Perhexiline 100mg tablets

The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e′ ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction. The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e′ ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction. Hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiovascular disease, affecting 1 in every 500 subjects. Its potential complications include asymmetric left ventricular (LV) hypertrophy, LV outflow tract (LVOT) obstruction,1Alsheikh-Ali AA Link MS Semsarian C Shen WK Estes 3rd, NAM Maron MS Haas TS Formisano F Boriani G Spirito P Maron BJ. Ventricular tachycardia/fibrillation early after defibrillator implantation in patients with hypertrophic cardiomyopathy is explained by a high-risk subgroup of patients.Heart Rhythm. 2013; 10: 214-218Google Scholar myocardial ischemia, arrhythmia,2Kubo T Kitaoka H Okawa M Hirota T Hayato K Yamasaki N Matsumura Y Yabe T Takata J Doi YL. Clinical impact of atrial fibrillation in patients with hypertrophic cardiomyopathy. Results from Kochi RYOMA study.Circ J. 2009; 73: 1599-1605Google Scholar sudden cardiac death, diastolic dysfunction, and mitral regurgitation.3Sikand N Sen S. Are cardiac myosin inhibitors useful in patients with hypertrophic obstructive cardiomyopathy and comorbid hypertension?.JACC Heart Fail. 2024; 12: 580-582Google Scholar The clinical diagnosis of HCM is based on the identification of unexplained LV hypertrophy detected through echocardiography or cardiovascular magnetic resonance imaging. Treatment strategies include the use of implantable defibrillators, medications, and surgical myectomy to relieve outflow tract obstruction and symptoms of heart failure.4Valeti US Nishimura RA Holmes DR Araoz PA Glockner JF Breen JF Ommen SR Gersh BJ Tajik AJ Rihal CS Schaff HV Maron BJ. Comparison of surgical septal myectomy and alcohol septal ablation with cardiac magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy.J Am Coll Cardiol. 2007; 49: 350-357Google Scholar Drug therapy constitutes a pivotal aspect of HCM management, whereas common drug treatments are considered nonspecific treatments. The novel small molecule targeted drug mavacamten has emerged as a promising option for modulating cardiac function at the sarcomere level. However, there is a deficiency in comprehensive evaluations regarding the efficacy of various medication treatment regimens. Therefore, this network meta-analysis (NMA) aims to compare the efficacy of different clinically common drugs, providing beneficial guidance for medication treatments tailored to patients with HCM. A search was conducted in the Cochrane, PubMed, Embase, and Web of Science databases for randomized controlled trials comparing the efficacy of currently different commonly used clinical drugs in patients with HCM, with the search cut-off date being January 10, 2024. The search used a combination of Medical Subject Headings “Cardiomyopathy, Hypertrophic” and free-text terms such as “Cardiomyopathies Hypertrophic, Hypertrophic Cardiomyopathies, Hypertrophic Cardiomyopathy, Cardiomyopathy Hypertrophic Obstructive, Cardiomyopathies Hypertrophic Obstructive, Hypertrophic Obstructive Cardiomyopathies, Hypertrophic Obstructive Cardiomyopathy, Obstructive Cardiomyopathies, Hypertrophic, Obstructive Cardiomyopathy, Hypertrophic.” The detailed search strategy is provided in Supplementary Material 1. The inclusion criteria were as follows: studies must involve adults diagnosed with HCM.5Elliott PM Anastasakis A Borger MA Borggrefe M Cecchi F Charron P Hagege AA Lafont A Limongelli G Mahrholdt H McKenna WJ Mogensen J Nihoyannopoulos P Nistri S Pieper PG Pieske B Rapezzi C Rutten FH Tillmanns C Watkins H Authors/Task Force members2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35: 2733-2779Google Scholar The treatment group received commonly used clinical drugs for treating HCM (mavacamten, perhexiline, ranolazine, spironolactone, trimetazidine, losartan, atorvastatin, candesartan, N-acetylcysteine, and valsartan). The control group should use a placebo. The primary outcome measures included peak oxygen consumption (PVO2), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), systolic blood pressure, LV mass index (LVMI), left atrial volume index (LAVI), maximum wall thickness, LV ejection fraction (LVEF), and septal E/e′ ratio. The study type must be a randomized controlled trial. The exclusion criteria were as follows: duplicates, animal experiments, case reports, conference abstracts, reviews, reports lacking accessible full texts, and studies involving patients with other organic diseases. Two authors meticulously screened the literature according to preestablished eligible criteria. Any discrepancies were resolved through deliberation or by seeking a third party's opinion to achieve consensus. The information extracted from the included studies encompassed key details such as the first author, year of publication, country, sample size, gender, mean age, interventions administered, and outcome measures. The risk of bias assessment was conducted according to the latest guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions.6Minozzi S Cinquini M Gianola S Gonzalez-Lorenzo M Banzi R. The revised Cochrane risk of bias tool for randomized trials (RoB 2) showed low interrater reliability and challenges in its application.J Clin Epidemiol. 2020; 126: 37-44Google Scholar The tool comprises 5 primary components: bias due to the randomization, bias due to deviations from intended interventions, bias due to missing outcome data, bias due to measurement of the outcome, and bias due to outcome selective reporting. The quality of studies was categorized as either “low risk of bias,” “some concerns,” or “high risk of bias.” The results were independently reviewed by 2 researchers, and any discrepancies were resolved through discussion or consultation with a third party to achieve consensus. Bayesian NMA was performed using a previous vague random-effects model with R v4.3.2. The Markov Chain Monte Carlo method7Jansen JP Crawford B Bergman G Stam W. Bayesian meta-analysis of multiple treatment comparisons: an introduction to mixed treatment comparisons.Value Health. 2008; 11: 956-964Google Scholar was used to obtain the best pooled estimate and probabilities of each treatment regimen. Continuous outcomes were reported as the posterior mean difference (MD) along with its corresponding 95% confidence interval (CI). The surface under the cumulative ranking curve (SUCRA) percentages were computed to assess the likelihood of each intervention being the most effective. Network plots and funnel plots were generated using STATA v15.0 (William Gould, James Hardin and Brian P. Poi). In the network plots, each node represented a medication, whereas the edges depicted the available comparisons. The size of each node was proportional to the patient cohort size. Cumulative probability plots were generated using the ggplot2 package. An initial database search retrieved 2,864 studies. After the elimination of 553 duplicates, 1,341 studies were excluded on the basis of title and abstract screening, with an additional 953 exclusions after full-text review. Ultimately, 17 studies8Abozguia K Elliott P McKenna W Phan TT Nallur-Shivu G Ahmed I Maher AR Kaur K Taylor J Henning A Ashrafian H Watkins H Frenneaux M Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.Circulation. 2010; 122: 1562-1569Google Scholar, 9Axelsson A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the Scholar, J S M C F C S F G and left ventricular mass in hypertrophic cardiomyopathy: a randomized J Clin 2007; Scholar, M A L R K AA M McKenna WJ Frenneaux R Elliott of therapy on exercise capacity in patients with hypertrophic cardiomyopathy: a randomized clinical Cardiol. Scholar, A K Schaff H C W L K AJ in patients with obstructive hypertrophic cardiomyopathy for septal Am Coll Cardiol. Scholar, Y P of and on the treatment of hypertrophic cardiomyopathy with ventricular J 2014; Scholar, M Elliott PM L DR A Ho W AJ I of mavacamten on in symptomatic patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. Scholar, A K R C H L L Taylor AR I P in hypertrophic cardiomyopathy: a randomized 2 Scholar, H G R Y S type I in patients with hypertrophic J. Scholar, MS R Maron BJ of on myocardial and other clinical in patients with hypertrophic J Scholar, AJ Y L J P M with in hypertrophic cardiomyopathy a study.Circ 122: Scholar, I PG PA Rapezzi C M G B F P A C A L A R G C F L G A of in patients with symptomatic hypertrophic cardiomyopathy: the study.Circ Heart Fail. Scholar, I A R A P S A M W J K J AJ W M A Ho study for treatment of symptomatic obstructive hypertrophic cardiomyopathy a 2020; Scholar, M P R K J use in Hypertrophic Cardiomyopathy The effects of candesartan on left ventricular hypertrophy and function in hypertrophic cardiomyopathy: a randomized 2009; 11: Scholar, C PA G S Ho MA of on left ventricular hypertrophy and in patients with hypertrophic Heart Fail. 2013; Scholar, L J P W F W J Y C S of mavacamten on patients with symptomatic obstructive hypertrophic cardiomyopathy: the randomized clinical Cardiol. Scholar, T R T Y K R. A therapeutic strategy for hypertrophic cardiomyopathy in A randomized and study with an Heart J. 2007; Scholar were eligible for analysis Seventeen studies, patients with HCM, were included in the The interventions encompassed mavacamten, perhexiline, ranolazine, spironolactone, trimetazidine, losartan, atorvastatin, candesartan, N-acetylcysteine, and of the studies are in 1. studies included in this analysis the The primary risk from deviations from the intended The risk of bias for the included studies is depicted in of included to or 5 or for was 5 with 1 at of valsartan every for the first to for an additional for 5 as 2 to to the was after 1 at of for year in a studies8Abozguia K Elliott P McKenna W Phan TT Nallur-Shivu G Ahmed I Maher AR Kaur K Taylor J Henning A Ashrafian H Watkins H Frenneaux M Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.Circulation. 2010; 122: 1562-1569Google M A L R K AA M McKenna WJ Frenneaux R Elliott of therapy on exercise capacity in patients with hypertrophic cardiomyopathy: a randomized clinical Cardiol. MS R Maron BJ of on myocardial and other clinical in patients with hypertrophic J I PG PA Rapezzi C M G B F P A C A L A R G C F L G A of in patients with symptomatic hypertrophic cardiomyopathy: the study.Circ Heart Fail. I A R A P S A M W J K J AJ W M A Ho study for treatment of symptomatic obstructive hypertrophic cardiomyopathy a 2020; M L Y AJ A F S AJ A of mavacamten in symptomatic patients with hypertrophic cardiomyopathy.J Am Coll Cardiol. 2020; Scholar with the network with mavacamten 95% to and perhexiline 95% to were to in patients with HCM with the perhexiline 95% to 1 in Supplementary Material to perhexiline first by mavacamten with comprehensive ranking of different blood wall in a A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the M A L R K AA M McKenna WJ Frenneaux R Elliott of therapy on exercise capacity in patients with hypertrophic cardiomyopathy: a randomized clinical Cardiol. A K Schaff H C W L K AJ in patients with obstructive hypertrophic cardiomyopathy for septal Am Coll Cardiol. I PG PA Rapezzi C M G B F P A C A L A R G C F L G A of in patients with symptomatic hypertrophic cardiomyopathy: the study.Circ Heart Fail. C PA G S Ho MA of on left ventricular hypertrophy and in patients with hypertrophic Heart Fail. 2013; Scholar with the network with mavacamten 95% to was to in patients with HCM Supplementary 2 in Supplementary Material to mavacamten first by and studies8Abozguia K Elliott P McKenna W Phan TT Nallur-Shivu G Ahmed I Maher AR Kaur K Taylor J Henning A Ashrafian H Watkins H Frenneaux M Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.Circulation. 2010; 122: 1562-1569Google J S M C F C S F G and left ventricular mass in hypertrophic cardiomyopathy: a randomized J Clin 2007; M A L R K AA M McKenna WJ Frenneaux R Elliott of therapy on exercise capacity in patients with hypertrophic cardiomyopathy: a randomized clinical Cardiol. H G R Y S type I in patients with hypertrophic J. AJ Y L J P M with in hypertrophic cardiomyopathy a study.Circ 122: M P R K J use in Hypertrophic Cardiomyopathy The effects of candesartan on left ventricular hypertrophy and function in hypertrophic cardiomyopathy: a randomized 2009; 11: Scholar with the network with medication was to significantly improve in patients with HCM Supplementary in Supplementary Material to first by valsartan and A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the H G R Y S type I in patients with hypertrophic J. C PA G S Ho MA of on left ventricular hypertrophy and in patients with hypertrophic Heart Fail. 2013; T R T Y K R. A therapeutic strategy for hypertrophic cardiomyopathy in A randomized and study with an Heart J. 2007; Scholar systolic blood with the network with 95% to was to systolic blood in patients with HCM Supplementary in Supplementary Material to first by and valsartan A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the A K Schaff H C W L K AJ in patients with obstructive hypertrophic cardiomyopathy for septal Am Coll Cardiol. M Elliott PM L DR A Ho W AJ I of mavacamten on in symptomatic patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. MS R Maron BJ of on myocardial and other clinical in patients with hypertrophic J AJ Y L J P M with in hypertrophic cardiomyopathy a study.Circ 122: Scholar with the network with mavacamten 95% to was to in patients with HCM Supplementary 5 in Supplementary Material to mavacamten first by and A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the M A L R K AA M McKenna WJ Frenneaux R Elliott of therapy on exercise capacity in patients with hypertrophic cardiomyopathy: a randomized clinical Cardiol. A K Schaff H C W L K AJ in patients with obstructive hypertrophic cardiomyopathy for septal Am Coll Cardiol. M Elliott PM L DR A Ho W AJ I of mavacamten on in symptomatic patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. Scholar with the network with mavacamten 95% to was to in patients with HCM in Supplementary Material to mavacamten first by and A Iversen K Vejlstrup N Ho C Norsk J Langhoff L Ahtarovski K Corell P Havndrup M and of the for hypertrophic cardiomyopathy: the M Elliott PM L DR A Ho W AJ I of mavacamten on in symptomatic patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. Scholar, A K R C H L L Taylor AR I P in hypertrophic cardiomyopathy: a randomized 2 Scholar, H G R Y S type I in patients with hypertrophic J. AJ Y L J P M with in hypertrophic cardiomyopathy a study.Circ 122: M P R K J use in Hypertrophic Cardiomyopathy The effects of candesartan on left ventricular hypertrophy and function in hypertrophic cardiomyopathy: a randomized 2009; 11: Scholar maximum wall with the network with candesartan 95% to mavacamten 95% to and valsartan 95% to were to the maximum wall in patients with HCM with the valsartan 95% to candesartan mavacamten 95% to mavacamten valsartan 95% to in Supplementary Material to candesartan first by valsartan mavacamten and M Elliott PM L DR A Ho W AJ I of mavacamten on in symptomatic patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. MS R Maron BJ of on myocardial and other clinical in patients with hypertrophic J I PG PA Rapezzi C M G B F P A C A L A R G C F L G A of in patients with symptomatic hypertrophic cardiomyopathy: the study.Circ Heart Fail. C PA G S Ho MA of on left ventricular hypertrophy and in patients with hypertrophic Heart Fail. 2013; Scholar septal E/e′ with the network with mavacamten 95% to was to the septal in patients with HCM 10, Supplementary in Supplementary Material to mavacamten first by and 10, bias for systolic blood pressure, maximum wall thickness, and septal was with funnel The results a small likelihood of bias for each outcome 1 to in Supplementary Material this is the first study to the efficacy of commonly used drugs, with a in other mavacamten, perhexiline, ranolazine, spironolactone, trimetazidine, losartan, atorvastatin, candesartan, N-acetylcysteine, and in treating patients with HCM. The NMA that drugs significantly improve clinical outcomes in patients with HCM. The in the results are from the 17 clinical studies eligible for this The key in the exercise is that the peak at oxygen consumption in that cardiac to as should be cardiac function is is a for the diagnosis of heart whereas in of LV hypertrophy and myocardial ischemia, are common in HCM. is an for the of LV HCM is by LV hypertrophy, and the of drugs to LV hypertrophy is an assessment of treatment the size and function of the left with HCM left LV diastolic and left atrial pressure, in the effects of on cardiac diastolic of the criteria for HCM is an in myocardial maximum wall thickness. a drug myocardial hypertrophy is an of treatment The is an of LV diastolic function and LV by with HCM for diastolic dysfunction, of the LV and in the may the of in diastolic function by blood pressure, a to the disease, has a impact on the of the disease, such as the of cardiac hypertrophy, is the was included in this study as an outcome for the efficacy of treatments for HCM on septal alcohol septal and the use of implantable is a of reports on A meta-analysis comparing the efficacy and of with of K in the treatment of patients with HCM that are significantly beneficial in reducing and compared with the K J J S H The efficacy and of compared with K in patients with hypertrophic cardiomyopathy and atrial J. 2024; Scholar The and of LV hypertrophy are primary of symptoms in patients with HCM, and that myocardial energy is a in HCM. However, most commonly used drugs clinical to Perhexiline improve myocardial function by the of reducing may myocardial and R J G AA R Semsarian C Randomized controlled of perhexiline on of left ventricular hypertrophy in patients with symptomatic hypertrophic cardiomyopathy Heart J. Scholar The in with perhexiline in this study its potential in myocardial However, the of this drug in the included studies the of its on maximum wall thickness. its in to with drugs such as N K RA and of perhexiline in A clinical of a novel Scholar with to of perhexiline, has in animal to improve and cardiac through the T L cardiac in by Scholar to effectively the of in animal therapy with and has to in treating HCM in However, its efficacy in to be M J. in hypertrophic J Cardiol. AJ effects of and therapy in a model of hypertrophic cardiomyopathy.J Scholar the on the myocardial reducing the of the of and the and reducing the of myocardial to In myocardial after and in and has promising therapeutic M J. in hypertrophic J Cardiol. 3rd, M A for treatment of or in hypertrophic cardiomyopathy patients Am Coll Cardiol. Scholar However, the efficacy of the drugs in this study was were conducted on the efficacy and of the drug mavacamten for patients with HCM. with mavacamten the of the primary risk 95% to improved Heart 95% to and reduced the of septal therapy 95% to M MA R Gersh BJ Mavacamten treatment for hypertrophic cardiomyopathy: a and meta-analysis of randomized controlled Cardiol. Scholar In there was a significant in peak at the at and after and the of MS T N K MS M A A K K A and meta-analysis of the efficacy and of Mavacamten therapy in cohort of patients with hypertrophic 2024; Scholar Mavacamten is a novel and selective myosin reducing and myocardial M MA R Gersh BJ Mavacamten treatment for hypertrophic cardiomyopathy: a and meta-analysis of randomized controlled Cardiol. Scholar of from drugs used to patients with HCM. However, the effects of mavacamten in patients with HCM to be the efficacy of and for patients with HCM an aspect of this The for results and to is as follows: is 1 of the outcome measures for cardiac the of blood that the left with each the is and In terms of the of of the there is a that mavacamten may heart to myocardial is to the of the drug and the cardiac The reports included in this study in to mavacamten, be by 2 of the studies the different in with mavacamten, with the of 5 treatment to criteria for a in to in 1 I A R A P S A M W J K J AJ W M A Ho study for treatment of symptomatic obstructive hypertrophic cardiomyopathy a 2020; M L Y AJ A F S AJ A of mavacamten in symptomatic patients with hypertrophic cardiomyopathy.J Am Coll Cardiol. 2020; Scholar to the generated blood at the are may a of the to obstruction of blood the results reported by other studies, the of and for this outcome literature analysis in this study its study the efficacy of commonly used drugs for treating patients with HCM, should be the on the effects of different of commonly used drugs on corresponding clinical outcome of should be in the inclusion of studies with small sample and of outcome measures generated a of drugs for in this to and combination therapy involving multiple drugs was in this be in In on the basis of current studies, be that commonly used drugs in clinical may effectively improve outcome measures in patients with HCM such as systolic blood pressure, maximum wall thickness, and septal E/e′ ratio. drugs, perhexiline indicated efficacy in whereas candesartan better efficacy in reducing the maximum wall thickness. other outcome significant therapeutic effects are with In the included studies, compared with drug significantly improved reports study and were provided by The remaining has to be available on with Supplementary Material 1. with Supplementary Material 1 to 1 to

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Cancer metabolic plasticity, including changes in fatty acid metabolism utilisation, is now widely appreciated as a key driver for cancer cell growth, survival and malignancy. Hence, cancer metabolic pathways have been the focus of much recent drug development. Perhexiline is a prophylactic antianginal drug known to act by inhibiting carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), mitochondrial enzymes critical for fatty acid metabolism. In this review, we discuss the growing evidence that perhexiline has potent anti-cancer properties when tested as a monotherapy or in combination with traditional chemotherapeutics. We review the CPT1/2 dependent and independent mechanisms of its anti-cancer activities. Finally, we speculate on the clinical feasibility and utility of repurposing perhexiline as an anti-cancer agent, its limitations including known side effects and its potential added benefit of limiting cardiotoxicity induced by other chemotherapeutics.

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Tumor-associated macrophages (TAMs) promote tumor development and metastasis and are categorized into M1-like macrophages, suppressing tumor cells, and M2-like macrophages. M2-like macrophages, occupying a major role in TAMs, can be repolarized into anti-tumoral phenotypes. In this study, outer membrane vesicles (OMVs) secreted by Escherichia coli Nissle 1917 carry perhexiline (OMV@Perhx) to explore the influence of OMVs and perhexiline on TAM repolarization. OMV@Perhx was internalized by macrophages and regulated the phenotype of TAMs from M2-like to M1-like efficiently to increase the level of tumor suppressor accordingly. Re-polarized macrophages promoted apoptosis and inhibited the mobility of tumor, cells including invasion and migration. The results indicate that OMVs improve the efficacy of perhexiline and also represent a promising natural immunomodulator. Combining OMVs with perhexiline treatments shows powerfully synergistic anti-tumor effects through co-culturing with re-polarized macrophages. This work is promising to exploit the extensive applications of OMVs and chemical drugs, therefore developing a meaningful drug carrier and immunomodulator as well as expanding the purposes of traditional chemical drugs.

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the human cancers with the poorest prognosis. Interestingly, we found that mitochondrial respiration in primary human PDAC cells depends mainly on the fatty acid oxidation (FAO) to meet basic energy requirements. Therefore, we treated PDAC cells with perhexiline, a well-recognized FAO inhibitor used in cardiac diseases. Some PDAC cells respond efficiently to perhexiline, which acts synergistically with chemotherapy (gemcitabine) in vitro and in two xenografts in vivo. Importantly, perhexiline in combination with gemcitabine induces complete tumor regression in one PDAC xenograft. Mechanistically, this co-treatment causes energy and oxidative stress promoting apoptosis but does not exert inhibition of FAO. Yet, our molecular analysis indicates that the carnitine palmitoyltransferase 1C (CPT1C) isoform is a key player in the response to perhexiline and that patients with high CPT1C expression have better prognosis. Our study reveals that repurposing perhexiline in combination with chemotherapy is a promising approach to treat PDAC.

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Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether Krüppel-like factor 14 (KLF14) is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6J mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1 expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in senescence-accelerated P8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14's transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

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Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS GSFM and drug efficacy, suggesting that RS GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimensions activities of the Functional Module, including gene-level, pathway-level and transcriptional regulatory network-level.

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