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Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis
Ruo-Jing Wei1, Xin-Shi Zhang1, Da-Lin He1
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy. The identification of small molecules that can establish the sensitivity of prostate cancer (PCa) cells to TRAIL-induced apoptosis is crucial for the targeted treatment of PCa. PC3, DU145, JAC-1, TsuPr1, and LNCaP cells were treated with Andrographolide (Andro) and TRAIL, and the apoptosis was measured using the Annexin V/PI double staining method. Real time-polymerase chain reaction (PCR) and Western blot analysis were performed to measure the expression levels of target molecules. RNA interference technique was used to down-regulate the expression of the target protein. We established a nude mouse xenograft model of PCa, which was used to measure the caspase-3 activity in the tumor cells using flow cytometry. In this research study, our results demonstrated that Andro preferentially increased the sensitivity of PCa cells to TRAIL-induced apoptosis at subtoxic concentrations, and the regulation mechanism was related to the up-regulation of DR4. In addition, it also increased the p53 expression and led to the generation of reactive oxygen species (ROS) in the cells. Further research revealed that the DR4 inhibition, p53 expression, and ROS generation can significantly reduce the apoptosis induced by the combination of TRAIL and Andro in PCa cells. In conclusion, Andro increases the sensitivity of PCa cells to TRAIL-induced apoptosis through the generation of ROS and up-regulation of p53 and then promotes PCa cell apoptosis associated with the activation of DR4.
Insights
Andrographolide enhances prostate cancer cell sensitivity to TRAIL-induced apoptosis by up-regulating DR4 and p53, and generating reactive oxygen species (ROS). This combination therapy offers a promising strategy for targeted prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) remains a significant health concern, necessitating novel therapeutic strategies.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for anticancer therapy, but its efficacy can be limited by cancer cell resistance.
- Identifying agents that sensitize PCa cells to TRAIL is crucial for effective targeted treatment.
Purpose of the Study:
- To investigate the potential of Andrographolide (Andro) in sensitizing prostate cancer cells to TRAIL-induced apoptosis.
- To elucidate the molecular mechanisms underlying Andro's sensitizing effects on PCa cells.
- To evaluate the therapeutic efficacy of the Andro and TRAIL combination in a preclinical model.
Main Methods:
- Prostate cancer cell lines (PC3, DU145, JAC-1, TsuPr1, LNCaP) were treated with Andro and TRAIL.
- Apoptosis was assessed using Annexin V/PI staining.
- Gene and protein expression levels were analyzed via real-time PCR and Western blot.
- RNA interference was employed to down-regulate target proteins.
- A nude mouse xenograft model was used to measure caspase-3 activity in vivo.
Main Results:
- Andrographolide significantly increased PCa cell sensitivity to TRAIL-induced apoptosis at subtoxic concentrations.
- The mechanism involves the up-regulation of DR4, increased p53 expression, and generation of reactive oxygen species (ROS).
- Inhibition of DR4, p53, or ROS significantly reduced TRAIL and Andro combination-induced apoptosis.
Conclusions:
- Andrographolide enhances prostate cancer cell sensitivity to TRAIL-induced apoptosis.
- This sensitization is mediated by ROS generation and the up-regulation of p53 and DR4.
- The combination of TRAIL and Andrographolide represents a promising therapeutic approach for prostate cancer, involving DR4 activation.
