RESUMO
Tamoxifen (TAM) is a classical anti-estrogenic drug that antagonizes estrogen by competitively binding to estrogen receptor α (ERα). However, drug resistance to TAM remains a significant challenge in breast cancer treatment. In this study, we aimed to design an actively targeted drug delivery system to enhance the proliferation inhibitory effects of TAM on ER positive breast cancer cells. Herein, chitosan (CS) was modified with genistein (GEN) to obtain the actively targeted GEN-CS. The TAM-loaded nanoparticles (TAM-GEN-CS-NPs) were constructed using an ionic-crosslinking method, with GEN-CS as the carrier material and sodium tripolyphosphate (TPP) as the crosslinking agent. As a result, TAM-GEN-CS-NPs exhibited a spherical morphology with an average size of 299.8 nm. The encapsulation efficiency and drug loading content were 85.77% and 14.13 µg/mg, respectively. Compared with free TAM, TAM-GEN-CS-NPs displayed obvious slow-release performance. In vitro cellular assays demonstrated that TAM-GEN-CS-NPs had active targeting and proliferation inhibitory effects on MCF-7 cells. The IC50 of TAM and TAM-GEN-CS-NPs were 10.25 µg/mL and 7.22 µg/mL, respectively. More importantly, the combination index (CI) value of TAM and GEN was less than 1, indicating synergistic effects. Therefore, TAM-GEN-CS-NPs hold the potential to enhance TAM therapy for breast cancer through active targeting and synergistic treatment strategies.
RESUMO
BACKGROUND: Adriamycin (ADM) is a drug commonly used for treating gastric cancer (GC). However, chemoresistance presents an obstacle to achieving successful outcomes in patients treated with chemotherapy. This study aimed to explore the effect of long non-coding RNA (lncRNA) H19 on chemoresistance in GC and its potential molecular mechanism. METHODS: The expression of H19 was detected in GC tissues and cell lines. The interaction between miR-152 with H19 and transcription factor 4 (TCF4) was validated by luciferase reporter assay. CCK-8 and flow cytometry were employed to measure cell viability and apoptosis, respectively. The levels of epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Slug, Snail, and Twist) were detected by Western blot assay. A mouse model was established by subcutaneously injecting MGC-803 cells stably transfected with sh-H19 to investigate the effect of H19/miR-152-3p/TCF4 axis on ADM in vivo. RESULTS: In vitro, we observed that H19 was overexpressed in GC tissues and cell lines. After knockdown of H19, the IC50 of ADM was decreased and cell apoptosis rates increased in both BGC-823ADM and MGC-803ADM cells. Furthermore, H19 shRNA was found to inhibit epithelial-mesenchymal transition (EMT), and induction of EMT counteracted the inhibitory effect of H19 shRNA on chemoresistance of GC cells. miR-152 was a target of H19, and its expression was downregulated in GC tissues and cell lines. Furthermore, the expression of TCF4 was negatively regulated by miR-152 but positively regulated by H19. In vivo, the data indicated that H19 shRNA enhanced the chemosensitivity of GC tumor cells to ADM through sponging miR-152 from TCF4, resulting in the suppression of EMT. CONCLUSIONS: The results of this study elucidated that H19 was overexpressed in GC tissues and cell lines, and knockdown of lncRNA H19 increased the chemosensitivity of GC cells to ADM via sponging miR-152 from TCF4. The H19/miR-152/TCF4 axis may provide a new perspective for treating GC.
