Current Research in Pharmacology and Drug Discovery最新文献

{"title":"Sildenafil prevents chronic psychosocial stress-induced working memory impairment: Role of brain-derived neurotrophic factor","authors":"Tareq I. Jibril ,&nbsp;Karem H. Alzoubi ,&nbsp;Nizar M. Mhaidat ,&nbsp;Omar F. Khabour ,&nbsp;Mohammad A.Y. Alqudah ,&nbsp;Abeer M. Rababa’h ,&nbsp;Nasr Alrabadi ,&nbsp;Doaa Al-udatt","doi":"10.1016/j.crphar.2024.100182","DOIUrl":"10.1016/j.crphar.2024.100182","url":null,"abstract":"<div><h3>Background</h3><p>Psychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress.</p></div><div><h3>Methods</h3><p>Psychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed.</p></div><div><h3>Results</h3><p>This study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P &gt; 0.05).</p></div><div><h3>Conclusion</h3><p>Chronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100182"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000099/pdfft?md5=09936b28ff220b5c7507ae39caa4c86c&pid=1-s2.0-S2590257124000099-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140782465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the chemotherapeutic potential of two platinum(IV) complexes in skin cancer: in vitro and in vivo Insights","authors":"Amjad Slika ,&nbsp;Christina Haydar ,&nbsp;Joelle Bou Chacra ,&nbsp;Seba Al Alam ,&nbsp;Stephanie Mehanna ,&nbsp;Anthony Lteif ,&nbsp;Maria George Elias ,&nbsp;Krishant M. Deo ,&nbsp;Robin I. Taleb ,&nbsp;Janice R. Aldrich-Wright ,&nbsp;Costantine F. Daher","doi":"10.1016/j.crphar.2024.100205","DOIUrl":"10.1016/j.crphar.2024.100205","url":null,"abstract":"<div><div>The present study investigates the chemotherapeutic potential of two platinum (IV) complexes, P-PENT and P-HEX, against skin cancer <em>in vitro and in vivo</em>. Both complexes exhibited potent cytotoxicity against HaCaT-II-4 cells with IC₅₀ values of 0.8 ± 0.08 μM and 1.3 ± 0.16 μM respectively, while demonstrating 8-10-fold selectivity compared to mesenchymal stem cells (MSCs). Western blot analysis revealed significant modulation of key apoptotic and survival pathways, including upregulation of Bax/Bcl2 ratio, cleaved caspase 3, and cytochrome <em>c</em>, suggesting induction of intrinsic apoptosis. The complexes also inhibited PI3K and MAPK pathways, as evidenced by decreased p-AKT/AKT and p-ERK/ERK ratios. Flow cytometry confirmed significant apoptotic cell death. Both complexes also increased reactive oxygen species production. In a DMBA/TPA-induced skin carcinogenesis mouse model, both complexes significantly suppressed tumor growth at doses considerably lower than the maximum tolerated dose, with no detectable toxicity. A dose escalation study in BALB/c mice showed that P-PENT and P-HEX were approximately 5-fold and 4-fold more tolerated than cisplatin, respectively. In conclusion, the present study provides evidence that P-PENT and P-HEX may have the characteristics of an effective and potentially safe anti-tumor drug that could be used in skin cancer treatment.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100205"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142571501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term effects of neonatal pain and sucrose treatment","authors":"Khawla Nuseir ,&nbsp;Karem H. Alzoubi ,&nbsp;Ahmad Altarifi ,&nbsp;Manal Kassab ,&nbsp;Omar F. Khabour ,&nbsp;Nour F. Al-Ghraiybah ,&nbsp;Roa'a Obiedat","doi":"10.1016/j.crphar.2024.100176","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100176","url":null,"abstract":"<div><h3>Purpose</h3><p>In neonatal intensive care units, applying sucrose solution for analgesia is now a routine treatment for mild procedural pain. Studies of animal and human infants provide clear evidence of benefits in the short term, but few studies have investigated the long term benefits. Thus, we determined whether sucrose could ameliorate painful stimulation during infancy in Sprague–Dawley rats and also explored the long-term effects of repeated sucrose administration during infancy. Female and male rats were included to investigate sex-related differences.</p></div><div><h3>Methods</h3><p>Rat pups were stimulated either with painful or tactile stimuli for the first 14 days of their lives. Pups were pretreated either with sucrose or not treated before stimulation. Behavioral tests were conducted during adolescence and adulthood. Hotplate, rotarod, open field, elevated plus maze, and radial arm water maze tests were employed to assess the behavioral consequences of early life manipulations and treatments.</p></div><div><h3>Results</h3><p>Painful stimulation during infancy increased the sensitivity to pain later in life, and sucrose did not remedy this effect. Motility, coordination, anxiety, and cognition tests in adulthood obtained mixed results. Pain during infancy appeared to increase anxiety during adulthood. Learning and memory in adulthood were affected by pain during infancy, and sucrose had a negative effect even in the absence of pain. No sex-related differences were observed in any of the behavioral tests by employing this model of neonatal pain.</p></div><div><h3>Conclusion</h3><p>Painful stimulation during infancy resulted in deficiencies in some behavioral tests later in life. Sucrose pretreatment did not mitigate these shortcomings and it actually resulted in negative outcomes.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100176"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000038/pdfft?md5=e636825cbac4fe60817ad63f4c571321&pid=1-s2.0-S2590257124000038-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139653653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abelacimab: A leap forward in anticoagulation with FXI and FXIa Inhibition","authors":"Hisham A. Badreldin ,&nbsp;Nada Alsuhebany ,&nbsp;Mohammed Alzahrani ,&nbsp;Abdulmajeed M. Alshehri ,&nbsp;Maha Aldoughaim ,&nbsp;Saleh Alqifari ,&nbsp;Omar Yassin ,&nbsp;Lama Alfehaid ,&nbsp;Tariq Alqahtani","doi":"10.1016/j.crphar.2024.100179","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100179","url":null,"abstract":"<div><p>Direct Oral Anticoagulants (DOACs) have revolutionized the treatment of thromboembolic disorders, offering targeted, effective, and safer alternatives to traditional anticoagulants like heparins and vitamin K antagonists (VKAs). Despite their benefits, DOACs have drawbacks, including an increased risk of gastrointestinal bleeding and unsuitability for patients with mechanical heart valves. Recent research has highlighted Factor XI (FXI) as a promising anticoagulation target due to its significant role in pathological thrombosis and minor involvement in normal hemostasis. Abelacimab, an antibody that inhibits FXI, has shown potential in transforming anticoagulation therapy by sparing hemostasis. This review provides a comprehensive analysis of abelacimab, examining its clinical pharmacology and its pharmacokinetic and pharmacodynamic properties. It scrutinizes abelacimab's safety profile and key monitoring parameters. The current evidence supporting its use and potential future research strengthening its position in anticoagulant therapy is also discussed. The objective is to enhance understanding and contribute to discussions around developing safer anticoagulants, particularly for patients at risk for thrombosis.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100179"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000063/pdfft?md5=57b84c5a9c099c657260d03887e08166&pid=1-s2.0-S2590257124000063-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140163560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms and therapeutic potential of natural flavonoids in diabetic nephropathy: Modulation of intracellular developmental signaling pathways","authors":"Mahaboob Khan Sulaiman","doi":"10.1016/j.crphar.2024.100194","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100194","url":null,"abstract":"<div><p>Recognized as a common microvascular complication of diabetes mellitus (DM), diabetic nephropathy (DN) is the principal cause of chronic end-stage renal disease (ESRD). Patients with diabetes have an approximately 25% risk of developing progressive renal disease. The underlying principles of DN control targets the dual outcomes of blood glucose regulation through sodium glucose cotransporter 2 (SGLT 2) blockade and hypertension management through renin-angiotensin-aldosterone inhibition. However, these treatments are ineffective in halting disease progression to kidney failure and cardiovascular comorbidities. Recently, the dysregulation of subcellular signaling pathways has been increasingly implicated in DN pathogenesis. Natural compounds are emerging as effective and side-effect-free therapeutic agents that target intracellular pathways. This narrative review synthesizes recent insights into the dysregulation of maintenance pathways in DN, drawing from animal and human studies. To compile this review, articles reporting DN signaling pathways and their treatment with natural flavonoids were collected from PubMed, Cochrane Library Web of Science, Google Scholar and EMBASE databases since 2000. As therapeutic interventions are frequently based on the results of clinical trials, a brief analysis of data from current phase II and III clinical trials on DN is discussed.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100194"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S259025712400021X/pdfft?md5=1f92eb2d0381845b0736d4728a947c8b&pid=1-s2.0-S259025712400021X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141582194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exacerbation of atherosclerosis, hyperlipidemia and inflammation by MK886, an inhibitor of leukotriene biosynthesis, in obese and diabetic mice","authors":"Katherine Keever ,&nbsp;Bardia Askari","doi":"10.1016/j.crphar.2024.100203","DOIUrl":"10.1016/j.crphar.2024.100203","url":null,"abstract":"<div><div>Leukotrienes are potent mediators of the inflammatory response and 5-lipoxygenase, the enzyme responsible for their synthesis, is dependent on its interaction with 5-lipoxygenase activating protein for optimum catalysis. Previous studies had demonstrated that macrophage infiltration into adipose tissue is associated with obesity and atherosclerosis in LDLR^−/− mice fed a high fat-high carbohydrate. The present study was undertaken to determine whether inhibition of 5-lipoxygenase activating protein is efficacious in attenuating adipose tissue inflammation in LDLR^−/− mice fed a high fat-high carbohydrate. 10-week old male LDLR^−/− mice were fed a high fat-high carbohydrate diet for 22-weeks, with or without MK886 (40 mg/kg/day, <em>ad libitum</em>) a well-established 5-lipoxygenase activating protein inhibitor. All mice had an approximate 2-fold increase in total body weight, but a 6-week course of MK886 treatment had differential effects on adipose tissue size, without affecting macrophage accumulation. MK886 exacerbated the dyslipidemia, increased serum amyloid A content of high-density lipoproteins and caused a profound hepatomegaly. Dyslipidemia and increased serum amyloid A were concomitant with increases in atherosclerosis. In conclusion, MK886 paradoxically exacerbated hyperlipidemia and the pro-inflammatory phenotype in a mouse model of diet-induced atherosclerosis, possibly via a disruption of hepatic lipid metabolism and increased inflammation.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100203"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-lipoic acid: A promising pharmacotherapy seen through the lens of kidney diseases","authors":"George J. Dugbartey ,&nbsp;Karl K. Alornyo ,&nbsp;Christabel O. Dapaa-Addo ,&nbsp;Emmanuel Botchway ,&nbsp;Emmanuel K. Kwashie ,&nbsp;Yvonne Harley","doi":"10.1016/j.crphar.2024.100206","DOIUrl":"10.1016/j.crphar.2024.100206","url":null,"abstract":"<div><div>Kidney diseases have rapidly increased in prevalence over the past few decades, and have now become a major global public health concern. This has put economic burden on the public healthcare system and causing significant morbidity and mortality worldwide. Unfortunately, drugs currently in use for the management of kidney diseases have long-term major adverse effects that negatively impact the quality of life of these patients, hence making these drugs a “necessary evil”. In recent times, antioxidant therapy has been explored as a potential pharmacological avenue for treatment of kidney diseases, and could offer a better therapeutic option with less adverse effect profile. One of such antioxidants is alpha-lipoic acid (ALA), a sulphur-containing multifunctional antioxidant that is endogenously produced by lipoic acid synthase in the mitochondria of many tissues, including the kidney. Burgeoning evidence indicates that ALA is showing clinical promise in the treatment and pharmacological management of many kidney diseases through its antioxidant and other therapeutic properties by activating several protective mechanisms while inhibiting deleterious signaling pathways. In this review, we present ALA as a potent naturally occurring antioxidant, its mitochondrial biosynthesis and pharmacological properties. In addition, we also discuss within the limit of present literature, ALA and its underlying molecular mechanisms implicated in experimental and clinical treatment of various kidney conditions, and thus, may offer nephrologists an additional and/or alternative avenue in the pharmacological management and treatment of kidney diseases while giving hope to these patients.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100206"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142537363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mefloquine-curcumin combinations improve host mitochondrial respiration and decrease mitotoxic effects of mefloquine in Plasmodium berghei-infected mice","authors":"John Oludele Olanlokun ,&nbsp;Oshireku Wisdom Abiodun ,&nbsp;Adekunle Theophilus Adegbuyi ,&nbsp;Neil Anthony Koorbanally ,&nbsp;Olufunso Olabode Olorunsogo","doi":"10.1016/j.crphar.2024.100180","DOIUrl":"10.1016/j.crphar.2024.100180","url":null,"abstract":"<div><p><em>Plasmodium</em> infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is limited.</p><p>Malaria was induced in two different studies using NK65 (chloroquine-susceptible, study 1), and ANKA (chloroquine-resistant, study 2) strains of <em>Plasmodium berghei</em> in 30 male Swiss mice (n = 5) in each study. Mice orally received 10 mL/kg distilled water, (infected control), Mefloquine (MF) (10 mg/kg), MF and Curcumin (CM) (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (un-infected) were used as the control. After treatment, total Ribonucleic acid (RNA) was isolated from liver and erythrocytes while Deoxyribonucleic acid (DNA)-free RNA were converted to cDNA. Polymerase Chain Reaction (PCR) amplification was performed and relative expressions of <em>FIKK12, AQP3, P38 MAPK, NADH</em> oxidoreductase, and cytochrome oxidase expressions were determined. Markers of glycolysis, toxicity and antioxidants were determined using ELISA assays. While the expression of <em>FIKK12</em> was blunted by MF in the susceptible study, co-treatment with curcumin (25 mg/kg) yielded the same results in the chloroquine-resistant study. Similar results were obtained on <em>AQP3</em> in both studies. Curcumin decreased <em>P38 MAPK</em> in both studies. <em>Plasmodium</em> infection decreased <em>NADH</em> oxidoreductase and cytochrome oxidase but mefloquine-curcumin restored the expression of these genes. While glycolysis and toxicity were inhibited, antioxidant systems improved in the treated groups. Curcumin is needed for effective therapeutic efficacy and prevention of toxicity. <em>Plasmodium</em> infection and treatment modulate the expressions of some genes in the host. Curcumin combination with mefloquine modulates the expression of some genes in the host.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100180"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000075/pdfft?md5=5c540566dbefe3538d1df92bdff79031&pid=1-s2.0-S2590257124000075-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140760778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energy substrate supplementation increases ATP levels and is protective to PD neurons","authors":"Andrey Y. Vinokurov ,&nbsp;Marina Y. Pogonyalova ,&nbsp;Larisa Andreeva ,&nbsp;Andrey Y. Abramov ,&nbsp;Plamena R. Angelova","doi":"10.1016/j.crphar.2024.100187","DOIUrl":"10.1016/j.crphar.2024.100187","url":null,"abstract":"<div><p>Alteration of mitochondrial metabolism by various mutations or toxins leads to various neurological conditions. Age-related changes in energy metabolism could also play the role of a trigger for neurodegenerative disorders. Nonetheless, it is not clear if restoration of ATP production or supplementation of brain cells with substrates for energy production could be neuroprotective. Using primary neurons and astrocytes, and neurons with familial forms of neurodegenerative disorders we studied whether various substrates of energy metabolism could improve mitochondrial metabolism and stimulate ATP production, and whether increased ATP levels could protect cells against glutamate excitotoxicity and neurodegeneration. We found that supplementation of neurons with several substrates, or combination thereof, for the TCA cycle and cellular respiration, and oxidative phosphorylation resulted in an increase in mitochondrial NADH level and in mitochondrial membrane potential and led to an increased level of ATP in neurons and astrocytes. Subsequently, these cells were protected against energy deprivation during ischemia or glutamate excitotoxicity. Provision of substrates for energy metabolism to cells with familial forms of Parkinson's disease also prevented triggering of cell death. Thus, restoration of energy metabolism and increase of ATP production can play neuroprotective role in neurodegeneration. A combination of a succinate salt of choline and nicotinamide provided the best results.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100187"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000142/pdfft?md5=fa4f852b11d98e050ced37db3c1bf9e8&pid=1-s2.0-S2590257124000142-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141139119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting c-Met in breast cancer: From mechanisms of chemoresistance to novel therapeutic strategies","authors":"Emeka Eze Joshua Iweala ,&nbsp;Doris Nnenna Amuji ,&nbsp;Abimbola Mary Oluwajembola ,&nbsp;Eziuche Amadike Ugbogu","doi":"10.1016/j.crphar.2024.100204","DOIUrl":"10.1016/j.crphar.2024.100204","url":null,"abstract":"<div><div>Breast cancer presents a significant challenge due to its heterogeneity and propensity for developing chemoresistance, particularly in the triple-negative subtype. c-Mesenchymal epithelial transition factor (c-Met), a receptor tyrosine kinase, presents a promising target for breast cancer therapy due to its involvement in disease progression and poor prognosis. However, the heterogeneous expression of c-Met within breast cancer subtypes and individual tumors complicates targeted therapy. Also, cancer cells can develop resistance to c-Met inhibitors through various mechanisms, including bypass signaling pathways and genetic mutations. The off-target effects of c-Met inhibitors further limit their clinical utility, necessitating the development of more selective agents. To overcome these challenges, personalized treatment approaches and combination therapies are being explored to improve treatment efficacy while minimizing adverse effects. Novel c-Met inhibitors with improved selectivity and reduced off-target toxicity show promise in preclinical studies. Additionally, targeted delivery systems aim to enhance drug localization and reduce systemic toxicity. Future directions involve refining inhibitor design and integrating c-Met inhibition into personalized treatment regimens guided by molecular profiling. This review explores the mechanisms by which c-Met contributes to chemoresistance in breast cancer and current challenges in targeting c-Met for breast cancer therapy. It discusses strategies to optimize treatment outcomes, ultimately improving patient prognosis and reducing mortality rates associated with this devastating disease.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100204"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}