study aimed to use real-world data to investigate the association between cancer incidence and sustained statin use over a 10-year period. METHODS Using territory-wide public electronic medical records in Hong Kong, we emulated a sequence of nested target trials on patients who met indications for statin initiation in each calendar month from January 2009 to December 2011. Statin initiators and noninitiators were matched in a 1:1 ratio to mimic the randomization of eligible person-trials at baseline. Pooled logistic regression was applied to obtain the hazard ratios for the cancer incidence of statin initiation in intention-to-treat analysis, with the adjustment of baseline confounders and the inverse probability weighting accounting for the postbaseline confounders in per-protocol analysis. RESULTS Among 8,560,051 eligible person-trials, 119,715 noninitiators were matched to 119,715 initiators for analysis. Over the 10-year study period, the estimated hazard ratio of overall cancer incidence was 0.96 (0.87, 1.05), and the standardized 10-year risk difference was -0.4% (-1.3%, 0.4%) in the per-protocol analysis. For the cancer subtypes of interest (ie, breast cancer, colorectal cancer, hematological cancer, pancreatic cancer, prostate cancer, urothelial carcinoma, and lung cancer), the 10-year risk differences ranged from -0.3% to 0.2% in the per-protocol analysis. No observable risk change for cancer was found in all patient subgroups with regards to their sex, age (<70/≥70 years), Charlson Comorbidity Index (≤4/>4), and statin indication. CONCLUSION Statin use has no impact on cancer incidence over a 10-year follow-up period, including all cancer subtypes of interest and patient subgroups with regards to sex, age, comorbidities, and statin indications.
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Affiliation(s)
- Wanchun Xu
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Linda Chan
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; The Bau Institute of Medical and Health Sciences Education, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Family Medicine and Primary Care, The University of Hong Kong - Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Goodarz Danaei
- Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Yuan Lu
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, USA
| | - Eric Yuk Fai Wan
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Sha Tin, Hong Kong Special Administrative Region, China.
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Zhang Y, Jiang Z, Chen L, Lei T, Zheng X. Repurposing lipid-lowering drugs on asthma and lung function: evidence from a genetic association analysis. J Transl Med 2024; 22:615. [PMID: 38961500 PMCID: PMC11223406 DOI: 10.1186/s12967-024-05359-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 05/29/2024] [Indexed: 07/05/2024] Open
Abstract
OBJECTIVE To explore the correlation between asthma risk and genetic variants affecting the expression or function of lipid-lowering drug targets. METHODS We conducted Mendelian randomization (MR) analyses using variants in several genes associated with lipid-lowering medication targets: HMGCR (statin target), PCSK9 (alirocumab target), NPC1L1 (ezetimibe target), APOB (mipomersen target), ANGPTL3 (evinacumab target), PPARA (fenofibrate target), and APOC3 (volanesorsen target), as well as LDLR and LPL. Our objective was to investigate the relationship between lipid-lowering drugs and asthma through MR. Finally, we assessed the efficacy and stability of the MR analysis using the MR Egger and inverse variance weighted (IVW) methods. RESULTS The elevated triglyceride (TG) levels associated with the APOC3, and LPL targets were found to increase asthma risk. Conversely, higher LDL-C levels driven by LDLR were found to decrease asthma risk. Additionally, LDL-C levels (driven by APOB, NPC1L1 and HMGCR targets) and TG levels (driven by the LPL target) were associated with improved lung function (FEV1/FVC). LDL-C levels driven by PCSK9 were associated with decreased lung function (FEV1/FVC). CONCLUSION In conclusion, our findings suggest a likely causal relationship between asthma and lipid-lowering drugs. Moreover, there is compelling evidence indicating that lipid-lowering therapies could play a crucial role in the future management of asthma.
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Affiliation(s)
- Yue Zhang
- Department of Pediatrics, Xiangya Hospital, Central South University, Hunan, 410008, China
| | - Zichao Jiang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Hunan, 410008, China
| | - Lingli Chen
- Department of Pediatrics, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Ting Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Hunan, 410008, China.
| | - Xiangrong Zheng
- Department of Pediatrics, Xiangya Hospital, Central South University, Hunan, 410008, China.
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Sonam Dongsar T, Tsering Dongsar T, Gupta G, Alsayari A, Wahab S, Kesharwani P. PLGA nanomedical consignation: A novel approach for the management of prostate cancer. Int J Pharm 2024; 652:123808. [PMID: 38224758 DOI: 10.1016/j.ijpharm.2024.123808] [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: 10/20/2023] [Revised: 12/27/2023] [Accepted: 01/12/2024] [Indexed: 01/17/2024]
Abstract
The malignancy of the prostate is a complicated ailment which impacts millions of male populations around the globe. Despite the multitude of endeavour accomplished within this domain, modalities that are involved in the ameliorative management of predisposed infirmity are still relent upon non-specific and invasive procedures, thus imposing a detrimental mark on the living standard of the individual. Also, the orchestrated therapeutic interventions are still incompetent in substantiating a robust and unabridged therapeutic end point owing to their inadequate solubility, low bioavailability, limited cell assimilation, and swift deterioration, thereby muffling the clinical application of these existing treatment modalities. Nanotechnology has been employed in an array of modalities for the medical management of malignancies. Among the assortment of available nano-scaffolds, nanocarriers composed of a bio-decomposable and hybrid polymeric material like PLGA hold an opportunity to advance as standard chemotherapeutic modalities. PLGA-based nanocarriers have the prospect to address the drawbacks associated with conventional cancer interventions, owing to their versatility, durability, nontoxic nature, and their ability to facilitate prolonged drug release. This review intends to describe the plethora of evidence-based studies performed to validate the applicability of PLGA nanosystem in the amelioration of prostate malignancies, in conjunction with PLGA focused nano-scaffold in the clinical management of prostate carcinoma. This review seeks to explore numerous evidence-based studies confirming the applicability of PLGA nanosystems in ameliorating prostate malignancies. It also delves into the role of PLGA-focused nano-scaffolds in the clinical management of prostate carcinoma, aiming to provide a comprehensive perspective on these advancements.
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Affiliation(s)
- Tenzin Sonam Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Tenzin Tsering Dongsar
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Garima Gupta
- Graphic Era Hill University, Dehradun, 248002, India; School of Allied Medical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Abdulrhman Alsayari
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
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Okita Y, Sobue T, Zha L, Kitamura T, Iwasaki M, Inoue M, Yamaji T, Tsugane S, Sawada N. Long-term use of anti-cholesterol drugs and cancer risks in a Japanese population. Sci Rep 2024; 14:2896. [PMID: 38316869 PMCID: PMC10844312 DOI: 10.1038/s41598-024-53252-4] [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: 08/16/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024] Open
Abstract
Several studies have investigated the association between the use of anti-cholesterol drugs and cancer risks, of which results have been inconsistent. This study included 67,768 participants from the Japan Public Health Center-based Prospective Study. The data on anti-cholesterol drug use was collected using three questionnaires of the survey conducted every five years. We divided the participants into three groups according to the duration of the anti-cholesterol drug use. Multivariable-adjusted Cox proportional hazard regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). During the 893,009 person-years of follow-up from the 10-year follow-up survey, 8,775 participants (5,387 men and 3,388 women) were newly diagnosed with cancers. The duration of anti-cholesterol drug use was significantly associated with a decreased risk of liver cancer (HR:0.26, 95% CI 0.11-0.64 in > 5 y group) and with an increased risk of pancreatic cancer (HR:1.59, 95% CI 1.03-2.47 in > 5 y group). Moreover, a different trend was observed between men and women in the association with the risk of lung cancer. This study suggested that long-term use of anti-cholesterol drugs may have associations with a decreased incidence of liver cancer and with an increased incidence of pancreatic cancers.
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Affiliation(s)
- Yuki Okita
- Division of Environmental Medicine and Population Sciences, Department of Social Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Tomotaka Sobue
- Division of Environmental Medicine and Population Sciences, Department of Social Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
| | - Ling Zha
- Division of Environmental Medicine and Population Sciences, Department of Social Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Tetsuhisa Kitamura
- Division of Environmental Medicine and Population Sciences, Department of Social Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
- National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Shinjuku-Ku, Tokyo, 162-8636, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Chuo-Ku, Tokyo, 104-0045, Japan
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Krishnan J, Symington A, Kernohan N, Bray S, Robertson A, Nabi G. HMG co-reductase expression and response to intravesical Bacillus Calmette-Guérin in patients with high grade non-muscle invasive urinary bladder cancer receiving statins. Scott Med J 2024; 69:3-9. [PMID: 37960856 DOI: 10.1177/00369330231213935] [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: 11/15/2023]
Abstract
BACKGROUND Cardiovascular disease affects over 7 million people in the UK and statins are often prescribed to mitigate cardiovascular risks. The effect of statins on a number of cancers is debated and their effect on Bacillus Calmette-Guérin (BCG) responsiveness in non-muscle invasive urinary bladder cancer (NMIBC) is not fully understood. AIMS This study aims to explore the difference in HMG Co-A reductase (HMGCR) expression in NMIBC on immunochemistry in BCG responders and non-responders while on statins. METHOD Three hundred and thirty-two cases of intravesical BCG treatment for high-risk NMIBC between November 2003 and December 2017 were identified. Patients taking statins for at least 12 months before the diagnosis of NIMBC and with a follow-up of at least 5 years were included. They were divided into BCG responders and non-responders. Tumour tissue from these patients was immunohistochemically stained and quantitative image analysis carried out to assess and compare HMGCR expression in the groups. RESULTS & CONCLUSION This study showed a differential expression of HMGCR in responders vs. non-responders to BCG for high-risk NMIBC on statins. This data should form the basis of a further research and multi-centre study in a larger cohort, using HMGCR as a biomarker of response in patients on statins.
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Affiliation(s)
- Jamie Krishnan
- Urology, Ninewells Hospital and Medical School, Dundee, UK
| | | | - Neil Kernohan
- Urology, Ninewells Hospital and Medical School, Dundee, UK
| | - Suan Bray
- Urology, Ninewells Hospital and Medical School, Dundee, UK
| | | | - Ghulam Nabi
- Urology, Ninewells Hospital and Medical School, Dundee, UK
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Suresh S, Begum RF, Singh SA, Vellapandian C. An Update to Novel Therapeutic Options for Combating Tuberculosis: Challenges and Future Prospectives. Curr Pharm Biotechnol 2024; 25:1778-1790. [PMID: 38310450 DOI: 10.2174/0113892010246389231012041120] [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: 01/26/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 02/05/2024]
Abstract
Drug repurposing is an ongoing and clever strategy that is being developed to eradicate tuberculosis amid challenges, of which one of the major challenges is the resistance developed towards antibiotics used in standard directly observed treatment, short-course regimen. Surpassing the challenges in developing anti-tuberculous drugs, some novel host-directed therapies, repurposed drugs, and drugs with novel targets are being studied, and few are being approved too. After almost 4 decades since the approval of rifampicin as a potent drug for drugsusceptible tuberculosis, the first drug to be approved for drug-resistant tuberculosis is bedaquiline. Ever since the urge to drug discovery has been at a brisk as this milestone in tuberculosis treatment has provoked the hunt for novel targets in tuberculosis. Host-directed therapy and repurposed drugs are in trend as their pharmacological and toxicological properties have already been researched for some other diseases making the trial facile. This review discusses the remonstrance faced by researchers in developing a drug candidate with a novel target, the furtherance in tuberculosis research, novel anti-tuberculosis agents approved so far, and candidates on trial including the host-directed therapy, repurposed drug and drug combinations that may prove to be potential in treating tuberculosis soon, aiming to augment the awareness in this context to the imminent researchers.
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Affiliation(s)
- Swathi Suresh
- Department of Pharmacology, SRM College of Pharmacy, SRMIST, Kattankulathur, 603 203, Tamil Nadu, India
| | - Rukaiah Fatma Begum
- Department of Pharmacology, SRM College of Pharmacy, SRMIST, Kattankulathur, 603 203, Tamil Nadu, India
| | - S Ankul Singh
- Department of Pharmacology, SRM College of Pharmacy, SRMIST, Kattankulathur, 603 203, Tamil Nadu, India
| | - Chitra Vellapandian
- Department of Pharmacology, SRM College of Pharmacy, SRMIST, Kattankulathur, 603 203, Tamil Nadu, India
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Li H, Zhang L, Yang F, Feng X, Fu R, Zhao R, Li X, Li H. Lipid-lowering drugs affect lung cancer risk via sphingolipid metabolism: a drug-target Mendelian randomization study. Front Genet 2023; 14:1269291. [PMID: 38034491 PMCID: PMC10687161 DOI: 10.3389/fgene.2023.1269291] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/02/2023] [Indexed: 12/02/2023] Open
Abstract
Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated. Results: APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70-0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71-0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46-0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56-0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43-0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17-4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38-6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07-0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43-0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition. Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition.
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Affiliation(s)
- Honglin Li
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Lei Zhang
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Feiran Yang
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiaoteng Feng
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Fu
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Ruohan Zhao
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiurong Li
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Huijie Li
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Sheridan P, Chen C, Thompson CA, Benmarhnia T. Immortal Time Bias With Time-Varying Exposures in Environmental Epidemiology: A Case Study in Lung Cancer Survival. Am J Epidemiol 2023; 192:1754-1762. [PMID: 37400995 PMCID: PMC10558188 DOI: 10.1093/aje/kwad135] [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: 02/22/2022] [Revised: 01/19/2023] [Accepted: 06/04/2023] [Indexed: 07/05/2023] Open
Abstract
Immortal time bias is a well-recognized bias in clinical epidemiology but is rarely discussed in environmental epidemiology. Under the target trial framework, this bias is formally conceptualized as a misalignment between the start of study follow-up (time 0) and treatment assignment. This misalignment can occur when attained duration of follow-up is encoded into treatment assignment using minimums, maximums, or averages. The bias can be exacerbated in the presence of time trends commonly found in environmental exposures. Using lung cancer cases from the California Cancer Registry (2000-2010) linked with estimated concentrations of particulate matter less than or equal to 2.5 μm in aerodynamic diameter (PM2.5), we replicated previous studies that averaged PM2.5 exposure over follow-up in a time-to-event model. We compared this approach with one that ensures alignment between time 0 and treatment assignment, a discrete-time approach. In the former approach, the estimated overall hazard ratio for a 5-μg/m3 increase in PM2.5 was 1.38 (95% confidence interval: 1.36, 1.40). Under the discrete-time approach, the estimated pooled odds ratio was 0.99 (95% confidence interval: 0.98, 1.00). We conclude that the strong estimated effect in the former approach was likely driven by immortal time bias, due to misalignment at time 0. Our findings highlight the importance of appropriately conceptualizing a time-varying environmental exposure under the target trial framework to avoid introducing preventable systematic errors.
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Affiliation(s)
- Paige Sheridan
- Correspondence to Dr. Paige Sheridan, Herbert Wertheim School of Public Health, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (e-mail: )
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Mohammadi KA, Brackin T, Schwartz GG, Steg PG, Szarek M, Manvelian G, Pordy R, Fazio S, Geba GP. Effect of proprotein convertase subtilisin/kexin type 9 inhibition on cancer events: A pooled, post hoc, competing risk analysis of alirocumab clinical trials. Cancer Med 2023; 12:16859-16868. [PMID: 37458138 PMCID: PMC10501297 DOI: 10.1002/cam4.6310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/15/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023] Open
Abstract
OBJECTIVE Assess the risk of new and worsening cancer events among participants who received the lipid-lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. DESIGN Pooled post hoc analysis. SETTING Six phase 3 or phase 4 placebo-controlled randomised trials with alirocumab. PARTICIPANTS A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). INTERVENTION Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low-density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high-intensity or maximum-tolerated statin therapy. OUTCOMES AND MEASURES The first new or worsening incident cancer events were assessed during the treatment-emergent adverse event period. Four outcomes were evaluated: any-neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancers, and stricter definition of hormone-sensitive cancers. Sub-distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. RESULTS Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancer and strict definition of hormone-sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub-distribution hazards ratio [95% CI], 0.93 [0.82-1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub-distribution hazards ratio 0.83; 95% CI, 0.70-0.99). CONCLUSIONS Intensive low-density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events.
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Affiliation(s)
| | | | | | - Philippe Gabriel Steg
- Université Paris‐CitéParisFrance
- FACT (French Alliance for Cardiovascular Trials) INSERM U1148ParisFrance
- Assistance Publique‐Hôpitaux de ParisHôpital BichatParisFrance
| | - Michael Szarek
- State University of New YorkDownstate School of Public HealthBrooklynNew YorkUSA
- CPC Clinical Research and Division of CardiologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | | | - Robert Pordy
- Regeneron Pharmaceuticals, Inc.TarrytownNew YorkUSA
| | - Sergio Fazio
- Regeneron Pharmaceuticals, Inc.TarrytownNew YorkUSA
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12
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Li Y, Wu S, Zhao X, Hao S, Li F, Wang Y, Liu B, Zhang D, Wang Y, Zhou H. Key events in cancer: Dysregulation of SREBPs. Front Pharmacol 2023; 14:1130747. [PMID: 36969840 PMCID: PMC10030587 DOI: 10.3389/fphar.2023.1130747] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.
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Affiliation(s)
- Yunkuo Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shouwang Wu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Xiaodong Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shiming Hao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yuxiong Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Difei Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
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13
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Kong L, Zhao Q, Han Z, Xue W, Hu Z, Niu Z, Duan G. Prognostic significance of TG/HDL-C and non-HDL-C/HDL-C ratios in patients with non-small cell lung cancer: a retrospective study. J Int Med Res 2022; 50:3000605221117211. [PMID: 35949158 PMCID: PMC9373166 DOI: 10.1177/03000605221117211] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Lung cancer is a malignancy with high a mortality rate that threatens human health. This study is aimed to explore the correlation among the triglyceride/high-density lipoprotein ratio (TG/HDL-C), non-high-density lipoprotein/high-density lipoprotein ratio (non-HDL-C/HDL-C) and survival of patients with non-small cell lung cancer (NSCLC) undergoing video-associated thoracic surgery (VATS). METHODS This retrospective study analyzed 284 patients with NSCLC who underwent VATS at Hebei General Hospital, Shijiazhuang, China. The time-dependent receiver operating characteristic curve was used to determine the optimal cutoff value and evaluate the area under the curve. Kaplan-Meier and Cox regression analyses were performed to determine the prognostic effect. RESULTS The median overall survival (OS) was 46 months. Patients with low TG/HDL-C and low non-HDL-C/HDL-C had a longer OS. The low non-HDL-C/HDL-C group showed a longer mean survival time (59.00 vs. 52.35 months). Multivariate analysis revealed that TG/HDL-C and non-HDL-C/HDL-C were significantly correlated with OS. CONCLUSIONS TG/HDL-C and non-HDL-C/HDL-C are associated with the prognosis of patients with NSCLC who received VATS. Preoperative serum TG/HDL-C and non-HDL-C/HDL-C may be effective independent prognostic factors for predicting the outcomes of patients with NSCLC.
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Affiliation(s)
- Lingxin Kong
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
- Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Qingtao Zhao
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
| | - Zhaohui Han
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
| | - Wenfei Xue
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
| | - Zhonghui Hu
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
| | - Zhancong Niu
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
| | - Guochen Duan
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, China
- Department of Thoracic Surgery, Children’s Hospital of Hebei Province, Shijiazhuang, China
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14
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Marcianò G, Palleria C, Casarella A, Rania V, Basile E, Catarisano L, Vocca C, Bianco L, Pelaia C, Cione E, D’Agostino B, Citraro R, De Sarro G, Gallelli L. Effect of Statins on Lung Cancer Molecular Pathways: A Possible Therapeutic Role. Pharmaceuticals (Basel) 2022; 15:589. [PMID: 35631415 PMCID: PMC9144184 DOI: 10.3390/ph15050589] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/06/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is a common neoplasm, usually treated through chemotherapy, radiotherapy and/or surgery. Both clinical and experimental studies on cancer cells suggest that some drugs (e.g., statins) have the potential to improve the prognosis of cancer. In fact, statins blocking the enzyme "hydroxy-3-methylglutaryl-coenzyme A reductase" exert pleiotropic effects on different genes involved in the pathogenesis of lung cancer. In this narrative review, we presented the experimental and clinical studies that evaluated the effects of statins on lung cancer and described data on the effectiveness and safety of these compounds. We also evaluated gender differences in the treatment of lung cancer to understand the possibility of personalized therapy based on the modulation of the mevalonate pathway. In conclusion, according to the literature data, statins exert multiple effects on lung cancer cells, even if the evidence for their use in clinical practice is lacking.
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Affiliation(s)
- Gianmarco Marcianò
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Caterina Palleria
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
| | - Alessandro Casarella
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Vincenzo Rania
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Emanuele Basile
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Luca Catarisano
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Cristina Vocca
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
| | - Luigi Bianco
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
| | - Corrado Pelaia
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ed. Polifunzionale, Arcavacata di Rende, 87036 Rende, Italy;
| | - Bruno D’Agostino
- Department of Experimental Medicine L. Donatelli, Section of Pharmacology, School of Medicine, University of Campania Luigi Vanvitelli, 80100 Naples, Italy;
| | - Rita Citraro
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
- Research Centre FAS@UMG, Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
- Research Centre FAS@UMG, Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy
| | - Luca Gallelli
- Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy; (G.M.); (A.C.); (V.R.); (E.B.); (L.C.); (C.V.); (R.C.); (G.D.S.)
- Operative Unit of Clinical Pharmacology and Pharmacovigilanze, Mater Domini Hospital, 88100 Catanzaro, Italy; (C.P.); (L.B.); (C.P.)
- Research Centre FAS@UMG, Department of Health Science, School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy
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Tulbah AS. Inhaled Atorvastatin Nanoparticles For Lung Cancer. Curr Drug Deliv 2022; 19:1073-1082. [PMID: 35473526 DOI: 10.2174/1567201819666220426091500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/05/2022] [Accepted: 01/29/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Lung cancer is one of the main causes of mortality globally. This research paper aims at the development of an inhaled nanotechnology for lung cancer to deliver an atorvastatin calcium compound, for lung cancer, capable of reaching the tumor site directly via inhalation. METHODS Atorvastatin calcium micellar nanoparticles (ATO-NPs) encapsulated with Pluronic F-127 and polyvinyl alcohol (PVA) were manufactured utilizing the solvent and anti-solvent precipitation technique. The physicochemical features of the formulation were evaluated in terms of their physicochemical characteristics using Fourier transform infrared spectroscopy, differential scanning calorimetry, and dynamic light scattering. Additionally, the Andersen Cascade impactor was used at 15 L/minutes to assist in the aerosols performances of the formulation. The ATO-NPs formula's cell viability was tested in vitro using the A549 non-small cell lung cancer cell type. RESULTS Transmission electron microscopy was utilized to determine the ATO-NPs particle morphology, demonstrating a spherical shape with a smooth surface. The fine particle fraction of the aerosol produced was 62.70 ± 1.18%. This finding suggests that atorvastatin micellar nanoparticles are suitable for medication administration by inhalation with a wide particle size dispersion. Moreover, it was found in vitro that concentrations up to 21 µg/mL of the atorvastatin nanoparticles were safe and non-toxic on the cell model. CONCLUSION This study found that atorvastatin micellar nanoparticles for inhalation could potentially be used for lung cancer treatment.
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Affiliation(s)
- Alaa S Tulbah
- Pharmaceutics Department, College of Pharmacy, Umm Al Qura University, Makkah, Saudi Arabia
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16
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Design and Characterization of Atorvastatin Dry Powder Formulation as a potential Lung Cancer Treatment. Saudi Pharm J 2022; 29:1449-1457. [PMID: 35002383 PMCID: PMC8720807 DOI: 10.1016/j.jsps.2021.11.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/05/2021] [Indexed: 11/20/2022] Open
Abstract
Lung cancer is the leading cause of cancer death. Many studies have shown the beneficial effects of Atorvastatin in decreasing the mortality risk and improving survival among patients with lung cancer. This research paper focuses on improving AVT cytotoxic activity and cellular uptake by developing mannitol microcarriers as a promising drug delivery system for lung cancer treatment and, studying the impact of improving inhalation deposition on the delivery and Dry Powder formulations efficiency. The AVT loaded mannitol (AM) microparticles (AVT-AM) formulation was prepared by spray drying and characterized for its physicochemical properties and aerodynamic deposition. The results revealed that the AVT-AM formulation has good flow properties and aerosol deposition with a particle size of 3418 nm ± 26.86. The formulation was also assessed in vitro for cytotoxicity effects (proliferation, apoptosis, and cell cycle progression) on A549 human lung adenocarcinoma. Compared with free AVT, the AVT-AM formulation has significantly higher cellular uptake and anti-cancer properties by disrupting cell cycle progression via either apoptosis or cell cycle arrest in the G2/M phase. This study shows that AVT loaded mannitol microcarriers may provide a potentially effective and sustained pulmonary drug delivery for lung cancer treatment.
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Patnaik SK, Petrucci C, Barbi J, Seager RJ, Pabla S, Yendamuri S. Obesity-Specific Association of Statin Use and Reduced Risk of Recurrence of Early Stage NSCLC. JTO Clin Res Rep 2021; 2:100254. [PMID: 34877556 PMCID: PMC8633682 DOI: 10.1016/j.jtocrr.2021.100254] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 02/03/2023] Open
Abstract
Introduction Statins, used for their lipid-lowering activity, have anti-inflammatory and anticancer properties as well. We evaluated this potential benefit of statin use in patients with NSCLC. Methods All 613 patients with pathologic stage 1 or 2 NSCLC who had lobectomy without neoadjuvant therapy at our institution during 2008 to 2015 were included. Association between presurgery statin use and overall survival and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression. Association of statin use with tumor transcriptome was evaluated in another 350 lung cancer cases. Results Univariable analyses did not reveal a statistically significant association of statin use with either overall survival or RFS, with hazard ratio equals to 1.19 and 0.70 (Wald p = 0.28 and 0.09), respectively. In subgroup analyses, significantly improved RFS was found in statin users, but only in overweight/obese patients (body mass index [BMI] > 25; n = 422), with univariable and multivariable hazard ratio of 0.49 and 0.46 (p = 0.005 and 0.002), respectively, but not in patients with BMI less than or equal to 25 (n = 191; univariable p = 0.21). Transcriptomes of tumor statin users had high expression of tumoricidal genes such as granzyme A and interferon-γ compared with those of nonusers among high- but not low-BMI patients with lung cancer. Conclusions Our study suggests that statins may improve the outcome of early stage NSCLC but only in overweight or obese patients. This benefit may stem from a favorable reprogramming of the antitumor immune response that statins perpetrate specifically in the obese.
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Affiliation(s)
- Santosh K Patnaik
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Cara Petrucci
- Department of Health Behavior, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Joseph Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | | | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York
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Luttman JH, Hoj JP, Lin KH, Lin J, Gu JJ, Rouse C, Nichols AG, MacIver NJ, Wood KC, Pendergast AM. ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells. Cell Rep 2021; 37:109880. [PMID: 34706244 PMCID: PMC8579324 DOI: 10.1016/j.celrep.2021.109880] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 08/29/2021] [Accepted: 10/04/2021] [Indexed: 12/25/2022] Open
Abstract
Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease. Metabolic reprogramming in tumors is an adaptation that generates vulnerabilities that can be exploited for developing new therapies. Here Luttman et al. identify synergism between ABL allosteric inhibitors and lipophilic statins to impair metastatic lung cancer cell outgrowth and colonization, leading to increased survival in mouse models of advanced disease.
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Affiliation(s)
- Jillian Hattaway Luttman
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jacob P Hoj
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Kevin H Lin
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jiaxing Lin
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Jing Jin Gu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Clay Rouse
- Division of Laboratory Animal Resources, Duke University School of Medicine, Durham, NC, USA
| | - Amanda G Nichols
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Nancie J MacIver
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Ann Marie Pendergast
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA.
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Ma C, Wang X, Guo J, Liu P. Prognostic significance of preoperative serum triglycerides and high-density lipoproteins cholesterol in patients with non-small cell lung cancer: a retrospective study. Lipids Health Dis 2021; 20:69. [PMID: 34598703 PMCID: PMC8487143 DOI: 10.1186/s12944-021-01492-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/17/2021] [Indexed: 01/22/2023] Open
Abstract
Background Abnormalities in serum lipids and lipoproteins have been documented to link to the risk of cancers in recent years, but its prognostic value for cancer is not known. This study retrospectively evaluated the significance of preoperative serum lipids and lipoproteins for NSCLC’s prognosis. Methods A retrospective review was implemented of 551 patients succumbed to NSCLC. A ROC curve was utilized to determine the best cut-off value and area under the ROC curve. Kaplan-Meier and a Cox proportional hazards model were utilized to perform survival analysis. Results With a median follow-up of 42 months, the NSCLC patients in the high TG (> 1.21 mmol/L) and low HDL-C (≤ 1.26 mmol/L) two groups exhibited shorter OS and DFS. In multivariable analysis, preoperative HDL-C and TG can work as independent prognosis factors for OS (P<0.001 for both) and DFS (P<0.05 for both) in patients succumbed to NSCLC. Conclusion Abnormalities of serum lipids and lipoproteins metabolism linked to the survival outcomes of NSCLC. Preoperative serum HDL-C and TG may be promising biomarkers to predict the NSCLC patients’ prognosis.
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Affiliation(s)
- Cong Ma
- Department of Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, Hubei, China
| | - Xiaoyan Wang
- Jiashan Maternal and Child Health Hospital, Jiaxing, Zhejiang, 314100, China
| | - Jingjing Guo
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ping Liu
- Department of Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, Hubei, China.
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Whelton SP, Marshall CH, Cainzos-Achirica M, Dzaye O, Blumenthal RS, Nasir K, McClelland RL, Blaha MJ. Pooled Cohort Equations and the competing risk of cardiovascular disease versus cancer: Multi-Ethnic study of atherosclerosis. Am J Prev Cardiol 2021; 7:100212. [PMID: 34611644 PMCID: PMC8387297 DOI: 10.1016/j.ajpc.2021.100212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/03/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND many of the modifiable variables in the Pooled Cohort Equations (PCE) are shared risk factors for cardiovascular disease (CVD) and cancer, which are the two leading causes of death in the United States. We sought to determine the utility of the PCE risk for the synergistic risk prediction of CVD and cancer. METHODS we identified 5,773 participants (61.5 years and 53% women) without baseline CVD or cancer from the Multi-Ethnic study of atherosclerosis. The primary outcome was time to first event of either incident CVD or incident cancer. We calculated competing risk and cause-specific hazard models to examine the association of the PCE groups (<7.5%, 7.5-<20%, ≥20%) with the competing risk of CVD and cancer. RESULTS the rate of incident CVD and cancer was higher with higher PCE risk, but the absolute event rate was low for both CVD and cancer when the PCE risk was <7.5%. Participants with a PCE <7.5% had a higher rate of cancer (4.8) compared to CVD (3.3) per 1000 person-years, while the rate of CVD (11.5) was higher than cancer (8.6) for PCE between 7.5 and <20%. The ratio of CVD to cancer increased in a logarithmic manner and at a PCE risk of approximately 7.2% the risk for CVD and cancer was equal. In adjusted competing risk modeling, a PCE risk of ≥20% compared to <7.5% was associated with a greater risk of both CVD [7.18 (95% CI 5.77-8.94)] and cancer [3.59 (95% CI 2.91-4.43)]. CONCLUSIONS these findings highlight the importance of age and modifiable risk factors for CVD and cancer prevention. In addition, it suggests that the PCE can provide important information for both CVD and cancer risk stratification, which may guide a synergistic approach to screening and preventive therapies for the two leading causes of death in the United States.
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Affiliation(s)
- Seamus P. Whelton
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
| | - Catherine Handy Marshall
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
- Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States
| | - Miguel Cainzos-Achirica
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
- Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, United States
| | - Omar Dzaye
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
| | - Roger S. Blumenthal
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
| | - Khurram Nasir
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
- Division of Cardiovascular Prevention and Wellness, Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, United States
| | | | - Michael J. Blaha
- Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease, 600 North Wolfe Street, Blalock 524A, Baltimore, MD 21287, United States
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21
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Wong YJ, Qiu TY, Ng GK, Zheng Q, Teo EK. Efficacy and Safety of Statin for Hepatocellular Carcinoma Prevention Among Chronic Liver Disease Patients: A Systematic Review and Meta-analysis. J Clin Gastroenterol 2021; 55:615-623. [PMID: 33606427 DOI: 10.1097/mcg.0000000000001478] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/29/2020] [Indexed: 02/05/2023]
Abstract
INTRODUCTION AND AIM Hepatocellular carcinoma (HCC) is a deadly complication among patients with chronic liver disease (CLD). Controversies on the efficacy and safety of statin to prevent HCC among patients with CLD remain despite the growing evidences. We aim to investigate the efficacy and safety of using statin for HCC prevention among adult with CLD. METHODS We performed a systematic search of 4 electronic databases (PubMed/MEDLINE, EMBASE, Cochrane library, and ClinicalTrial.gov) up to April 15, 2020. We selected all types of studies evaluating the statin use and the risk of HCC among CLD patients, regardless of language, region, publication date, or status. The primary endpoint was the pooled risk of HCC. The secondary endpoint was the risk of statin-associated myopathy. RESULT From 583 citations, we included a total of 13 studies (1,742,260 subjects, 7 types of statins), fulfilling the inclusion criteria, evaluating efficacy and safety of statin in CLD patients for HCC prevention. All studies were observational (2 nested case-control studies, 11 cohort studies), and no randomised trial was identified. We found that statin user has a lower pooled risk of HCC development (hazard ratio=0.57, 95% confidence interval: 0.52-0.62, I2=42%). HCC reduction was consistent among statin users in cirrhosis, hepatitis B virus, and hepatitis C virus infections. The risk of statin-associated myopathy was similar between statin user and nonuser (hazard ratio=1.07, 95% confidence interval=0.91-1.27). CONCLUSION Statin use was safe and associated with a lower pooled risk of HCC development among adults with CLD. Given the bias with observation studies, prospective randomised trial is needed to confirm this finding.
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Affiliation(s)
- Yu-Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital
- Yong Loo Lin School of Medicine, National University of Singapore
| | - Tian-Yu Qiu
- Department of Gastroenterology and Hepatology, Changi General Hospital
| | | | | | - Eng Kiong Teo
- Department of Gastroenterology and Hepatology, Changi General Hospital
- Yong Loo Lin School of Medicine, National University of Singapore
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22
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Comparison of Transcriptomic Profiles of MiaPaCa-2 Pancreatic Cancer Cells Treated with Different Statins. Molecules 2021; 26:molecules26123528. [PMID: 34207840 PMCID: PMC8226792 DOI: 10.3390/molecules26123528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 01/24/2023] Open
Abstract
Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.
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23
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Liang W, Shi J, Xia H, Wei X. A Novel Ruthenium-Fluvastatin Complex Downregulates SNCG Expression to Modulate Breast Carcinoma Cell Proliferation and Apoptosis via Activating the PI3K/Akt/mTOR/VEGF/MMP9 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5537737. [PMID: 34221232 PMCID: PMC8221895 DOI: 10.1155/2021/5537737] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/16/2021] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
Breast cancer is the most common cause of malignancy and cancer-related morbidity and death worldwide that requests effective and safe chemotherapy. Evaluation of metallodrug-based anticancer agents and statins as chemotherapeutics with fewer side effects is a largely unexplored research field. Synthesis and characterization of the ruthenium-fluvastatin complex were achieved using multiple spectroscopic techniques and thus further examined to evaluate its chemotherapeutic prospects in both MDA-MB-231 and MCF-7 cancer lines and eventually in vivo models of DMBA-induced mammary carcinogenesis in rodents. Our studies indicate that the metal and ligand chelation was materialized by the ligand's functional groups of carbonyl (=O) oxygen and hydroxyl (-OH), and the complex has been observed to be crystalline and able to chelate with CT-DNA. The complex was able to reduce cell proliferation and activate apoptotic events in breast carcinoma cell lines MCF-7 and MDA-MB-231. In addition, the complex was able to modify p53 expressions to interfere with apoptosis in the carcinoma of the breast, stimulated by the intrinsic apoptotic path assisted by Bcl2 and Bax in vivo, yet at the same point, controlling the PI3K/Akt/mTOR/VEGF pathway, as obtained from western blotting, correlates with the MMP9-regulated tumor mechanisms. Our research reveals that ruthenium-fluvastatin chemotherapy may disrupt, rescind, or interrupt breast carcinoma progression by modifying intrinsic apoptosis as well as the antiangiogenic cascade, thereby taking the role of a potential candidate in cancer therapy for the immediate future.
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Affiliation(s)
- Wei Liang
- Department of Oncology, Nanjing First Hospital Nanjing Medical University, Nanjing 210006, China
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital Nanjing Medical University, Nanjing 210006, China
| | - Haiyan Xia
- Department of Oncology, Nanjing First Hospital Nanjing Medical University, Nanjing 210006, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital Nanjing Medical University, Nanjing 210006, China
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24
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Batais M, Almigbal T, Alotaibi K, Alodhayani A, Alkhushail A, Altheaby A, Alhantoushi M, Alsaad S, Dalbhi SA, Alghamdi Y. Angiotensin converting enzyme inhibitors and risk of lung cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e25714. [PMID: 33907158 PMCID: PMC8084080 DOI: 10.1097/md.0000000000025714] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND We performed a meta-analysis to determine whether a consistent relationship exists between the use of angiotensin converting enzyme inhibitors (ACEIs) and the risk of lung cancer. Accordingly, we summarized and reviewed previously published quantitative studies. METHODS Eligible studies with reference lists published before June 1st, 2019 were obtained from searching several databases. Random effects' models were used to summarize the overall estimate of the multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Thirteen observational studies involving 458,686 ACEI users were included in the analysis, Overall, pooled risk ratios indicate that ACEIs use was not a risk factor for lung cancer (RR 0.982, 95% C.I. 0.873 - 1.104; P = .76). There was significant heterogeneity between the studies (Q = 52.54; P < .001; I2 = 86.07). There was no significant association between ACEIs use and lung cancer in studies with over five years of ACEIs exposure (RR 0.95, 95% C.I. 0.75 - 1.20; P = .70); and ≤ 5years of exposure to ACEIs (RR 0.98, 95% C.I. 0.83 - 1.15; P = .77). There were no statistically significant differences in the pooled risk ratio obtained according to the study design (Q = 0.65; P = .723) and the comparator regimen (Q = 3.37; P = .19). CONCLUSIONS The use of ACEIs was not associated with an increased risk of lung cancer. Nevertheless, well-designed observational studies with different ethnic populations are still needed to evaluate the long-term (over 10 years) association between ACEIs use and lung cancer.
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Affiliation(s)
- Mohammed Batais
- King Saud University Medical City, College of Medicine, King Saud University
| | - Turky Almigbal
- King Saud University Medical City, College of Medicine, King Saud University
| | | | | | | | | | | | - Saad Alsaad
- King Saud University Medical City, College of Medicine, King Saud University
| | | | - Yasser Alghamdi
- Prince Mohammed Bin Abdulaziz Hospital, Riyadh, Saudi Arabia
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25
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Gormley M, Yarmolinsky J, Dudding T, Burrows K, Martin RM, Thomas S, Tyrrell J, Brennan P, Pring M, Boccia S, Olshan AF, Diergaarde B, Hung RJ, Liu G, Legge D, Tajara EH, Severino P, Lacko M, Ness AR, Davey Smith G, Vincent EE, Richmond RC. Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study. PLoS Genet 2021; 17:e1009525. [PMID: 33886544 PMCID: PMC8096036 DOI: 10.1371/journal.pgen.1009525] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 05/04/2021] [Accepted: 03/31/2021] [Indexed: 01/04/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
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Affiliation(s)
- Mark Gormley
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - James Yarmolinsky
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Tom Dudding
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Richard M. Martin
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- National Institute for Health Research Bristol Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, United Kingdom
| | - Steven Thomas
- Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
- National Institute for Health Research Bristol Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, United Kingdom
| | - Jessica Tyrrell
- University of Exeter Medical School, RILD Building, RD&E Hospital, Exeter, United Kingdom
| | - Paul Brennan
- Genetic Epidemiology Group, World Health Organization, International Agency for Research on Cancer, Lyon, France
| | - Miranda Pring
- Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom
| | - Stefania Boccia
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italia
- Department of Woman and Child Health and Public Health, Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, United States of America
| | - Rayjean J. Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Geoffrey Liu
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Princess Margaret Cancer Centre, Toronto, Canada
| | - Danny Legge
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | | | - Patricia Severino
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Martin Lacko
- Department of Otorhinolaryngology and Head and Neck Surgery, Research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Andrew R. Ness
- National Institute for Health Research Bristol Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, United Kingdom
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Emma E. Vincent
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Rebecca C. Richmond
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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26
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Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol 2021; 14:101043. [PMID: 33751965 PMCID: PMC8010885 DOI: 10.1016/j.tranon.2021.101043] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022] Open
Abstract
Abnormality in blood cholesterol level is significantly correlated with risk of different cancers. Majority of tumor tissue from cancer patient exhibits overexpression of LDLR and ACAT for supporting rapid cancer cell proliferation. Alteration of the cholesterol metabolism in cancer cells hampers therapeutic response. Targeting cholesterol metabolism for treatment of cancer with other conventional chemotherapeutic drugs appears to be beneficial. Cholesterol is a fundamental molecule necessary for the maintenance of cell structure and is vital to various normal biological functions. It is a key factor in lifestyle-related diseases including obesity, diabetes, cardiovascular disease, and cancer. Owing to its altered serum chemistry status under pathological states, it is now being investigated to unravel the mechanism by which it triggers various health complications. Numerous clinical studies in cancer patients indicate an alteration in blood cholesterol level (either decreased or increased) in comparison to normal healthy individuals. This article elaborates on our understanding as to how cholesterol is being hijacked in the malignancy for the development, survival, stemness, progression, and metastasis of cancerous cells. Also, it provides a glimpse of how cholesterol derived entities, alters the signaling pathway towards their advantage. Moreover, deregulation of the cholesterol metabolism pathway has been often reported to hamper various treatment strategies in different cancer. In this context, attempts have been made to bring forth its relevance in being targeted, in pre-clinical and clinical studies for various treatment modalities. Thus, understanding the role of cholesterol and deciphering associated molecular mechanisms in cancer progression and therapy are of relevance towards improvement in the management of various cancers.
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Affiliation(s)
| | - Abhijeet Singh
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Ajay D Pillai
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India
| | - Manoj Kumar Bhat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411 007, India.
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27
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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: 25] [Impact Index Per Article: 6.3] [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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28
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Skajaa N, Nagy D, Troelsen FS, Farkas DK, Sørensen HT. Venous thromboembolism and risk of cancer in users of statins: A Danish population-based cohort study. Thromb Res 2021; 201:1-5. [PMID: 33621859 DOI: 10.1016/j.thromres.2021.02.015] [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: 10/14/2020] [Revised: 01/15/2021] [Accepted: 02/06/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Venous thromboembolism (VTE) may be the first symptom of cancer. Statins are suggested to prevent VTE, but the risk of cancer in VTE patients using statins remains poorly understood. OBJECTIVES To examine if VTE is a marker of cancer in users of statins. METHODS We identified all Danish patients during 1996-2017 with a first-time diagnosis of VTE and a filled prescription for a statin within 90 days prior to the VTE diagnosis. We classified patients as prevalent users if the first filling of a statin occurred more than one year preceding the VTE diagnosis, and as new users if the first filling occurred within the preceding year. We computed cumulative incidences of cancer, with death as a competing risk, and age-, sex-, and calendar-period standardized incidence ratios (SIRs), comparing the observed cancer incidence with the expected based on national cancer statistics. RESULTS Among 9280 (85%) prevalent users of statin and 1580 (15%) new users, the one-year cumulative incidence of any cancer was 6.6 (95% CI: 6.1-7.2) for prevalent users and 6.4 (95% CI: 5.2-7.6) for new users; the corresponding SIRs were 3.1 (95% CI: 2.9-3.3) and 3.5 (95% CI: 2.9-4.3). In the second and subsequent years, the SIRs diminished and approached unity for both prevalent (1.1 [95% CI: 1.1-1.2]) and new users (1.1 [95% CI: 0.9-1.3]). CONCLUSIONS VTE patients using statins had a 3-fold increased rate of cancer in the first year after diagnosis. A first VTE serves as an important marker of cancer, regardless of statin use.
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Affiliation(s)
- Nils Skajaa
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
| | - David Nagy
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark
| | | | - Dóra Körmendiné Farkas
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark
| | - Henrik Toft Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark
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29
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Franco-Peláez JA, Esteban-Lucia L, Zambrano Chacón MDLÁ, Pello-Lázaro AM, Venegas Rodriguez AM, Nieto Roca L, García-Talavera CS, Kallmeyer Mayor A, Villar Alvarez F, Fernandez Roblas R, Gonzalez-Lorenzo O, Tuñón J, Ibañez B, Aceña A. Statin use is associated with reduced mortality after respiratory viral infection. ERJ Open Res 2021; 7:00365-2020. [PMID: 33569498 PMCID: PMC7861028 DOI: 10.1183/23120541.00365-2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 11/05/2020] [Indexed: 12/15/2022] Open
Abstract
Background Several studies suggest that statins, besides reducing cardiovascular disease, have anti-inflammatory properties which might provide a benefit in downregulating the immune response after a respiratory viral infection (RVI) and, hence, decreasing subsequent complications. We aim to analyse the effect of statins on mortality after RVI. Methods A single-centre, observational and retrospective study was carried out including all adult patients with a RVI confirmed by PCR tests from October 2, 2017 to May 20, 2018. Patients were divided between statin users and non-statin users and followed-up for 1 year, and all causes of death were recorded. In order to analyse the effect of statin treatment on mortality after RVI we planned two different approaches, a multivariate Cox regression model with the overall population and a univariate Cox model with a propensity-score matched population. Results We included 448 patients, 154 (34.4%) of whom were under statin treatment. Statin users had a worse clinical profile (older population with more comorbidities). During the 1-year follow-up, 67 patients died, 17 (11.0%) in the statin group and 50 (17.1%) in the non-statin group. Multivariate Cox analysis showed that statins were associated with mortality benefit (HR 0.47, 95% CI 0.26–0.83; p=0.01). In a matched population (101 statins users and 101 non-statins users) statins also remained associated with mortality benefit (HR 0.32, 95% CI 0.14–0.72; p=0.006). Differences were mainly driven by non-cardiovascular mortality (HR 0.31, 95% CI 0.13–0.73; p=0.004). Conclusions Chronic statin treatment was associated with reduced 1-year mortality in patients with laboratory-confirmed RVI. Further studies are needed to determine the exact role of statin therapy after RVI. Statin treatment is associated with reduced 1-year mortality after respiratory viral infections, despite the higher risk profile of patients on statins. Statins seem a good candidate to be tested during the current global pandemic.https://bit.ly/36t0tDh
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Affiliation(s)
| | - Laura Esteban-Lucia
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | | | - Ana María Pello-Lázaro
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | | | - Luis Nieto Roca
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | | | - Andrea Kallmeyer Mayor
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | - Felipe Villar Alvarez
- Dept of Pneumology, Instituto de Investigación Sanitaria -Fundación Jiménez Díaz, Madrid, Spain.,Autonoma University, Madrid, Spain.,CIBERES, Madrid, Spain
| | - Ricardo Fernandez Roblas
- Dept of Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | - Oscar Gonzalez-Lorenzo
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain
| | - José Tuñón
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.,Autonoma University, Madrid, Spain.,CIBERCV, Madrid, Spain
| | - Borja Ibañez
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.,CIBERCV, Madrid, Spain.,Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Alvaro Aceña
- Dept of Cardiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.,Autonoma University, Madrid, Spain
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Bedimo RJ, Park LS, Shebl FM, Sigel K, Rentsch CT, Crothers K, Rodriguez-Barradas MC, Goetz MB, Butt AA, Brown ST, Gibert C, Justice AC, Tate JP. Statin exposure and risk of cancer in people with and without HIV infection. AIDS 2021; 35:325-334. [PMID: 33181533 PMCID: PMC7775280 DOI: 10.1097/qad.0000000000002748] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To determine whether statin exposure is associated with decreased cancer and mortality risk among persons with HIV (PWH) and uninfected persons. Statins appear to have immunomodulatory and anti-inflammatory effects and may reduce cancer risk, particularly among PWH as they experience chronic inflammation and immune activation. DESIGN Propensity score-matched cohort of statin-exposed and unexposed patients from 2002 to 2017 in the Veterans Aging Cohort Study (VACS), a large cohort with cancer registry linkage and detailed pharmacy data. METHODS We calculated Cox regression hazard ratios (HRs) and 95% confidence intervals (CI) associated with statin use for all cancers, microbial cancers (associated with bacterial or oncovirus coinfection), nonmicrobial cancers, and mortality. RESULTS :The propensity score-matched sample (N = 47 940) included 23 970 statin initiators (31% PWH). Incident cancers were diagnosed in 1160 PWH and 2116 uninfected patients. Death was reported in 1667 (7.0%) statin-exposed, and 2215 (9.2%) unexposed patients. Statin use was associated with 24% decreased risk of microbial-associated cancers (hazard ratio 0.76; 95% CI 0.69-0.85), but was not associated with nonmicrobial cancer risk (hazard ratio 1.00; 95% CI 0.92-1.09). Statin use was associated with 33% lower risk of death overall (hazard ratio 0.67; 95% CI 0.63-0.72). Results were similar in analyses stratified by HIV status, except for non-Hodgkin lymphoma where statin use was associated with reduced risk (hazard ratio 0.56; 95% CI 0.38-0.83) for PWH, but not for uninfected (P interaction = 0.012). CONCLUSION In both PWH and uninfected, statin exposure was associated with lower risk of microbial, but not nonmicrobial cancer incidence, and with decreased mortality.
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Affiliation(s)
- Roger J Bedimo
- Veterans Affairs North Texas Healthcare System, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Lesley S Park
- Stanford University School of Medicine, Palo Alto, California
| | - Fatima M Shebl
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Keith Sigel
- Icahn School of Medicine at Mt. Sinai, New York, New York, USA
| | | | - Kristina Crothers
- VA Puget Sound Healthcare System, University of Washington School of Medicine, Seattle, Washington
| | | | - Matthew Bidwell Goetz
- Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Adeel A Butt
- VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvamia
- Weill Cornell Medical College, New York, New York, USA
- Weill Cornell Medical College, Doha, Qatar
| | - Sheldon T Brown
- James J. Peters Veterans Affairs Medical Center, Bronx
- Icahn School of Medicine at Mt. Sinai, New York, New York
| | - Cynthia Gibert
- Washington DC Veterans Affairs Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Amy C Justice
- VA Connecticut Healthcare System, West Haven
- Yale School of Medicine, New Haven, Connecticut, USA
| | - Janet P Tate
- VA Connecticut Healthcare System, West Haven
- Yale School of Medicine, New Haven, Connecticut, USA
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Peymani P, Dehesh T, Aligolighasemabadi F, Sadeghdoust M, Kotfis K, Ahmadi M, Mehrbod P, Iranpour P, Dastghaib S, Nasimian A, Ravandi A, Kidane B, Ahmed N, Sharma P, Shojaei S, Bagheri Lankarani K, Madej A, Rezaei N, Madrakian T, Los MJ, Labouta HI, Mokarram P, Ghavami S. Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients. TRANSLATIONAL MEDICINE COMMUNICATIONS 2021; 6:3. [PMID: 33521322 PMCID: PMC7829327 DOI: 10.1186/s41231-021-00082-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 01/08/2021] [Indexed: 05/07/2023]
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients. RESULTS After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61-2.99), P = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07-2.33), P = 0.312]. CONCLUSIONS Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19.
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Affiliation(s)
- Payam Peymani
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tania Dehesh
- Department of Biostatistics and Epidemiology, School of Public Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Farnaz Aligolighasemabadi
- Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammadamin Sadeghdoust
- Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Katarzyna Kotfis
- Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Parvaneh Mehrbod
- Influenza and Respiratory Viruses Department, Pasteur Institute of IRAN, Tehran, Iran
| | - Pooya Iranpour
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sanaz Dastghaib
- Shiraz Endocrine and Metabolism Research Center, Namazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Nasimian
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Ravandi
- Section of Cardiology, St. Boniface Hospital, University of Manitoba, Winnipeg, MB Canada
| | - Biniam Kidane
- Department of Surgery, University of Manitoba, Winnipeg, Manitoba Canada
| | - Naseer Ahmed
- Department of Radiology, University of Manitoba, Winnipeg, Manitoba Canada
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada
| | - Pawan Sharma
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA USA
| | - Shahla Shojaei
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba Canada
| | - Kamran Bagheri Lankarani
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Andrzej Madej
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Marek J. Los
- Biotechnology Center, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Hagar Ibrahim Labouta
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba Canada
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Ghavami
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba Canada
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Carter P, Vithayathil M, Kar S, Potluri R, Mason AM, Larsson SC, Burgess S. Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank. eLife 2020; 9:57191. [PMID: 33046214 PMCID: PMC7553780 DOI: 10.7554/elife.57191] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022] Open
Abstract
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
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Affiliation(s)
- Paul Carter
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | | | - Siddhartha Kar
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.,Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Rahul Potluri
- ACALM Study Unit, Aston Medical School, Birmingham, United Kingdom
| | - Amy M Mason
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Stephen Burgess
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.,MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
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Dickerman BA, García-Albéniz X, Logan RW, Denaxas S, Hernán MA. Emulating a target trial in case-control designs: an application to statins and colorectal cancer. Int J Epidemiol 2020; 49:1637-1646. [PMID: 32989456 PMCID: PMC7746409 DOI: 10.1093/ije/dyaa144] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous case-control studies have reported a strong association between statin use and lower cancer risk. It is unclear whether this association reflects a benefit of statins or is the result of design decisions that cannot be mapped to a (hypothetical) target trial (that would answer the question of interest). METHODS We outlined the protocol of a target trial to estimate the effect of statins on colorectal cancer incidence among adults with low-density lipoprotein (LDL) cholesterol below 5 mmol/L. We then emulated the target trial using linked electronic health records of 752 469 eligible UK adults (CALIBER 1999-2016) under both a cohort design and a case-control sampling of the cohort. We used pooled logistic regression to estimate intention-to-treat and per-protocol effects of statins on colorectal cancer, with adjustment for baseline and time-varying risk factors via inverse-probability weighting. Finally, we compared our case-control effect estimates with those obtained using previous case-control procedures. RESULTS Over the 6-year follow-up, 3596 individuals developed colorectal cancer. Estimated intention-to-treat and per-protocol hazard ratios were 1.00 (95% confidence interval [CI]: 0.87, 1.16) and 0.90 (95% CI: 0.71, 1.12), respectively. As expected, adequate case-control sampling yielded the same estimates. By contrast, previous case-control analytical approaches yielded estimates that appeared strongly protective (odds ratio 0.57, 95% CI: 0.36, 0.91, for ≥5 vs. <5 years of statin use). CONCLUSIONS Our study demonstrates how to explicitly emulate a target trial using case-control data to reduce discrepancies between observational and randomized trial evidence. This approach may inform future case-control analyses for comparative effectiveness research.
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Affiliation(s)
- Barbra A Dickerman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Xabier García-Albéniz
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- RTI Health Solutions, Barcelona, Spain
| | - Roger W Logan
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Spiros Denaxas
- Institute of Health Informatics Research, University College London, London, UK
- Health Data Research UK (HDR UK) London, University College London, London, UK
- Alan Turing Institute, London, UK
| | - Miguel A Hernán
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
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34
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Jarimba R, Lima JP, Eliseu M, Carvalho J, Antunes H, Tavares da Silva E, Moreira P, Figueiredo A. Statins Prevent Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy: A Single-center Retrospective Study with a Median Follow-up of 51.20 Months. Res Rep Urol 2020; 12:439-446. [PMID: 33062623 PMCID: PMC7533899 DOI: 10.2147/rru.s258267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/04/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Prostate cancer is the most commonly diagnosed cancer in men. Radical prostatectomy is a potentially curative alternative for localized disease, although a significant percentage of these patients will suffer a biochemical recurrence with associated mortality. A wide spectrum of anticancer properties of statins has been demonstrated and the role of these drugs in prevention and treatment of other types of cancer is being increasingly studied. OBJECTIVE The aim of this study was to investigate whether the use of statins is associated with reduced risk of biochemical recurrence among patients submitted to radical prostatectomy. PATIENTS AND METHODS We retrospectively reviewed 875 patients submitted to radical prostatectomy between January 2009 and December 2018. Approximately 45.7% of the patients were on medication with statins at the time of surgery. We evaluated a possible association between statin use and biochemical recurrence and which patients would benefit the most with statin treatment. RESULTS Overall, statins were associated with an approximately 40% reduction in risk of biochemical recurrence at a median follow-up time of 51.2 months (HR 0.599, p<0.05). Patients with pT2c staging (HR 0.486, p=0.017) and ISUP ≥3 (HR 0.61, p=0.011) seem to have benefited more from statin use. CONCLUSION In this cohort, use of statins proved beneficial in reducing the risk of biochemical recurrence among patients submitted to radical prostatectomy. Prospective studies are required to confirm this result and to evaluate its safety profile in those patients.
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Affiliation(s)
- Roberto Jarimba
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - João Pedroso Lima
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Miguel Eliseu
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - João Carvalho
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Hugo Antunes
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Edgar Tavares da Silva
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Pedro Moreira
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Arnaldo Figueiredo
- Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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35
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Dong Y, Wang H, Shan D, Yu Z. [Research Progress on the Relationship between Blood Lipids and
Lung Cancer Risk and Prognosis]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:824-829. [PMID: 32773011 PMCID: PMC7519960 DOI: 10.3779/j.issn.1009-3419.2020.102.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
近年来，肺癌成为导致癌症相关死亡的主要原因。越来越多证据表明，许多脂类和脂类类似物是肿瘤发生的关键调节因子，吸烟、饮食及肥胖等影响血脂水平的因素可能与癌症的风险相关。目前随着脂质与肿瘤发生过程关系的研究逐渐深入，探索血脂与肺癌风险及预后相关性已成为研究的热点。本文就血脂水平与肺癌发病风险、血脂水平与肺癌患者预后相关性及调整血脂药物与防治肺癌方向的研究进展进行综述。
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Affiliation(s)
- Ya Dong
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Haocheng Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Dongfeng Shan
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Zhuang Yu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
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Kang J, Jeong SM, Shin DW, Cho M, Cho JH, Kim J. The Associations of Aspirin, Statins, and Metformin With Lung Cancer Risk and Related Mortality: A Time-Dependent Analysis of Population-Based Nationally Representative Data. J Thorac Oncol 2020; 16:76-88. [PMID: 32950701 DOI: 10.1016/j.jtho.2020.08.021] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 08/24/2020] [Accepted: 08/31/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The aim of this study was to investigate the associations of aspirin, metformin, and statins with lung cancer risk and mortality using population-based nationwide cohort data. METHODS This study included a total of 732,199 participants who underwent a national health check-up from 2002 to 2003. Lung cancer incidence and mortality were identified using a registered lung cancer diagnosis code (International Classification of Diseases, 10th revision, code C34) and the Korean National Death Registry. The study participants were followed up from January 1, 2004 to December 31, 2013. Medication exposure was defined by the cumulative duration of use and cumulative defined daily dose per 2-year interval. To avoid immortal-time bias, drug exposure was inserted as a time-dependent variable in Cox analysis, which evaluated the associations of these medications with lung cancer. RESULTS Metformin use had a protective association with lung cancer incidence (p's for trend 0.008) and mortality (p's for trend < 0.001) in a dose-response fashion, and these associations were prominent among participants with a metformin cumulative defined daily dose of 547.5 and above compared with patients without diabetes. Lung cancer mortality was dose-dependently reduced with the use of aspirin (p's for trends 0.046) and statin (p's for trends < 0.001). The combined use of aspirin, statins, and metformin exhibited more prominent protective associations with lung cancer risk and mortality. CONCLUSIONS The use of aspirin, metformin, and statins had independent protective associations with lung cancer mortality, and metformin had an inverse association with lung cancer risk. Further studies are necessary to develop clinically applicable anticancer strategies using these drugs for the reduction of lung cancer and related mortality.
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Affiliation(s)
- Jihun Kang
- Department of Family Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Su-Min Jeong
- Department of Family Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Dong Wook Shin
- Supportive Care Center, Samsung Comprehensive Cancer Center, Seoul, Korea; Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, Korea; Center for Clinical Epidemiology, SAIHST, Sungkyunkwan University, Seoul, Korea.
| | - Mihee Cho
- Samsung C&T Medical Clinic, Kangbuk Samsung Hospital, Seoul, Korea
| | - Jong Ho Cho
- Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea
| | - Jehun Kim
- Division of Pulmonology, Department of Internal Medicine, Kosin University Gospel Hospital, Busan, South Korea
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Su VYF, Yang KY, Huang TY, Hsu CC, Chen YM, Yen JC, Chou YC, Chang YL, He CH. The efficacy of first-line tyrosine kinase inhibitors combined with co-medications in Asian patients with EGFR mutation non-small cell lung cancer. Sci Rep 2020; 10:14965. [PMID: 32917914 PMCID: PMC7486374 DOI: 10.1038/s41598-020-71583-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 08/18/2020] [Indexed: 01/05/2023] Open
Abstract
The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71) and erlotinib (HR 0.62, 95% CI 0.46–0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08–2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.
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Affiliation(s)
- Vincent Yi-Fong Su
- Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Kuang-Yao Yang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Ting-Yu Huang
- Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Chia-Chen Hsu
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jiin-Cherng Yen
- Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Yueh-Ching Chou
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan. .,Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. .,School of Pharmacy, Taipei Medical University, Taipei, Taiwan. .,Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan.
| | - Yuh-Lih Chang
- Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan. .,Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. .,Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan.
| | - Chien-Hui He
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, Wu BJ, Li X. Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Front Oncol 2020; 10:1510. [PMID: 32974183 PMCID: PMC7472741 DOI: 10.3389/fonc.2020.01510] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/14/2020] [Indexed: 12/14/2022] Open
Abstract
Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.
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Affiliation(s)
- Linyuan Xue
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Hongyu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - He Zhang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Lu Ding
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Qingxia Huang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Boyang Jason Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, United States
| | - Xiangyan Li
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
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Yarmolinsky J, Bull CJ, Walker VM, Nounu A, Davey Smith G. Mendelian randomization applied to pharmaceutical use: the case of metformin and lung cancer. Int J Epidemiol 2020; 49:1410-1411. [PMID: 32356895 PMCID: PMC7660135 DOI: 10.1093/ije/dyaa059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Caroline J Bull
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Venexia M Walker
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Aayah Nounu
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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Ahn SV, Lee E, Park B, Jung JH, Park JE, Sheen SS, Park KJ, Hwang SC, Park JB, Park HS, Park JH. Cancer development in patients with COPD: a retrospective analysis of the National Health Insurance Service-National Sample Cohort in Korea. BMC Pulm Med 2020; 20:170. [PMID: 32539764 PMCID: PMC7296952 DOI: 10.1186/s12890-020-01194-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND COPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove the hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients. METHODS This study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 16,757 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. This cohort enrolled six arms consisting of never-smokers without COPD (N = 313,553), former smokers without COPD (N = 41,359), smokers without COPD (N = 112,627), never-smokers with COPD (N = 7789), former smokers with COPD (N = 1085), and smokers with COPD (N = 2677). RESULTS Incident rate of lung cancer per 100,000 person-year was higher according to smoking and COPD (216 in non-COPD and 757 in COPD among never-smokers, 271 in non-COPD and 1266 in COPD among former smokers, 394 in non-COPD and 1560 in COPD among smokers, p < 0.01). Old age, male sex, lower BMI, low exercise level, history of diabetes mellitus, smoking, and COPD were independent factors associated with the development of lung cancer (p < 0.01). Multi-variable analyses showed that COPD, regardless of smoking status, contributed to the development of lung cancer, and colorectal cancer and liver cancer among other major cancers (p < 0.01). CONCLUSION Our data suggested that COPD was an independent risk factor for the development of lung cancer, and colorectal cancer and liver cancer among other major cancers in the Korean population, regardless of smoking status.
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Affiliation(s)
- Song Vogue Ahn
- Department of Health Convergence, Ewha Womans University, Seoul, South Korea
| | - Eunyoung Lee
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.,Office of Biostatistics, Medical Research Collaborating Center, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, South Korea
| | - Bumhee Park
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.,Office of Biostatistics, Medical Research Collaborating Center, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, South Korea
| | - Jin Hee Jung
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.,Office of Biostatistics, Medical Research Collaborating Center, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, South Korea
| | - Ji Eun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea
| | - Seung Soo Sheen
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea
| | - Kwang Joo Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea
| | - Sung Chul Hwang
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea
| | - Jae Bum Park
- Department of Occupational and Environmental Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Hae-Sim Park
- Department of Allergy and Clinical Immunolgy, Ajou University School of Medicine, Suwon, South Korea
| | - Joo Hun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea.
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Raymakers A, Sin DD, Sadatsafavi M, FitzGerald JM, Marra CA, Lynd LD. Statin use and lung cancer risk in chronic obstructive pulmonary disease patients: a population-based cohort study. Respir Res 2020; 21:118. [PMID: 32429927 PMCID: PMC7236956 DOI: 10.1186/s12931-020-01344-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/26/2020] [Indexed: 01/03/2023] Open
Abstract
Background Patients living with chronic obstructive pulmonary disease (COPD) are at an increased risk of lung cancer. A common comorbidity of COPD is cardiovascular disease; as such, COPD patients often receive statins. This study sought to understand the association between statin exposure and lung cancer risk in a population-based cohort of COPD patients. Methods We identified a population-based cohort of COPD patients based on having filled at least three prescriptions for an anticholinergic or short-acting beta-agonist (SABA). We used an array of methods of defining medication exposure including three conventional methods (ever statin exposure, cumulative duration of use, and cumulative dose) and two novel methods (recency-weighted cumulative duration of use and recency-weighted cumulative dose). To assess residual confounding, a negative control exposure was used to test the validity of our results. All exposure variables were time-dependent. Results The population-based cohort of COPD had 39,879 patients with mean age of 70.6 (SD: 11.2) years and, of which, 53.5% were female. There were 12,469 patients who received at least one statin prescription. Results from the reference case multivariable analysis indicated a reduced risk from statin exposure (HR: 0.85 (95% CI: 0.73–1.00) in COPD patients, but this result not statistically significant. Using the two recency-weighted modelling approaches, statin exposure was associated with a statistically significant reduction in lung cancer risk (recency-weighted cumulative dose, HR: 0.85 (95% CI: 0.77–0.93) and recency-weighted cumulative duration of use, HR: 0.97 (95% CI: 0.96–0.99). Multivariable analysis incorporating the negative control exposure was not statistically significant (HR: 0.89 (95% CI: 0.75–1.10). Conclusions The results of this population-based analysis indicate that statin use in COPD patients may reduce the risk of lung cancer. While the effect was not statistically significantly across all exposure definitions, the overall results support the hypothesis that COPD patients might benefit from statin therapy.
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Affiliation(s)
- Ajn Raymakers
- Collaboration for Outcomes Research and Evaluation (CORE), Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T1Z3, Canada.,BC Cancer, Vancouver, Canada.,Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
| | - D D Sin
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada.,Division of Respiratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - M Sadatsafavi
- Collaboration for Outcomes Research and Evaluation (CORE), Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T1Z3, Canada
| | - J M FitzGerald
- Division of Respiratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - C A Marra
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - L D Lynd
- Collaboration for Outcomes Research and Evaluation (CORE), Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T1Z3, Canada. .,Centre for Health Evaluation and Outcome Sciences, Providence Health Research Institute, Vancouver, Canada.
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Ashraf-Uz-Zaman M, Bhalerao A, Mikelis CM, Cucullo L, German NA. Assessing the Current State of Lung Cancer Chemoprevention: A Comprehensive Overview. Cancers (Basel) 2020; 12:E1265. [PMID: 32429547 PMCID: PMC7281533 DOI: 10.3390/cancers12051265] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/06/2020] [Accepted: 05/14/2020] [Indexed: 12/14/2022] Open
Abstract
Chemoprevention of lung cancer is thought to significantly reduce the risk of acquiring these conditions in the subpopulation of patients with underlying health issues, such as chronic obstructive pulmonary disorder and smoking-associated lung problems. Many strategies have been tested in the previous decades, with very few translating to successful clinical trials in specific subpopulations of patients. In this review, we analyze these strategies, as well as new approaches that have emerged throughout the last few years, including synthetic lethality concept and microbiome-induced regulation of lung carcinogenesis. Overall, the continuous effort in the area of lung chemoprevention is required to develop practical therapeutical approaches. Given the inconsistency of results obtained in clinical trials targeting lung cancer chemoprevention in various subgroups of patients that differ in the underlying health condition, race, and gender, we believe that individualized approaches will have more promise than generalized treatments.
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Affiliation(s)
- Md Ashraf-Uz-Zaman
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (M.A.-U.-Z.); (A.B.); (C.M.M.); (L.C.)
| | - Aditya Bhalerao
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (M.A.-U.-Z.); (A.B.); (C.M.M.); (L.C.)
| | - Constantinos M. Mikelis
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (M.A.-U.-Z.); (A.B.); (C.M.M.); (L.C.)
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Luca Cucullo
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (M.A.-U.-Z.); (A.B.); (C.M.M.); (L.C.)
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Nadezhda A. German
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (M.A.-U.-Z.); (A.B.); (C.M.M.); (L.C.)
- Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Karavias D, Thomas P, Koh A, Irving G, Navarro AP, Cameron IC, Gomez D. Statin therapy does not influence the outcome of patients undergoing surgery for pancreatic cancer. ANZ J Surg 2019; 90:1671-1676. [PMID: 31845479 DOI: 10.1111/ans.15600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/22/2019] [Accepted: 11/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently, statins have been associated with improved survival in certain cancers. The aim of this study was to evaluate the impact of statins on the outcome of patients undergoing surgery for pancreatic cancer. In addition, the effect of statins on the histopathological characteristics of the disease was assessed. METHODS A retrospective review of the prospectively maintained hepato-pancreatico-biliary database was performed and patients with pancreatic cancer who underwent surgery between January 2014 and December 2017 were included. Statistical analysis was performed to assess the impact of statins on histopathological characteristics and survival outcome. RESULTS A total of 151 patients were included, of whom 71 underwent pancreatic resections and 80 underwent trial dissection and bypass procedures. In the operated group, 20 patients were on statin therapy preoperatively. With respect to disease-free survival, tumour size (P = 0.023) and lymphatic invasion (P = 0.015) were significant variables on univariate analysis. Gender (P = 0.022), adjuvant chemotherapy (P < 0.001), lymphatic invasion (P = 0.021) and tumour size (P = 0.041) were significant variables on univariate analysis with respect to overall survival. Multivariate analysis identified adjuvant chemotherapy as the only independent predictor of overall survival (P < 0.001). No correlations between the use of statins and the histopathological characteristics were identified. CONCLUSION Adjuvant chemotherapy is an independent predictor of overall survival in patients undergoing surgery for pancreatic cancer. Statin therapy does not influence survival outcomes and histopathological characteristics following surgery for pancreatic cancer.
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Affiliation(s)
- Dimitrios Karavias
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Paul Thomas
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Amanda Koh
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Glen Irving
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Alex P Navarro
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Iain C Cameron
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Dhanny Gomez
- Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.,NIHR Nottingham Digestive Disease Biomedical Research Unit, The University of Nottingham, Nottingham, UK
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Fatehi Hassanabad A. Current perspectives on statins as potential anti-cancer therapeutics: clinical outcomes and underlying molecular mechanisms. Transl Lung Cancer Res 2019; 8:692-699. [PMID: 31737505 DOI: 10.21037/tlcr.2019.09.08] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins have been shown to inhibit cell proliferation in vitro and tumor growth in animal models. Various studies have also shown a decreased cancer-specific mortality rate in patients who were prescribed these medications. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway. Statins induce tumour-specific apoptosis through mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate (GGPP) biosynthesis. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Several studies have been conducted to further assess the association between statin use and mortality in different types of cancer. In this review, current perspectives on clinical significance of statins in prevention and treatment of various types of cancers and proposed mechanisms are discussed.
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Dickerman BA, García-Albéniz X, Logan RW, Denaxas S, Hernán MA. Avoidable flaws in observational analyses: an application to statins and cancer. Nat Med 2019; 25:1601-1606. [PMID: 31591592 PMCID: PMC7076561 DOI: 10.1038/s41591-019-0597-x] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 08/28/2019] [Indexed: 01/16/2023]
Abstract
The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. Although such discrepancies are often attributed to a lack of randomization in the observational studies, they might be explained by flaws that can be avoided by explicitly emulating a target trial (the randomized trial that would answer the question of interest). Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-yr follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-yr cancer-free survival differences were -0.5% (95% confidence interval (CI) -1.0%, 0.0%) and -0.3% (95% CI -1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared to be strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.
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Affiliation(s)
- Barbra A Dickerman
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
| | - Xabier García-Albéniz
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- RTI Health Solutions, Barcelona, Spain
| | - Roger W Logan
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Spiros Denaxas
- Institute of Health Informatics Research, University College London, London, UK
- Health Data Research UK (HDR UK) London, University College London, London, UK
- The Alan Turing Institute, London, UK
| | - Miguel A Hernán
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
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Zhang T, Bai R, Wang Q, Wang K, Li X, Liu K, Ryu J, Wang T, Chang X, Ma W, Bode AM, Xia Q, Song Y, Dong Z. Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non-Small Cell Lung Carcinogenesis. Cancer Prev Res (Phila) 2019; 12:837-848. [PMID: 31554629 DOI: 10.1158/1940-6207.capr-19-0211] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/06/2019] [Accepted: 09/18/2019] [Indexed: 11/16/2022]
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.
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Affiliation(s)
- Tianshun Zhang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Ruihua Bai
- The Hormel Institute, University of Minnesota, Austin, Minnesota.,Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qiushi Wang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Keke Wang
- The Hormel Institute, University of Minnesota, Austin, Minnesota.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Xiang Li
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Kangdong Liu
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Joohyun Ryu
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Ting Wang
- The Hormel Institute, University of Minnesota, Austin, Minnesota.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Xiaoyu Chang
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Weiya Ma
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Qingxin Xia
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yongping Song
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zigang Dong
- The Hormel Institute, University of Minnesota, Austin, Minnesota. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
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Zhang L, Huang Y, Gan X, He S, Cheng X, Yang N, Li S, Li Z, Zheng F. The Pharmacogenomics "Side-effect" of TP53/EGFR in Non-small Cell Lung Cancer Accompanied with Atorvastatin Therapy: A Functional Network Analysis. Anticancer Agents Med Chem 2019; 19:2060-2071. [PMID: 31544704 DOI: 10.2174/1871520619666190712203217] [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: 03/12/2019] [Revised: 05/01/2019] [Accepted: 05/11/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Atorvastatin belongs to the group of statins and is the leading drug for hypercholesterolemia treatment. Although, its anticancer effects are highly appreciated, its properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer. METHODS Target genes of atorvastatin were collected by the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and non-small cell lung cancer pathway was conducted by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter. RESULTS To identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated by cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to the KM analysis. CONCLUSION Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.
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Affiliation(s)
- Lei Zhang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yifang Huang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xuedong Gan
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Siying He
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiaohuan Cheng
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Na Yang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Siwei Li
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zuhua Li
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fang Zheng
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
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Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu CS, Chen L, Chin TM, Tenen DG. CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Am J Cancer Res 2019; 9:6157-6174. [PMID: 31534543 PMCID: PMC6735519 DOI: 10.7150/thno.35805] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 07/28/2019] [Indexed: 02/06/2023] Open
Abstract
Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.
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