#0533
Enhanced Tumor Suppressive Effect of Combining Vorinostat with Cyproheptadine and Their Conjugation Derivatives in Bladder Cancer
. Cheng-Huang1, W. Jin-Yi1, L. Hsin-Ting1, L. Ming-Yang1, L. Yi-Wen1
1Taiwan
Introduction:
Bladder cancer, predominantly urothelial carcinoma, is a common malignancy, especially in older adults, with hematuria as a key symptom. Despite generally favorable prognosis for non-muscle-invasive bladder cancer (NMIBC), survival rates haven't improved significantly in decades, and recurrence with progression to muscle-invasive disease (MIBC) is frequent. Epigenetic dysregulation, particularly histone acetylation/deacetylation imbalances mediated by histone deacetylases (HDACs), plays a role in cancer development. HDAC inhibitors (HDACi), like the FDA-approved vorinostat (SAHA), show promise but often have limited efficacy as monotherapy in solid tumors, prompting combination strategies and derivative development. Cyproheptadine, a first-generation antihistamine with reported anti-cancer effects in bladder cancer, offers another potential therapeutic avenue. This study aimed to enhance bladder cancer treatment by combining vorinostat and cyproheptadine, and by synthesizing novel conjugated derivatives, leveraging their potential synergistic effects.
Material and methods:
Bladder cancer cell lines 5637, BFTC 905, and MB49 were cultured in standard RPMI 1640 medium. Vorinostat, cyproheptadine, and their derivatives, dissolved in DMSO, were used in cytotoxicity assays. Cell viability was assessed using MTT assays for drugs alone and in combination. Western blot analysis examined histone acetylation and apoptosis-related proteins. HDAC activity assays determined the inhibitory effects on HDAC. In vivo tumor suppression studies were conducted in C57BL/6 mice, with 8C administered via intraperitoneal injection and 8C-HCl via oral gavage, and tumor volumes were monitored.
Results:
This study highlights the potential of vorinostat-cyproheptadine conjugates in bladder cancer therapy. The conjugates demonstrated superior cytotoxicity, HDAC inhibition, and in vivo efficacy compared to vorinostat alone. The mechanisms underlying their anticancer effects include cell cycle arrest, apoptosis, and histone acetylation. The therapeutic limitations of HDAC inhibitors in solid tumors necessitate novel strategies, such as drug conjugation, to enhance their efficacy. 8C and O8C showed promising results, particularly in BFTC 905 cells, where vorinostat alone had limited cytotoxicity. Future studies should explore the selectivity of these compounds for specific HDAC classes to minimize toxicity and improve clinical applicabilit