Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis

Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. And a spe-cific drug that is closely related to the mechanism is urgently required to sensitize GEM. Here, tissue inhibitor of matrix metalloproteinases 1 (TIMP1) and phosphorylated mammalian target of rapamycin (p-mTOR) were found to be substantially elevated in PDAC patients and were associated with worse overall survival. The TIMP1/PI3K/ AKT/mTOR pathway was found in GEM-resistant PDAC cells and was revealed to be involved in epithelial-mesen-chymal transition (EMT) and apoptosis. Furthermore, arsenic trioxide (ATO), a basic therapeutic drug for acute promyelocytic leukemia, mediated TIMP1 reduction by inducing reactive oxygen species generation and ham-pered the subsequent PI3K/AKT/mTOR axis. Moreover, the combination of ATO and GEM cooperatively sup-pressed the TIMP1/PI3K/AKT/mTOR pathway, synergistically inhibited EMT and promoted apoptosis. In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.

Automated summary

TIMP1 and p-mTOR are elevated in pancreatic ductal adenocarcinoma (PDAC) patients and are associated with worse overall survival. The TIMP1/PI3K/AKT/mTOR pathway is involved in epithelial-mesenchymal transition and apoptosis, and can be suppressed by the combination of ATO and GEM, leading to sensitization and reversal of GEM resistance. The combination therapy has synergistic anticancer effects in vitro and in vivo.