Cancer Chemotherapy and Pharmacology最新文献

{"title":"Aclarubicin: contemporary insights into its mechanism of action, toxicity, pharmacokinetics, and clinical standing.","authors":"Aleksandra Murzyn, Justyna Orzeł, Natalia Obajtek, Anna Mróz, Dominika Miodowska, Patrycja Bojdo, Bartosz Gąsiorkiewicz, Paulina Koczurkiewicz-Adamczyk, Kamil Piska, Elżbieta Pękala","doi":"10.1007/s00280-024-04693-1","DOIUrl":"10.1007/s00280-024-04693-1","url":null,"abstract":"<p><p>Aclarubicin (aclacinomycin A) is one of the anthracycline antineoplastic antibiotics with a multifaceted mechanism of antitumor activity. As a second-generation drug, it offers several advantages compared to standard anthracycline drugs such as doxorubicin or daunorubicin, which could position it as a potential blockbuster drug in antitumor therapy. Key mechanisms of action for aclarubicin include the inhibition of both types of topoisomerases, suppression of tumor invasion processes, generation of reactive oxygen species, inhibition of chymotrypsin-like activity, influence on cisplatin degradation, and inhibition of angiogenesis. Therefore, aclarubicin appears to be an ideal candidate for antitumor therapy. However, despite initial interest in its clinical applications, only a limited number of high-quality trials have been conducted thus far. Aclarubicin has primarily been evaluated as an induction therapy in acute myeloid and lymphoblastic leukemia. Studies have indicated that aclarubicin may hold significant promise for combination therapies with other anticancer drugs, although further research is needed to confirm its potential. This paper provides an in-depth exploration of aclarubicin's diverse mechanisms of action, its pharmacokinetics, potential toxicity, and the clinical trials in which it has been investigated.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"123-139"},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533716","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":"Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer.","authors":"Koutaro Ono, Remi Murase, Natsumi Matsumoto, Yutaro Kubota, Hiroo Ishida, Ken-Ichi Fujita","doi":"10.1007/s00280-024-04649-5","DOIUrl":"10.1007/s00280-024-04649-5","url":null,"abstract":"<p><strong>Purpose: </strong>Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR.</p><p><strong>Methods: </strong>To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients.</p><p><strong>Results: </strong>The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C-C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others.</p><p><strong>Conclusions: </strong>These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment.</p><p><strong>Trial registration number and date: </strong>UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"57-66"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140064968","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 2 study of glucarpidase in patients with delayed methotrexate elimination after high-dose methotrexate therapy.","authors":"Atsushi Ogawa, Hiroshi Kawamoto, Junichi Hara, Atsushi Kikuta, Chitose Ogawa, Hiroaki Hiraga, Kenichi Yoshimura, Kazunari Miyairi, Reiko Omori, Tokihiro Ro, Yuna Kamei, Toshimi Kimura","doi":"10.1007/s00280-024-04664-6","DOIUrl":"10.1007/s00280-024-04664-6","url":null,"abstract":"<p><strong>Purpose: </strong>High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted.</p><p><strong>Methods: </strong>The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them.</p><p><strong>Results: </strong>The rate of CIR was 76.9% (95% confidence interval, 46.2-95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events.</p><p><strong>Conclusion: </strong>Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"89-101"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118887","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":"Impact of bariatric surgery on oral anticancer drugs: an analysis of real-world data.","authors":"Cedric Lau, Ma Ida Mohmaed Ali, Lishi Lin, Dorieke E M van Balen, Bart A W Jacobs, Bastiaan Nuijen, Robert M Smeenk, Neeltje Steeghs, Alwin D R Huitema","doi":"10.1007/s00280-024-04640-0","DOIUrl":"10.1007/s00280-024-04640-0","url":null,"abstract":"<p><strong>Purpose: </strong>The number of patients with bariatric surgery who receive oral anticancer drugs is rising. Bariatric surgery may affect the absorption of oral anticancer drugs. Strikingly, no specific drug dosing recommendations are available. We aim to provide practical recommendations on the application of oral anticancer drugs in patients who underwent bariatric surgery.</p><p><strong>Methods: </strong>Patients with any kind of bariatric surgery were extracted retrospectively in a comprehensive cancer center. In addition, a flowchart was proposed to assess the risk of inadequate exposure to oral anticancer drugs in patients who underwent bariatric surgery. Subsequently, the flowchart was evaluated retrospectively using routine Therapeutic drug monitoring (TDM) samples.</p><p><strong>Results: </strong>In our analysis, 571 cancer patients (0.4% of 140.000 treated or referred patients) had previous bariatric surgery. Of these patients, 78 unique patients received 152 oral anticancer drugs equaling an overall number of 30 unique drugs. The 30 different prescribed oral anticancer drugs were categorized as low risk (13%), medium risk (67%), and high risk (20%) of underdosing. TDM plasma samples of 25 patients (82 samples) were available, of which 21 samples post-bariatric surgery (25%) were below the target value.</p><p><strong>Conclusions: </strong>The proposed flowchart can support optimizing the treatment with orally administered anticancer drugs in patients who underwent bariatric surgery. We recommend performing TDM in drugs that belong to BCS classes II, III, or IV. If more risk factors are present in BCS classes II or IV, a priori switches to other drugs may be advised. In specific cases, higher dosages can be provided from the start (e.g., tamoxifen).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"25-34"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995730","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":"Predictive performance of population pharmacokinetic models of imatinib in chronic myeloid leukemia patients.","authors":"Jaya Shree Dilli Batcha, Vikram Gota, Saikumar Matcha, Arun Prasath Raju, Mahadev Rao, Karthik S Udupa, Surulivelrajan Mallayasamy","doi":"10.1007/s00280-024-04644-w","DOIUrl":"10.1007/s00280-024-04644-w","url":null,"abstract":"<p><strong>Background and aim: </strong>Chronic myeloid leukemia is a myeloproliferative neoplasm associated with the specific chromosomal translocation known as the Philadelphia chromosome. Imatinib is a potent BCR-ABL tyrosine kinase inhibitor, which is approved as the first line therapy for CML patients. There are various population pharmacokinetic studies available in the literature for this population. However, their use in other populations outside of their cohort for the model development has not been evaluated. This study was aimed to perform the predictive performance of the published population pharmacokinetic models for imatinib in CML population and propose a dosing nomogram.</p><p><strong>Methods: </strong>A systematic review was conducted through PubMed, and WoS databases to identify PopPK models. Clinical data collected in adult CML patients treated with imatinib was used for evaluation of these models. Various prediction-based metrics were used for assessing the bias and precision of PopPK models using individual predictions.</p><p><strong>Results: </strong>Eight imatinib PopPK model were selected for evaluating the model performance. A total of 145 plasma imatinib samples were collected from 43 adult patients diagnosed with CML and treated with imatinib. The PopPK model reported by Menon et al. had better performance than all other PopPK models.</p><p><strong>Conclusion: </strong>Menon et al. model was able to predict well for our clinical data where it had the relative mean prediction error percentage ≤ 20%, relative median absolute prediction error ≤ 30% and relative root mean square error close to zero. Based on this final model, we proposed a dosing nomogram for various weight groups, which could potentially help to maintain the trough concentrations in the therapeutic range.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"35-44"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027488","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":"Phase I pharmacokinetic, safety, and preliminary efficacy study of tiragolumab in combination with atezolizumab in Chinese patients with advanced solid tumors.","authors":"Colby S Shemesh, Yongsheng Wang, Andrew An, Hao Ding, Phyllis Chan, Qi Liu, Yih-Wen Chen, Benjamin Wu, Qiong Wu, Xian Wang","doi":"10.1007/s00280-024-04650-y","DOIUrl":"10.1007/s00280-024-04650-y","url":null,"abstract":"<p><strong>Purpose: </strong>Tiragolumab is an immunoglobulin G1 monoclonal antibody targeting the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor ITIM domains. Targeting multiple immune pathways may improve anti-tumor responses. The phase I YP42514 study assessed the pharmacokinetics (PK), safety, and preliminary efficacy of tiragolumab plus atezolizumab in Chinese patients with advanced solid tumors.</p><p><strong>Methods: </strong>Adult patients from mainland China with Eastern Cooperative Oncology Group performance score 0/1, life expectancy of ≥ 12 weeks, and adequate hematologic/end organ function were eligible. Patients received tiragolumab 600 mg and atezolizumab 1200 mg intravenous every 3 weeks. Key endpoints were PK (serum concentrations of tiragolumab and atezolizumab) and safety. Results from this study were compared with the global phase I study, GO30103 (NCT02794571).</p><p><strong>Results: </strong>In this study, 20 patients received a median of five doses of tiragolumab plus atezolizumab. Median age was 57.5 years, 85.0% of patients were male and the most common tumor type was non-small cell lung cancer. Exposures in Chinese patients were comparable to the global GO30103 population: geometric mean ratio was 1.07 for Cycle 1 tiragolumab area under the concentration-time curve_0-21 and 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. Treatment-related adverse events were consistent across the Chinese and global populations. Two patients (10.0%) in this study achieved a partial response.</p><p><strong>Conclusion: </strong>In this study, tiragolumab plus atezolizumab was tolerable and demonstrated preliminary anti-tumor activity. There were no meaningful differences in the PK or safety of tiragolumab plus atezolizumab between the Chinese and global populations.</p><p><strong>Clinical trial registration number: </strong>China Clinical Trial Registry Identifier CTR20210219/YP42514. Date of registration 16 March 2021.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"45-55"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048857","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":"Phase I study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in Japanese patients with advanced or metastatic solid tumors.","authors":"Noboru Yamamoto, Takafumi Koyama, Jun Sato, Tatsuya Yoshida, Kazuki Sudo, Satoru Iwasa, Shunsuke Kondo, Kan Yonemori, Atsuko Kawasaki, Kyoko Satake, Shoyo Shibata, Toshio Shimizu","doi":"10.1007/s00280-023-04627-3","DOIUrl":"10.1007/s00280-023-04627-3","url":null,"abstract":"<p><strong>Purpose: </strong>Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926).</p><p><strong>Methods: </strong>Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity.</p><p><strong>Results: </strong>Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C_max 217 μg/mL; C_min 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t_1/2, 17.6 days. Best overall response was stable disease in two patients.</p><p><strong>Conclusion: </strong>Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials.</p><p><strong>Trial registration number: </strong>jRCT2080224926.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"109-115"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416455","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":"Impact of loperamide on the pharmacokinetics and tissue disposition of ritonavir-boosted oral docetaxel therapy; a preclinical assessment.","authors":"Nancy H C Loos, Viët Bui, Daniëlle H de Jong, Maria C Lebre, Hilde Rosing, Jos H Beijnen, Alfred H Schinkel","doi":"10.1007/s00280-024-04662-8","DOIUrl":"10.1007/s00280-024-04662-8","url":null,"abstract":"<p><strong>Purpose: </strong>An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel.</p><p><strong>Methods: </strong>We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured.</p><p><strong>Results: </strong>The plasma exposure (AUC and C_max) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir.</p><p><strong>Conclusion: </strong>These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"79-87"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058687","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":"Vitamin D suppresses CD133+/CD44 + cancer stem cell stemness by inhibiting NF-κB signaling and reducing NLRP3 expression in triple-negative breast cancer.","authors":"Wei Zheng, Wei Peng, Fuyong Qian, Mingshuai Zhang, Bofeng Duan, Zhifeng Fan, Yi Xie, Xiaoying Fu","doi":"10.1007/s00280-024-04660-w","DOIUrl":"10.1007/s00280-024-04660-w","url":null,"abstract":"<p><strong>Background and objective: </strong>This study aims to investigate the role of Vitamin D (VD) in regulating the stemness and survival of CD133+/CD44 + breast cancer stem cells, and to explore the role of NLRP3 in this process.</p><p><strong>Methods: </strong>Breast cancer tissues were collected for RXRα and VDR expression analysis. A triple-negative breast cancer cell line was cultured and stem-like cells (CD133 + CD44+) isolated using flow cytometry. These cells were treated with VD, analyzing their stem-like properties, apoptosis and proliferation, as well as P65 nuclear expression and NLRP3 expression. After NLRP3 inflammasome activator treatment, the parameters were reassessed. RXRα and VDR interaction was confirmed using co-immunoprecipitation (CoIP). Finally, a subcutaneous xenograft model of triple-negative breast cancer was treated with VD and subsequently analyzed for stem-like properties, proliferation, apoptosis, and NLRP3 expression levels.</p><p><strong>Results: </strong>CD133+/CD44 + stem cells expressed high levels of SOX2 and OCT4. VD treatment resulted in a significant decrease in SOX2 and OCT4 expression, fewer sphere-forming colonies, lower proliferation ability, and more apoptosis. Additionally, VD treatment inhibited NF-κB signaling and reduced NLRP3 expression. The NLRP3 activator BMS-986,299 counteracted the effects of VD in vitro. In vivo, VD inhibited the growth of breast cancer stem cells, reducing both tumor volume and weight, and decreased NLRP3, SOX2, and OCT4 expression within tumor tissues.</p><p><strong>Conclusion: </strong>Findings elucidate that VD mediates the modulation of stemness in CD133+/CD44 + breast cancer stem cells through the regulation of NLRP3 expression. The research represents novel insights on the implications for the application of VD in cancer therapies.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"67-78"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058744","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":"Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review.","authors":"Sashana Dixon, Ann Tenneil O'connor, Chloe Brooks-Noreiga, Michelle A Clark, Arkene Levy, Ana M Castejon","doi":"10.1007/s00280-024-04686-0","DOIUrl":"10.1007/s00280-024-04686-0","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"1-23"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445697","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}