Abstract 840
Background
Dihydroorotate dehydrogenase (DHODH) is one of the essential enzymes in the de novo biosynthesis of pyrimidine and might be a potential therapeutic target for cancer suppress. The anti-proliferative and apoptosis-inducing effects of leflunomide, a potent DHODH blocker, have been demonstrated in multiple human cancers. This study aims to investigate the cytostatic effects of leflunomide on bladder cancer and the involved mechanism.
Methods
Two human bladder cancer cell lines, T24 and 5637, were used in this study. After incubation with varied doses of leflunomide, the cell viability, apoptosis and cell cycle assay were determined with MTS, cell colony assay and flow cytometry. Western blot was used to evaluate the expression changes of cleaved-PARP, proteins involved in Akt/mTOR/P70S6K signaling pathway and cell autophagy pathway. AVO stain assay was performed to detect the autophagosome. Moreover, the cytostatic effects of leflunomide were further investigated after the modulation of cell autophagy with autophagy agonist rapamycin and inhibitor chloroquine.
Results
Our data demonstrated that leflunomide markedly inhibited the growth of both bladder cancer cells via inducing cell apoptosis and cell cycle arrest in S phase in a time- and dose-dependent manner. After leflunomide treatment, the phosphorylation levels of Akt, mTOR and p70S6K proteins in both cells were significantly down-regulated. Furthermore, AVO stain assay revealed the decline of autophagosome under the incubation of leflunomide. Modulation of autophagy with rapamycin and chloroquine observably attenuated and enhanced the cytostatic effects of leflunomide, respectively.
Conclusions
Leflunomide significantly reduced the cell viability of bladder cancer cells via Akt/mTOR/P70S6K signaling pathway. In addition, cell autophagy was demonstrated to be involved, combination leflunomide with autophagy modifier exerted enhanced antitumor effects in bladder cancer, which offered novel ideas for bladder cancer treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The author.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
1851 - Nivolumab-induced and radiation recall pneumonitis in patients with non-small cell lung cancer: a multicenter real world analysis of 669 patients
Presenter: Nobuaki Mamesaya
Session: Poster Display session 1
Resources:
Abstract
851 - Retrospective analysis of immunotherapy prognostic scores in advanced NSCLC at Nottingham University Hospitals (UK)
Presenter: Cristina Lopez Escola
Session: Poster Display session 1
Resources:
Abstract
3639 - Applicability of lung immune prognostic index (LIPI) to predict efficacy of first-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC)
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 1
Resources:
Abstract
2950 - Delayed Onset Immune Related Adverse Effects (IRAEs) of Pembrolizumab in Non-Small Cell Lung Cancer
Presenter: Haixi Yan
Session: Poster Display session 1
Resources:
Abstract
3659 - Clinical implication of multiplex IHC and serologic biomarkers on Hyperprogression in NSCLC patients receiving Immune checkpoint blockers in real world.
Presenter: Joori Kim
Session: Poster Display session 1
Resources:
Abstract
4882 - Local ablative treatment and treatment beyond progression for oligo-progression in stage IV non-small cell lung cancer after tumor response to anti-PD1 treatment
Presenter: Florian Guisier
Session: Poster Display session 1
Resources:
Abstract
1358 - Atezolizumab in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs)
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract
2170 - Prognostic Impact of Metastatic Sites for Pembrolizumab Efficacy as First-line therapy in Patients with PD-L1 tumor proportion score (TPS) ≥ 50% Advanced Non–Small Cell Lung Cancer: A Retrospective Multicenter Study
Presenter: Hayato Kawachi
Session: Poster Display session 1
Resources:
Abstract
3051 - Impact of visceral fat area as independent predictive factor in patients with advanced non-small cell lung cancer treated with nivolumab
Presenter: Yuki Sato
Session: Poster Display session 1
Resources:
Abstract
3409 - Effect and safety of immune checkpoint inhibitors for brain metastases from non-small cell lung cancer
Presenter: Toshihiko Iuchi
Session: Poster Display session 1
Resources:
Abstract