O-Desmethyltramadol Enhanced Anti-Cancer Efficacy over Tramadol Through Non-μ-Opioid Receptor and Differential Cellular Contexts of Human Breast Cancer Cells DOI Open Access
Zih-Syuan Wu, Yi‐Hsuan Huang, Shih‐Ming Huang

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4139 - 4139

Published: April 27, 2025

Tramadol, a widely used analgesic, has recently been explored for its potential anti-cancer effects. However, the antitumor dosage of tramadol is over current clinical application. Its primary metabolite, O-desmethyltramadol, greater μ-opioid receptor affinity and stronger pharmacological activity. Hence, we sought to examine whether cytotoxic effect O-desmethyltramadol was better than on breast cancer cells. Our results showed that significantly reduced cell viability in cells, with IC50 values 64.2 μg/mL (MDA-MB-231) 96.7 (MCF-7), demonstrating ten-fold potency tramadol. The presence antagonist Alvimopan did not alter effects indicating non-opioid receptor-mediated mechanism. Compared activity mediated through ER stress, confirmed induced stress proteins, including p-eIF2α/eIF2α ratio, ATF4, CHOP. In MDA-MB-231 treatment elevated mRNA expression levels CHAC1, DDIT3 by approximately 2-fold. MCF-7 induction even more pronounced, ATF4 increased 1.7-fold, CHAC1 12-fold, 9-fold. Beyond opioid pathway, further analyzed differential functions using RNA-seq analysis. pathway enrichment analyses revealed influenced immune inflammatory pathways, such as TNF IL-6/JAK/STAT3 signaling while it affected metabolic transcriptional mTOR MAPK signaling. Gene Set Enrichment Analysis highlighted O-desmethyltramadol's role interferon response tumor microenvironment modulation. Four upregulated genes five downregulated were modulated Overall, our findings indicated exerted potent multiple mechanisms, distinct from depending subtype. These only highlight therapeutic novel adjunct treatment, but also emphasize need investigation into safety applicability oncology.

Language: Английский

Tumor gene expression signatures associated with outcome in large B−cell lymphoma treated with CD19-directed CAR T−cell therapy (axicabtagene ciloleucel) DOI Creative Commons
Yuan Tian, Justin A. Budka, Frederick L. Locke

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 27, 2025

CAR T cell therapy provided transformative outcomes for patients with B-cell lymphoma; however, a large fraction of remains at risk relapse, underlying the need to uncover mechanisms resistance and predictive biomarkers. Herein, we leveraged ZUMA-7 phase III randomized trial relapsed/refractory lymphoma (LBCL) treated axicabtagene ciloleucel (axi-cel; CD19-targeting cells) discover tumor gene expression signatures (GES) associated outcome. With transcriptomics from 134 axi-cel patients, employed multivariate penalized Cox models analyzing event-free survival (EFS), progression-free (PFS), duration response (DOR). We identified two novel GES, six-gene/transcript signature (6-GES; CD19, CD45RA, CCL22, KLRK1, SOX11, SIGLEC5) correlated improved outcome after (HR: 0.27, 95% CI: 0.16-0.44 EFS), representing lymphomas abundant target antigen (CD19) expression, adhesion molecules, relatively low immune infiltration mostly composed cytotoxic lymphocytes (T NK DCs, secondly, 17-gene/transcript (17-GES; CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN,GLUD1, ESR1, ARID1A, SLC16A1) disease progression 6.12, 3.57-10.50 consistent high inflammation escape mechanisms, such as upregulation genes involved in repair damaged DNA or chromatin remodeling, inhibition apoptosis, metabolically restrictive environment. These did not correlate standard-of-care arm (chemotherapy, followed by transplant) frontline therapy, supporting their rather than prognostic value. The findings were technically reproduced subset samples profiled RNA-seq (axi-cel, n=124; SOC, n=125). 6-GES was reduced, whereas 17-GES elevated post axi-cel, notion that these represent features relevant T-cell therapy. Our transcriptomic analysis potentially CD19-directed are informative stratification development next-generation products.

Language: Английский

Citations

0
O-Desmethyltramadol Enhanced Anti-Cancer Efficacy over Tramadol Through Non-μ-Opioid Receptor and Differential Cellular Contexts of Human Breast Cancer Cells DOI Open Access
Zih-Syuan Wu, Yi‐Hsuan Huang, Shih‐Ming Huang

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4139 - 4139

Published: April 27, 2025

Tramadol, a widely used analgesic, has recently been explored for its potential anti-cancer effects. However, the antitumor dosage of tramadol is over current clinical application. Its primary metabolite, O-desmethyltramadol, greater μ-opioid receptor affinity and stronger pharmacological activity. Hence, we sought to examine whether cytotoxic effect O-desmethyltramadol was better than on breast cancer cells. Our results showed that significantly reduced cell viability in cells, with IC50 values 64.2 μg/mL (MDA-MB-231) 96.7 (MCF-7), demonstrating ten-fold potency tramadol. The presence antagonist Alvimopan did not alter effects indicating non-opioid receptor-mediated mechanism. Compared activity mediated through ER stress, confirmed induced stress proteins, including p-eIF2α/eIF2α ratio, ATF4, CHOP. In MDA-MB-231 treatment elevated mRNA expression levels CHAC1, DDIT3 by approximately 2-fold. MCF-7 induction even more pronounced, ATF4 increased 1.7-fold, CHAC1 12-fold, 9-fold. Beyond opioid pathway, further analyzed differential functions using RNA-seq analysis. pathway enrichment analyses revealed influenced immune inflammatory pathways, such as TNF IL-6/JAK/STAT3 signaling while it affected metabolic transcriptional mTOR MAPK signaling. Gene Set Enrichment Analysis highlighted O-desmethyltramadol's role interferon response tumor microenvironment modulation. Four upregulated genes five downregulated were modulated Overall, our findings indicated exerted potent multiple mechanisms, distinct from depending subtype. These only highlight therapeutic novel adjunct treatment, but also emphasize need investigation into safety applicability oncology.

Language: Английский

Citations

0