Cancer Chemotherapy and Pharmacology最新文献

{"title":"Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.","authors":"Anna M Mc Laughlin, Dagmar Hess, Robin Michelet, Ilaria Colombo, Simon Haefliger, Sara Bastian, Manuela Rabaglio, Michael Schwitter, Stefanie Fischer, Katrin Eckhardt, Stefanie Hayoz, Christoph Kopp, Marian Klose, Cristiana Sessa, Anastasios Stathis, Stefan Halbherr, Wilhelm Huisinga, Markus Joerger, Charlotte Kloft","doi":"10.1007/s00280-024-04679-z","DOIUrl":"10.1007/s00280-024-04679-z","url":null,"abstract":"<p><strong>Study objectives: </strong>TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling.</p><p><strong>Methods: </strong>The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicin_entrapped, doxorubicin_free, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored.</p><p><strong>Results: </strong>Medians  <math><mo>±</mo></math> standard deviations of dose-normalised doxorubicin_{entrapped+free} C_max and AUC_0-∞ were 0.342 <math><mo>±</mo></math> 0.134 mg/L and 40.1 <math><mo>±</mo></math> 18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicin_entrapped), a two-compartment model with linear elimination (doxorubicin_free), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate.</p><p><strong>Conclusion: </strong>The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov-NCT03387917-January 2, 2018.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"349-360"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327264","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":"Postoperative chemotherapy relative dose intensity and overall survival in patients with colon cancer.","authors":"Justin C Brown, Jeffrey A Meyerhardt, Shengping Yang, Bette J Caan","doi":"10.1007/s00280-024-04665-5","DOIUrl":"10.1007/s00280-024-04665-5","url":null,"abstract":"<p><strong>Purpose: </strong>Quantifying the association of chemotherapy relative dose intensity (RDI) with overall survival may enable supportive care interventions that improve chemotherapy RDI to estimate their magnitude of potential clinical benefit.</p><p><strong>Methods: </strong>This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 12 cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposure was chemotherapy RDI. The primary outcome was overall survival. Restricted cubic splines estimated hazard ratios (HR).</p><p><strong>Results: </strong>Chemotherapy regimen RDI was associated with overall survival in an L-shaped pattern (linear P = 0.006; nonlinear P = 0.057); the risk of death was flat above 85% but increased linearly below 85%. For example, a decrease in RDI from 85 to 75% was associated with an increased risk of death [HR: 1.20 (95% CI: 1.08, 1.52)], whereas an increase in RDI from 85 to 95% was not associated with the risk of death [HR: 1.06 (95% CI: 0.82, 1.38)].</p><p><strong>Conclusion: </strong>If chemotherapy RDI is considered a potential surrogate of overall survival, supportive care interventions that improve chemotherapy RDI might confer a potential clinical benefit in this population.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"461-465"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193446","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":"Correction to: Inhibition of proteinase-activated receptor 2 (PAR2) decreased the malignant progression of lung cancer cells and increased the sensitivity to chemotherapy.","authors":"Hongjie Huo, Yu Feng, Qiong Tang","doi":"10.1007/s00280-024-04646-8","DOIUrl":"10.1007/s00280-024-04646-8","url":null,"abstract":"","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"489"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292893","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":"Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice.","authors":"Joshua J Deppas, Brian F Kiesel, Jianxia Guo, Robert A Parise, D Andy Clump, David Z D'Argenio, Christopher J Bakkenist, Jan H Beumer","doi":"10.1007/s00280-024-04675-3","DOIUrl":"10.1007/s00280-024-04675-3","url":null,"abstract":"<p><strong>Background: </strong>The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is an apical initiator of DNA damage response pathways. Several ATR inhibitors (ATRi) are in clinical development including berzosertib (formerly M6620, VX-970). Although clinical studies have examined plasma pharmacokinetics (PK) in humans, little is known regarding dose/exposure relationships and tissue distribution. To understand these concepts, we extensively characterized the PK of berzosertib in mouse plasma and tissues.</p><p><strong>Methods: </strong>A highly sensitive LC-MS/MS method was utilized to quantitate berzosertib in plasma and tissues. Dose proportionality was assessed in female BALB/c mice following single IV doses (2, 6, 20 or 60 mg/kg). A more extensive PK study was conducted in tumor-bearing mice following a single IV dose of 20 mg/kg to evaluate distribution to tissues. PK parameters were calculated by non-compartmental analysis (NCA). A compartmental model was developed to describe the PK behavior of berzosertib. Plasma protein binding was determined in vitro.</p><p><strong>Results: </strong>Increased doses of berzosertib were associated with less than proportional increases in early plasma concentrations and greater than proportional increase in tissue exposure, attributable to saturation of plasma protein binding. Berzosertib extensively distributed into bone marrow, tumor, thymus, and lymph nodes, however; brain and spinal cord exposure was less than plasma.</p><p><strong>Conclusion: </strong>The nonlinear PK of berzosertib displayed here can be attributed to saturation of plasma protein binding and occurred at concentrations close to those observed in clinical trials. Our results will help to understand preclinical pharmacodynamic and toxicity data and to inform optimal dosing and deployment of berzosertib.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"271-283"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920930","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":"Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.","authors":"Ciao-Sin Chen, Gary Zirpoli, G Thomas Budd, William E Barlow, Lajos Pusztai, Gabriel N Hortobagyi, Kathy S Albain, Andrew K Godwin, Alastair Thompson, N Lynn Henry, Christine B Ambrosone, Kathleen A Stringer, Daniel L Hertz","doi":"10.1007/s00280-024-04680-6","DOIUrl":"10.1007/s00280-024-04680-6","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity.</p><p><strong>Methods: </strong>Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm.</p><p><strong>Results: </strong>In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality.</p><p><strong>Conclusions: </strong>This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"311-321"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174908","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":"Combined treatment of All-trans retinoic acid with Tamoxifen suppresses ovarian cancer.","authors":"Rui Xu, Xiaowen Yang, Bin Tang, Yifan Mao, Feiyun Jiang","doi":"10.1007/s00280-024-04671-7","DOIUrl":"10.1007/s00280-024-04671-7","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer is a malignant tumor of the female reproductive system, and its mortality rate is as high as 70%. Estrogen receptor α (ERα)-positive ovarian cancer accounted for most of all ovarian cancer patients. ERα can promote the growth and proliferation of tumors.</p><p><strong>Methods: </strong>The combined effect of All-trans retinoic acid (ATRA) and tamoxifen was obtained by the combination screening of tamoxifen and compound library by MTS. In addition, colony formation assay, flow cytometry analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blot, and tumor xenotransplantation models were used to further evaluate the efficacy of tamoxifen and ATRA in vitro and in vivo for ER-α-positive ovarian cancer.</p><p><strong>Results: </strong>In our study, we found that All-trans retinoic acid (ATRA) can cooperate with tamoxifen to cause cell cycle arrest and apoptosis and inhibit ERα-positive ovarian cancer in vivo and in vitro. Further exploration of the mechanism found that ATRA can Inhibit genes related to the ERα signaling pathway, enhance the sensitivity of ERα-positive ovarian cancer cells to tamoxifen, and ascertain the effectiveness of tamoxifen and ATRA as treatments for ovarian cancer with an ERα-positive status.</p><p><strong>Conclusion: </strong>Combination of ATRA and tamoxifen is a new way for the treatment of ERα-positive ovarian cancer.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"259-270"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875861","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":"Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia.","authors":"Takahiro Kobayashi, Honami Sato, Masatomo Miura, Yayoi Fukushi, Wataru Kuroki, Fumiko Ito, Kazuaki Teshima, Atsushi Watanabe, Naohito Fujishima, Isuzu Kobayashi, Yoshihiro Kameoka, Naoto Takahashi","doi":"10.1007/s00280-024-04673-5","DOIUrl":"10.1007/s00280-024-04673-5","url":null,"abstract":"<p><strong>Purpose: </strong>An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.</p><p><strong>Methods: </strong>The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.</p><p><strong>Results: </strong>Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC_0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC_0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007).</p><p><strong>Conclusion: </strong>Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"285-296"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086906","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":"Physiologically-based pharmacokinetic models versus allometric scaling for prediction of tyrosine-kinase inhibitor exposure from adults to children.","authors":"Maddalena Centanni, Omar Zaher, David Elhad, Mats O Karlsson, Lena E Friberg","doi":"10.1007/s00280-024-04678-0","DOIUrl":"10.1007/s00280-024-04678-0","url":null,"abstract":"<p><strong>Purpose: </strong>Model-based methods can predict pediatric exposure and support initial dose selection. The aim of this study was to evaluate the performance of allometric scaling of population pharmacokinetic (popPK) versus physiologically based pharmacokinetic (PBPK) models in predicting the exposure of tyrosine kinase inhibitors (TKIs) for pediatric patients (≥ 2 years), based on adult data. The drugs imatinib, sunitinib and pazopanib were selected as case studies due to their complex PK profiles including high inter-patient variability, active metabolites, time-varying clearances and non-linear absorption.</p><p><strong>Methods: </strong>Pediatric concentration measurements and adult popPK models were derived from the literature. Adult PBPK models were generated in PK-Sim® using available physicochemical properties, calibrated to adult data when needed. PBPK and popPK models for the pediatric populations were translated from the models for adults and were used to simulate concentration-time profiles that were compared to the observed values.</p><p><strong>Results: </strong>Ten pediatric datasets were collected from the literature. While both types of models captured the concentration-time profiles of imatinib, its active metabolite, sunitinib and pazopanib, the PBPK models underestimated sunitinib metabolite concentrations. In contrast, allometrically scaled popPK simulations accurately predicted all concentration-time profiles. Trough concentration (C_trough) predictions from the popPK model fell within a 2-fold range for all compounds, while 3 out of 5 PBPK predictions exceeded this range for the imatinib and sunitinib metabolite concentrations.</p><p><strong>Conclusion: </strong>Based on the identified case studies it appears that allometric scaling of popPK models is better suited to predict exposure of TKIs in pediatric patients ≥ 2 years. This advantage may be attributed to the stable enzyme expression patterns from 2 years old onwards, which can be easily related to adult levels through allometric scaling. In some instances, both methods performed comparably. Understanding where discrepancies between the model methods arise, can further inform model development and ultimately support pediatric dose selection.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"297-310"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086908","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":"Effect of food on the pharmacokinetics and safety profiles of a new PARP inhibitor fuzuloparib capsules in healthy volunteers.","authors":"Pengfei Du, Yao Long, Minhui Wang, Yunzhe Huang, Yaqin Wang, Xinyan Chen, Yuhong Lin, Jianbang Wu, Jie Shen, Yuanwei Jia","doi":"10.1007/s00280-024-04672-6","DOIUrl":"10.1007/s00280-024-04672-6","url":null,"abstract":"<p><strong>Purpose: </strong>This study assessed effect of food on pharmacokinetics (PK) and safety of fuzuloparib capsules.</p><p><strong>Methods: </strong>A randomized, open-label, two-cycle, two-sequence, crossover clinical trial was conducted. 20 subjects were randomly assigned to 2 groups at a 1:1 ratio. The first group subjects were orally administered 150 mg fuzuloparib capsules under fasting condition in first dosing cycle. The same dose of fuzuloparib capsules were taken under postprandial state after a 7-day washout period. The second group was reversed. 3 ml whole blood was collected at each blood collection point until 72 h post dose. PK parameters were calculated. Furthermore, safety assessment was performed.</p><p><strong>Results: </strong>The time to maximum concentration (T_max) was prolonged to 3 h and maximum concentration (C_max) decreased by 18.6% on high-fat diets. 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for C_max, area under the concentration-time curve from time zero to time t (AUC_0-t), and area under the concentration-time curve extrapolated to infinity (AUC_0-∞) after high-fat meal were 71.6-92.6%, 81.7-102.7% and 81.6-102.5%, respectively. All treatment-emergent adverse events (TEAEs) were grade 1; No serious adverse events (SAEs), serious unexpected suspected adverse reaction (SUSAR) or deaths were reported.</p><p><strong>Conclusion: </strong>Food decreased the absorption rate and slowed time to peak exposure of fuzuloparib capsules, without impact on absorption extent. Dosing with food was found to be safe for fuzuloparib capsules in this study.</p><p><strong>Clinical trial registration: </strong>This study was registered with chinadrugtrials.org.cn (identifier: CTR20221498).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"251-257"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853174","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":"A polo-like kinase 1 inhibitor enhances erastin sensitivity in head and neck squamous cell carcinoma cells in vitro.","authors":"Xiangping Wu, Jing Wu","doi":"10.1007/s00280-024-04654-8","DOIUrl":"10.1007/s00280-024-04654-8","url":null,"abstract":"<p><strong>Background: </strong>Polo-like kinase 1 (PLK1) is a critical therapeutic target in the treatment of head and neck squamous cell carcinoma (HNSCC). The objective of this study was to investigate the therapeutic effect of the combination of BI 2536, a PLK1 inhibitor, and erastin, a ferroptosis inducer, in HNSCC.</p><p><strong>Methods: </strong>The proliferation, invasion, and migration abilities of Tu177 and FaDu cells upon exposure to BI 2536 and erastin, used in combination or alone, were tested. Fe²⁺, glutathione (GSH), and malondialdehyde (MDA) detection kits were used to determine whether the addition of BI 2536 enhanced the accumulation of Fe²⁺ and MDA, along with the depletion of GSH. Quantitative real-time PCR, western blot analyses were performed to investigate whether BI 2536 further altered the mRNA and expression level of ferroptosis genes. Furthermore, si PLK1 was used to investigate whether targeting PLK1 gene promoted erastin-induced ferroptosis.</p><p><strong>Results: </strong>The combination of BI 2536 and erastin exerted a stronger cytotoxicity than treatment with a single agent. Compared with erastin treatment alone, the combination of BI 2536 and erastin lowered the ability of tumor cells to self-clone, invade, and migrate. BI 2536 enhanced the accumulation of Fe²⁺ and MDA, and the depletion of GSH. BI 2536 increased erastin-induced changes in ferroptosis-related gene mRNA and expression. Importantly, targeting PKL1 enhanced the anti-cancer effect of erastin.</p><p><strong>Conclusion: </strong>BI 2536 enhanced the sensitivity of HNSCC cells to erastin, which provides a new perspective for cancer treatment.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"183-195"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304993","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}