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Antiprotease strategy in pancreatic cancer treatment: emergence from a preclinical study
Giovanni Brandi1, Simona Tavolari, Tiziana Guarnieri
1From the *Department of Experimental, Diagnostic and Specialty Medicine, †"G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), and ‡Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi University Hospital; §Department of Biological, Geological and Environmental Sciences; and ∥Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy.
Objectives:
Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells.
Methods:
The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated.
Results:
Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog.
Conclusions:
Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.
Insights
Gabexate mesilate enhances gemcitabine
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic cancer often resists gemcitabine treatment.
- Nuclear factor κB (NF-κB) activation contributes to gemcitabine resistance.
- Gabexate mesilate, a protease inhibitor, can inhibit NF-κB.
Purpose of the Study:
- To investigate if combined gabexate mesilate and gemcitabine improves antitumoral efficacy in pancreatic cancer.
- To explore the molecular mechanisms underlying the combined treatment's effects.
Main Methods:
- Assessed in vitro effects of gabexate mesilate and gemcitabine on pancreatic cancer cell growth, invasion, and angiogenesis.
- Investigated molecular mechanisms including NF-κB pathway, metalloproteinases, VEGF, IL-8, ERK1/2, and AKT signaling.
Main Results:
- Gabexate mesilate significantly enhanced gemcitabine's anti-invasive and antiangiogenic effects.
- Combined treatment inhibited gemcitabine-induced NF-κB activation by preventing RelA/p65 nuclear translocation.
- Down-regulation of MMP-2, MMP-9, VEGF, and IL-8 was observed, alongside inhibition of ERK1/2 and AKT activation.
Conclusions:
- Combined gabexate mesilate and gemcitabine sensitizes pancreatic cancer cells to gemcitabine via NF-κB pathway inhibition.
- This therapeutic strategy warrants further clinical investigation for pancreatic cancer patients.
