Cancer Chemotherapy and Pharmacology最新文献

{"title":"Thymine as potential biomarker to predict 5-FU systemic exposure in patients with gastro-intestinal cancer: a prospective pharmacokinetic study (FUUT-trial).","authors":"Maarten A Hanrath, Evi Banken, Sebastian A H van den Wildenberg, Daan van de Kerkhof, Dirk Jan A R Moes, Michele Boisdron-Celle, Bianca J C van den Bosch, Ramon Bax, Pierre M Bet, Jan Gerard Maring, Geert-Jan M Creemers, Irene E G van Hellemond, Maarten J Deenen","doi":"10.1007/s00280-025-04759-8","DOIUrl":"10.1007/s00280-025-04759-8","url":null,"abstract":"<p><strong>Purpose: </strong>In 20-30% of the patients, fluoropyrimidines (5-FU) based chemotherapy leads to severe toxicity, which is associated with dihydropyridine dehydrogenase (DPD) deficiency. Therefore, DPYD genotyping became standard practice before treatment with fluoropyrimidines. Nevertheless, only 17% of the patients with severe toxicity have a DPYD variant. Therefore, an urgent need persists to investigate other strategies contributing to prediction and prevention of toxicity. Endogenous DPD substrates are considered as potential biomarkers to predict toxicity, yet contradictional data exist on demonstrating uracil as a reliable biomarker. Thymine as biomarker for toxicity has been investigated less. The aim of this study was to determine the association between the concentrations of uracil, thymine dihydrouracil (DHU) and dihydrothymine (DHT), with the systemic drug exposure of 5-FU and DPD enzyme activity in patients treated with 5-FU.</p><p><strong>Methods: </strong>We included 36 patients with gastrointestinal malignancy who received 5-FU infusion. DPYD genotyping was conducted before start of treatment. Blood samples for determining 5-FU, uracil and thymine concentrations during infusion and DPD enzyme activity were taken.</p><p><strong>Results: </strong>We found a significant correlation between the 5-FU systematic exposure and baseline thymine concentrations (R² = 0.1468; p = 0.0402). DPD enzyme activity was significantly correlated with baseline thymine concentrations but no correlation was found between DPD enzyme activity and 5-FU systemic drug exposure.</p><p><strong>Conclusion: </strong>5-FU dose individualization based on thymine concentrations could be a promising addition to DPYD genotyping to predict 5-FU-induced toxicity. Larger prospective trials are needed to examine thymine as predictor for toxicity in daily practice.</p><p><strong>Trial registration: </strong>Trial NL7539 at 'Overview of Medical Research in the Netherlands' (ID NL-OMON21471). Date of registration 19-02-2019.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"34"},"PeriodicalIF":2.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose adjustment strategy for high-dose methotrexate-induced toxicities in pediatric acute lymphoblastic leukemia: based on population PK analysis and exposure-toxicity relationship.","authors":"Ailing Cao, Yanping Guan, Jian Wang, Xinyu Li, Shu Liu, Qiaolan Xuan, Kunyin Qiu, Yating Zhang, Lvhong Xu, Jianpei Fang, Zhong Zuo, Min Huang, Xueding Wang, Dunhua Zhou","doi":"10.1007/s00280-025-04750-3","DOIUrl":"https://doi.org/10.1007/s00280-025-04750-3","url":null,"abstract":"<p><strong>Purpose: </strong>High-dose methotrexate (HD-MTX) is the cornerstone of the therapy for acute lymphoblastic leukemia (ALL). However, severe adverse events are frequently reported despite standard supportive cares. Therefore, we aim to develop a new strategy to individualize HD-MTX and improve patient safety.</p><p><strong>Methods: </strong>A retrospective study was conducted in which toxicity were evaluated in 134 patients with 461 HD-MTX treatment courses. All of the patients experienced standard supportive cares. Exposure-toxicity analysis was conducted to obtain the target concentration and area under the curve (AUC) of MTX. Population PK model was established for dose simulations.</p><p><strong>Results: </strong>A high rate of severe toxicities (78.1%) was observed. Patients with C_24h above 75 µmol/L were at high risk for developing serious myelosuppression (P < 0.001) or hepatic injury (P = 0.005) within each cycle. Moreover, although no effect of AUC_0-24 h was found on toxicities within the relative cycle, a prolonged effect of MTX overexposure was observed on the toxicities in the next cycle. When the AUC_0-24 h levels were above 1447 µmol/L·h, patients were more likely to develop serious myelosuppression (P = 0.004) in the subsequent cycle. Based on the C_24h and AUC_0-24 h levels and the known required effective doses, reducing the dose from 5 g/m² to 2-3 g/m² according to the risk stratification is recommended to prevent related toxicities.</p><p><strong>Conclusion: </strong>MTX C_24h and AUC_0-24 h levels are the predictors of HD-MTX-related toxicity. For patients with overdose of HD-MTX, a new dose adjustment strategy is established to improve patient safety and optimize clinical benefit.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"33"},"PeriodicalIF":2.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New approach to busulfan dosing in infants and children based on a population pharmacokinetic analysis.","authors":"Frank M Balis, Elizabeth Rieger, Nancy J Bunin, JoAnn Gardiner, Leslie M Shaw, Timothy S Olson, Michael C Milone","doi":"10.1007/s00280-025-04757-w","DOIUrl":"10.1007/s00280-025-04757-w","url":null,"abstract":"<p><strong>Purpose: </strong>Apply population pharmacokinetic modeling to a single institution busulfan therapeutic drug monitoring (TDM) data set from infants and children to refine dosing methods.</p><p><strong>Methods: </strong>One-compartment pharmacokinetic model was fit to busulfan TDM data from 328 infants and children with malignant and non-malignant diseases treated with busulfan-containing transplant conditioning regimens. Age-dependence of busulfan clearance scaled to body weight and body surface area (BSA) was compared, and busulfan AUC was simulated for a BSA-scaled dose of 100 mg/m² combined with a BSA-banded dosing table for infants and children with a BSA < 0.5 m².</p><p><strong>Results: </strong>Busulfan clearance scaled to body weight is age-dependent. Clearance in children ≤ 3 years (0.234 L/[h•kg]) is higher than the typical value for the population, (0.205 L/[h•kg]), and 48% of children < 5 years have subtherapeutic busulfan AUCs after the first dose. Busulfan clearance scaled to BSA (typical value, 5.47 L/[h•m²]) is more uniform across the pediatric age span, except for infants (≤ 1 year, 4.27 L/[h•m²]). Simulated busulfan AUCs with a dose of 100 mg/m² for patients with a BSA ≥ 0.5 m² combined with a BSA-banded dosing table for patients with a BSA < 0.5 m² achieved a therapeutic AUC after the first dose in 49% more patients than body weight scaled doses.</p><p><strong>Conclusion: </strong>Our model predicts a greater proportion of children would achieve a therapeutic busulfan AUC after the first dose with a dose of 100 mg/m²/d combined with the infant dosing table for patients with a BSA < 0.5 m² compared to body weight-scaled dosing.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"32"},"PeriodicalIF":2.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food effect trial of the pharmacokinetics and safety of TQ05105 in healthy Chinese subjects.","authors":"Jun Dai, Yang Cheng, Yannan Zhou, Yanli Wang, Zhengzhi Liu, Qing Ren, Zhengjie Su, Qiaohuan Deng, Haimiao Yang, Yingzi Cui","doi":"10.1007/s00280-025-04754-z","DOIUrl":"https://doi.org/10.1007/s00280-025-04754-z","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to investigate the effect of food intake on the pharmacokinetics of TQ05105 tablets in healthy Chinese subjects, and to evaluate the safety in these subjects.</p><p><strong>Methods: </strong>This Phase I clinical trial involved healthy subjects who received a single oral dose of 15 mg TQ05105, with a 2-day washout period between each period. The plasma concentrations of TQ05105 and its metabolite TQ12550 were quantified using a validated liquid chromatography-tandem mass spectrometry method. Safety assessments were conducted throughout the study.</p><p><strong>Results: </strong>The study enrolled 16 healthy Chinese subjects (10 males and 6 females). Compared with the fasting condition, the postprandial administration of TQ05105 resulted in significant reductions in the maximum concentration (C_max) and area under the curve (AUC) of both TQ05105 and its metabolite TQ12550. Additionally, both the time to peak concentration (T_max) and half-life (t_1/2) of TQ05105 and its metabolite were prolonged under postprandial conditions. No serious adverse events were reported during the study.</p><p><strong>Conclusion: </strong>The findings demonstrate that food intake significantly alters the pharmacokinetic parameters of TQ05105 and its metabolite TQ12550, with a notable decrease in C_max and AUC, and an increase in T_max and t_1/2. The single dose of the drug was well tolerated.</p><p><strong>Registration information: </strong>This trial had registered at the Clinical Trials.gov on August 08, 2023 ( https://clinicaltrials.gov , NCT05982106).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"31"},"PeriodicalIF":2.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma.","authors":"Hui Zhang, Yan Guo, Yongsheng Song, Chao Shang","doi":"10.1007/s00280-025-04758-9","DOIUrl":"https://doi.org/10.1007/s00280-025-04758-9","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"30"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1 assists the predictive value of tumor PD-L1 expression for the efficacy of anti-PD-1/PD-L1 antibody in NSCLC.","authors":"Kunihiko Funaishi, Kakuhiro Yamaguchi, Hiroki Tanahashi, Koji Kurose, Shinjiro Sakamoto, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Hiroshi Iwamoto, Hironobu Hamada, Toru Oga, Mikio Oka, Noboru Hattori","doi":"10.1007/s00280-025-04751-2","DOIUrl":"10.1007/s00280-025-04751-2","url":null,"abstract":"<p><strong>Background: </strong>The expression of anti-programmed cell death ligand-1 (PD-L1) in tumors is widely used as a biomarker to predict the therapeutic efficacy of anti-programmed cell death-1(PD-1)/PD-L1 antibodies. However, the predictive accuracy of this method is limited. High-mobility group box 1 (HMGB1) is known to modulate cancer immunity. Therefore, we investigated the potential of circulatory HMGB1 in combination with PD-L1 expression to predict the efficacy of anti-PD-1/PD-L1 antibody monotherapy.</p><p><strong>Patients and methods: </strong>This multicenter retrospective study analyzed blood samples collected from 114 patients with non-small cell lung cancer (NSCLC) prior to anti-PD-1/PD-L1 antibody monotherapy at two university hospitals (Hiroshima University Hospital and Kawasaki Medical School Hospital) between December 2015 and October 2020. We evaluated the association of serum HMGB1 levels with tumor response and progression-free survival (PFS).</p><p><strong>Results: </strong>Serum HMGB1 levels were significantly higher in patients with complete or partial response than in those with stable or progressive disease. Using receiver operating characteristic analysis, the cut-off level of serum HMGB1 to predict tumor response was determined to be 3.83 ng/mL. PFS was significantly longer in the HMGB1^high group than that in the HMGB1^low group in the entire cohort (4.3 months vs. 2.3 months) and in patients with NSCLC with PD-L1 tumor proportion score (TPS) ≥ 50% (12.4 months vs. 4.4 months), but not in those with PD-L1 TPS < 50% or unknown.</p><p><strong>Conclusion: </strong>HMGB1 may serve as a predictive biomarker for the efficacy of anti-PD-1/PD-L1 antibody therapy in the patients with NSCLC, especially in those with PD-L1 TPS ≥ 50%.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"28"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling of plasma from patients with multiple myeloma receiving bortezomib: an exploratory biomarker study of JCOG1105 (JCOG1105A1).","authors":"Masaki Ri, Shinsuke Iida, Kosuke Saito, Yoshiro Saito, Dai Maruyama, Arisa Asano, Suguru Fukuhara, Hideki Tsujimura, Kana Miyazaki, Shuichi Ota, Noriko Fukuhara, Eiju Negoro, Junya Kuroda, Shinichiro Yoshida, Eiichi Ohtsuka, Tsukamoto Norifumi, Takayuki Tabayashi, Nobuyuki Takayama, Toko Saito, Yasuhiro Suzuki, Yasuhiko Harada, Ishikazu Mizuno, Isao Yoshida, Masaki Maruta, Yasushi Takamatsu, Hiroo Katsuya, Makoto Yoshimitsu, Yosuke Minami, Keisuke Kanato, Wataru Munakata, Hirokazu Nagai","doi":"10.1007/s00280-025-04752-1","DOIUrl":"https://doi.org/10.1007/s00280-025-04752-1","url":null,"abstract":"<p><strong>Purpose: </strong>A comprehensive analysis of metabolites (metabolomics) has been proposed as a new strategy for analyzing liquid biopsies and has been applied to identify biomarkers predicting clinical responses or adverse events associated with specific treatments. Here, we aimed to identify metabolites associated with bortezomib (Btz)-related toxicities and response to treatment in newly diagnosed multiple myeloma (MM).</p><p><strong>Methods: </strong>Fifty-four plasma samples from transplant-ineligible MM patients enrolled in a randomized phase II study comparing two less-intensive regimens of melphalan, prednisolone and Btz (MPB) were subjected to the lipidomic profiling analysis. The amount of each lipid metabolite in plasma obtained prior to MPB therapy was compared to toxicity grades and responses to MPB therapy.</p><p><strong>Results: </strong>High levels of 7 phospholipids (4 lysophosphatidylcholines and 3 phosphatidylcholines) were observed in cases with Btz-induced ≥ grade 2 peripheral neuropathy (BiPN) (n = 11). In addition, low levels of 3 fatty acids (FAs)-FA (18:2), FA (18:1), and FA (22:6)-were observed in patients who developed severe skin disorders ≥ grade 2 (n = 10). No metabolite significantly associated with treatment response was identified.</p><p><strong>Conclusion: </strong>We conclude that levels of specific plasma lipid metabolites are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz-containing therapy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"29"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406).","authors":"Anuradha Krishnamurthy, Hong Wang, John C Rhee, Diwakar Davar, Ryan H Moy, Lee Ratner, Susan M Christner, Julianne L Holleran, Joshua Deppas, Carina Sclafani, John C Schmitz, Steve Gore, Edward Chu, Christopher J Bakkenist, Jan H Beumer, Liza C Villaruz","doi":"10.1007/s00280-024-04745-6","DOIUrl":"https://doi.org/10.1007/s00280-024-04745-6","url":null,"abstract":"<p><strong>Background: </strong>ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models.</p><p><strong>Methods: </strong>To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m²) and 5-FU (2000 mg/m²).</p><p><strong>Results: </strong>The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed.</p><p><strong>Conclusions: </strong>The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov id: </strong>NCT04535401.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"27"},"PeriodicalIF":2.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydropyrimidine enzyme activity and its effect on chemotherapy toxicity: importance of genetic testing.","authors":"Alexia Shamaei Zadeh, Danielle Roberts, Abby Williams, Deepali Pandey, John L Villano","doi":"10.1007/s00280-024-04740-x","DOIUrl":"https://doi.org/10.1007/s00280-024-04740-x","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with partial or complete DPD deficiency have decreased capacity to degrade fluorouracil and are at risk of developing toxicity, which can be even life-threatening.</p><p><strong>Case: </strong>A 43-year-old man with moderately differentiated rectal adenocarcinoma on capecitabine presented to the emergency department with complaints of nausea, vomiting, diarrhea, weakness, and lower abdominal pain for several days. Laboratory findings include grade 4 neutropenia (ANC 10) and thrombocytopenia (platelets 36,000). Capecitabine is used as a component of first-line adjuvant therapy by approximately 2 million patients worldwide each year. Capecitabine is metabolized to fluorouracil via the enzyme dihydropyrimidine dehydrogenase (DPD). With worsening pancytopenia and diarrhea, genetic testing for DPD deficiency was sent. Prompt treatment with uridine triacetate was initiated for presumed DPD deficiency. Unfortunately, he passed away from an infectious complication and was later confirmed to have a heterozygous DPYD*2A mutation.</p><p><strong>Discussion: </strong>Our case demonstrates uneven testing guidelines for DPD prior to initiating 5-FU chemotherapy, appropriateness of treating with uridine triacetate, and analysis of next-generation sequencing (NGS) on tumor samples and co-incidentally obtaining germline DPD deficiency status. Our case also highlights the severe clinical impact of having DPD deficiency even with early uridine triacetate therapy.</p><p><strong>Conclusion: </strong>It is our recommendation to perform DPD deficiency in curative intent cancer treatment and this information can increasingly be obtained in standard tumor NGS profiling, a growing norm in medical oncology.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"26"},"PeriodicalIF":2.7,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells.","authors":"João Marcos Oliveira-Silva, Leilane Sales Oliveira, Carolina Berraut Chiminazo, Rafael Fonseca, Carlos Vinicius Expedito de Souza, Alexandre Ferro Aissa, Graziela Domingues de Almeida Lima, Marisa Ionta, Angel Mauricio Castro-Gamero","doi":"10.1007/s00280-024-04731-y","DOIUrl":"https://doi.org/10.1007/s00280-024-04731-y","url":null,"abstract":"<p><strong>Purpose: </strong>Histone deacetylase 6 (HDAC6) plays a critical role in tumorigenesis and tumor progression, contributing to proliferation, chemoresistance, and cell motility by regulating microtubule architecture. Despite its upregulation in melanoma tissues and cell lines, the specific biological roles of HDAC6 in melanoma are not well understood. This study aims to explore the functional effects and underlying mechanisms of WT161, a selective HDAC6 inhibitor, in melanoma cell lines.</p><p><strong>Methods: </strong>Cell proliferation was assessed using both 2D and 3D cell culture systems, including MTT assays, spheroid growth analyses, and colony formation assays. The interaction between WT161 and the chemotherapeutic agents temozolomide (TMZ) or dacarbazine (DTIC) was evaluated using the Chou-Talalay method. Apoptotic cell death was analyzed through flow cytometry, while migration, adhesion, and invasion assays were conducted to evaluate the motility capacities of melanoma cells. Western blot assays quantified α-tubulin acetylation (Lys40), PARP cleavage, and protein levels of β-catenin and E-cadherin.</p><p><strong>Results: </strong>WT161 significantly reduced cell growth in both 2D and 3D cultures, decreased clonogenic capacity, and showed synergistic interactions with TMZ and DTIC. The inhibitor also induced apoptotic cell death and enhanced TMZ-induced apoptosis. Additionally, WT161 reduced cell migration and invasion while increasing cell adhesion. These effects were linked to changes in β-catenin and E-cadherin levels, depending on the specific cell type evaluated.</p><p><strong>Conclusion: </strong>Our study underscores the pivotal role of HDAC6 in melanoma progression, establishing it as a promising therapeutic target. We provide the first comprehensive evidence of WT161's anti-melanoma effects, setting the stage for further research into HDAC6 inhibitors as a potential strategy for melanoma treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"95 1","pages":"22"},"PeriodicalIF":2.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}