Abstract
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 specific 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-mesenchymal
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 hampered the subsequent PI3K/AKT/mTOR axis. Moreover,
the combination of ATO and GEM cooperatively suppressed 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.
Abbreviations:
ATO (Arsenic Trioxide), CI (Combined Index), DHE (Dihydroethidium), DMEM (Dulbecco's modified Eagle's medium), EMT (Epithelial-mesenchymal transition), GEM (Gemcitabine), HR (Hazard ratio), IHC (Immunohistochemistry), mTOR (Mammalian target of rapamycin), NAC (N-acetyl-L-cysteine), OS (Overall survival), PBS (Phosphate buffer solution), PDAC (Pancreatic ductal adenocarcinoma), p-mTOR (Phosphorylated mammalian target of rapamycin), qRT-PCR (Quantitative real time polymerase chainreaction), ROS (Reactive oxygen species), siRNA (Small interfering RNA), TIMP1 (Tissue inhibitor of matrix metalloproteinases 1)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: November 14, 2022
Accepted:
November 9,
2022
Received in revised form:
November 9,
2022
Received:
June 17,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
