Metabolomic profiling identifies novel biomarkers and mechanisms in human bladder cancer treated with submucosal injection of gemcitabine

Abstract

Bladder cancer (Bca) is a common urinary tract malignancy with frequent recurrences after initial resection. Submucosal injection of gemcitabine prior to transurethral resection of bladder tumor (TURBT) may prevent recurrence of urothelial cancer. However, the underlying mechanism remains unknown. In the present study, ultra-performance liquid chromatography Q-Exactive mass spectrometry was used to profile tissue metabolites from 12 BCa patients. The 48 samples included pre-and post-gemcitabine treatment Bca tissues, as well as adjacent normal tissues. Principal component analysis (PcA) revealed that the metabolic profiles of pre-gemcitabine BCa tissues differed significantly from those of pre-gemcitabine normal tissues. A total of 34 significantly altered metabolites were further analyzed. Pathway analysis using MetaboAnalyst identified three metabolic pathways closely associated with Bca, including glutathione, purine and thiamine metabolism, while glutathione metabolism was also identified by the enrichment analysis using MetaboAnalyst. In search of the possible targets of gemcitabine, metabolite profiles were compared between the pre-gemcitabine normal and post-gemcitabine Bca tissues. Among the 34 metabolites associated with Bca, the levels of bilirubin and retinal recovered in Bca tissues treated with gemcitabine. When comparing normal bladder tissues with and without gemcitabine treatment, among the 34 metabolites associated with Bca, it was observed that histamine change may be associated with the prevention of relapse, whereas thiamine change may be involved in possible side effects. Therefore, by employing a hypothesis-free tissue-based metabolomics study, the present study investigated the metabolic signatures of Bca and found that bilirubin and retinal may be involved in the mechanism underlying the biomolecular action of submucosal injection of gemcitabine in urothelial Bca.

Metabolic Profiling of Bladder Cancer Patients’ Serum Reveals Their Sensitivity to Neoadjuvant Chemotherapy

“…Glutathione (GSH) is an antioxidant metabolite capable of scavenging ROS [32]. Dysregulation of glutathione metabolism is present in bladder cancer patients [39]. Our previous study found that GSH reduction caused by overexpression of mir-218 increased the sensitivity of bladder cancer to cisplatin [40].…”

Metabolomic Signatures of Treatment Response in Bladder Cancer

“…Our search yielded two studies that investigated the impact of TURBT on the metabolic profile characteristic of BC using human biofluids (blood serum and urine) [113,114]. Additionally, another study focused on evaluating the impact of submucosal injection of gemcitabine prior to TURBT on both BC and adjacent normal tissue [115], while a separate investigation aimed to identify biomarkers in blood serum for predicting the effectiveness of neoadjuvant chemotherapy in BC [116]. Table 4 provides a concise overview of the biological samples, cases under study, analytical techniques and main findings found in these studies.…”

“…The submucosal injection of gemcitabine prior to TURBT may prevent BC recurrence, but the underlying mechanism remains unknown. In this context, Yang et al applied a MS-based metabolomic approach to analyze metabolic changes in BC and normal bladder tissues before and after treatment with gemcitabine [115]. The study participants comprised a small cohort of 12 BC patients (nine men and three women), all of whom had undergone TURBT.…”

Pharmacometabolomics Applied to Personalized Medicine in Urological Cancers

“…Regarding BCa, Table 2 depicts the three pharmacometabolomic studies performed in the last 10 years including the methodology used and a summary of the main findings. Two in vitro pharmacometabolomic studies [ 13 , 92 ] were conducted to address the metabolic implications of cisplatin resistance and one additional study was performed to predict the response to gemcitabine as neoadjuvant therapy [ 93 ].…”

“…The combination of gemcitabine and cisplatin is frequently recommended in BCa treatment. A study performed by Yang et al [ 93 ] aimed to identify predictive biomarkers of efficacy to treatment with gemcitabine as neoadjuvant therapy for transurethral resection of bladder tumors. Metabolite analysis using high-resolution LC-MS was performed on tissue collected from BCa patients before and after submucosal gemcitabine injection.…”