Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells.

Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR-3-65 and WXM-1-170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3ß/ß-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR-3-65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR-3-65 and WXM-1-170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR-3-65. Our study unveils a novel mechanism by which SR-3-65 and WXM-1-170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.

The Effectiveness of Chemoradiotherapy in Elderly Patients with Pancreatic Cancer: A Population-Based Study Based on the SEER Database.

INTRODUCTION: Chemotherapy (CT) is the main treatment for patients with unresected pancreatic cancer (PC). Whether the addition of radiotherapy to chemotherapy improves the prognosis of elderly patients with unresected PC is unclear. The aim of our study was to compare the efficacy of chemoradiotherapy (CRT) with chemotherapy alone in elderly patients with unresected PC. METHODS: The clinical data of elderly patients with unresected PC who received chemotherapy between 2004 and 2017 were determined from the Surveillance, Epidemiology, and End Results (SEER) database, and the patients were divided into CT and CRT groups. The primary outcome was overall survival (OS), and secondary endpoints were cancer-specific survival (CSS) and cancer-specific mortality (CSM). Propensity matching analysis (PSM) was used to balance the differences between the two groups. OS and CSS were assessed using Kaplan-Meier analysis, while CSM was assessed using a competing risk model. Subgroup analyses were also performed, and Cox regression was used to adjust for confounding factors. RESULTS: A total of 17,814 patients were diagnosed with PC including 14,222 who received CT alone and 3592 who received CRT. The 1-year OS of the CT and CRT groups after PSM was 30.1% and 40.8%, and the 1-year CSS was 31.4% and 42.1%, respectively. Overall, the CRT group had better OS, CSS, and CSM rates than the CT group before and after PSM (P < 0.05). After adjustment for age, sex, race, histological grade, stage, and other factors, the CRT group still had a lower risk of death than the CT group, and subgroup analysis further revealed the survival benefit of CRT in each population. CONCLUSIONS: CRT improves the outcome of patients with non-surgical PC over 65 years of age. But prospective studies are needed to validate our results.