Bajraktari-Sylejmani Gzona, Piribauer Marlene, Groessl Sven, Bernhard Patrick, Dyckhoff Gerhard, Warta Rolf, Herold-Mende Christel, Theile Dirk, Weiss Johanna
Heidelberg University, Medical Faculty Heidelberg, Heidelberg University Hospital, Internal Medicine IX - Department of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Heidelberg University, Medical Faculty Heidelberg, Heidelberg University Hospital, Internal Medicine IX - Department of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany.
Toxicol Appl Pharmacol. 2025 Jun 16:117443. doi: 10.1016/j.taap.2025.117443.
Efficacy of the standard cytotoxic drugs against head and neck squamous cell carcinoma (HNSCC) is limited, underlining the potential relevance of multidrug resistance (MDR), mediated by drug transporters and drug-metabolising enzymes. While the major regulator of these proteins, the pregnane-X-receptor, is of minor relevance for HNSCC, little is known about the aryl hydrocarbon receptor (AhR) signaling, its transcriptional effect on MDR genes and phenotypic MDR upon activation. Using established HNSCC cell lines, AhR reporter gene assays, quantitative reverse transcription polymerase chain reaction, and proliferation assays, this study demonstrates that AhR and its major cofactors (heat shock protein 90, AhR nuclear translocator, and AhR-interacting protein 1) are expressed and that AhR is active, and druggable. The potent AhR ligand, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) increased AhR activity in these cells up to 5.4-fold and strongly induced mRNA expression of cytochrome P450 (CYP) 1A1 (up to 224-fold) and CYP1B1 (up to 20-fold), while breast cancer resistance protein (ABCG2) was hardly enhanced (up to 2.2-fold). The endogenous ligand of AhR kynurenine (2-4-fold) and its "activated" condensation product (2-250-fold) also enhanced these genes' expression levels. However, AhR activation and target gene induction were not accompanied by relevant alterations of the antiproliferative effects of docetaxel, paclitaxel, cisplatin, carboplatin, or 5-fluorouracil. Together, this data shows that AhR signaling is in fact active in HNSCC, but its therapeutic role in HNSCC is unlikely related to induction of MDR genes. In contrast, the immune system-regulating effects of kynurenine-mediated AhR activation is likely of higher relevance and thus needs further evaluation.
标准细胞毒性药物对头颈部鳞状细胞癌（HNSCC）的疗效有限，这凸显了由药物转运体和药物代谢酶介导的多药耐药性（MDR）的潜在相关性。虽然这些蛋白的主要调节因子孕烷X受体与HNSCC的相关性较小，但关于芳烃受体（AhR）信号传导、其对MDR基因的转录作用以及激活后的表型MDR知之甚少。本研究使用已建立的HNSCC细胞系、AhR报告基因检测、定量逆转录聚合酶链反应和增殖检测，证明AhR及其主要辅助因子（热休克蛋白90、AhR核转运体和AhR相互作用蛋白1）有表达，且AhR具有活性且可被药物作用。强效AhR配体2,3,7,8-四氯二苯并对二恶英（TCDD）使这些细胞中的AhR活性增加高达5.4倍，并强烈诱导细胞色素P450（CYP）1A1（高达224倍）和CYP1B1（高达20倍）的mRNA表达，而乳腺癌耐药蛋白（ABCG2）几乎没有增强（高达2.2倍）。AhR的内源性配体犬尿氨酸（2 - 4倍）及其“活化”缩合产物（2 - 250倍）也增强了这些基因的表达水平。然而，AhR激活和靶基因诱导并未伴随多西他赛、紫杉醇、顺铂、卡铂或5-氟尿嘧啶的抗增殖作用发生相关改变。总体而言，这些数据表明AhR信号传导在HNSCC中实际上是有活性的，但其在HNSCC中的治疗作用不太可能与MDR基因的诱导有关。相比之下，犬尿氨酸介导的AhR激活对免疫系统的调节作用可能具有更高的相关性，因此需要进一步评估。
