Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

Abstract

a b s t r a c tPatients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-kB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization.

Gemcitabine induces cell senescence in human pancreatic cancer cell lines

“…We previously unraveled the involvement of ROS generation in gemcitabine-induced CXCL8 expression [20]. Likewise, NAC, an inhibitor of ROS, significantly reduced gemcitabine-induced increases in SA-β-gal-positive cell numbers, suggesting that gemcitabine induced cell senescence partly through gemcitabine-induced ROS generation, as previously observed [27].…”

“…We previously observed that gemcitabine treatment enhanced intra-tumoral CXCL8 expression and that anti-CXCL8 antibody administration reduced tumor formation when it was given with the combination of gemcitabine [20]. On the contrary, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-gal-positive cell numbers ( Figure 3C).…”

“…We previously observed that gemcitabine induced ROS generation and that NAC with the capacity to scavenge ROS by interacting with OH· and H 2 O 2 reduced gemcitabine-induced ROS generation [20]. Hence, we examined the effects of NAC on gemcitabine-induced senescence and observed that NAC decreased gemcitabine-induced increased SA β-gal-positive cell numbers ( Figure 3A).…”

“…However, it still remains elusive on the roles of SASP in cell senescence. We previously observed that Miapaca-2 and Panc-1 cells did not express receptors for CXCL8, CXCR1 and CXCR2, but that anti-CXCL8 antibody reduced in vivo tumor formation with the combined administration of gemcitabine [20]. We explored the possibility of the paracrine effects of CXCL8 in gemcitabine-induced cell senescence, by administering anti-CXCL8…”

“…We previously observed that human pancreatic cancer cell lines exhibited enhanced CXCL8 expression, which is reminiscent of SASP, in the presence of gemcitabine [20].…”