Dexamethasone enhances the antitumor efficacy of Gemcitabine by glucocorticoid receptor signaling

Abstract

Gemcitabine (Gem) is currently used as the first-line therapy for liver and pancreatic cancer but has limited efficacy in most cases. Dexamethasone (Dex) have been applied as a chemoprotectant and chemosensitizer in cancer chemotherapy. This study further explored the potential of combination of Gem and Dex and tested the hypothesis that glucocorticoid receptor signaling is essential for the synergistic antitumor activity. In the HepG2 and AsPC-1 xenograft models, the combination treatment showed a significantly synergistic antitumor activity. Immunohistochemistry of post-treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. Dex alone and the combination with Gem inhibited the expression of glucocorticoid receptor. The combination of Dex and Gem showed synergistic cytotoxicity in cell lines in vitro. The antiproliferative synergism is prevented by used glucocorticoid receptor (GR) small interfering RNA, demonstrating that the glucocorticoid receptor is required for the antiproliferative synergism of Gem and Dex. The inhibition of glucocorticoid receptor signaling pathway and induction of apoptosis via activation of caspases 3, 8 and 9, PARP, contributed to the synergistic effect of this combination therapy. These results demonstrate that Dex could potentiate the antitumor efficacy of Gem. The synergistic antitumor activity of the combination of Dex and Gem was through glucocorticoid receptor signaling. Taken together, a combination of Dex and Gem shows a significant synergistic antitumor activity and lesser toxicity both in vitro and in vivo and could be a combination chemotherapy for the treatment of highly expression of glucocorticoid receptor patients.

Dexamethasone Inhibits Cytokine-Induced, DUOX2-Related VEGF-A Expression and DNA damage in Human Pancreatic Cancer Cells and Growth of Pancreatic Cancer Xenografts

“…In summary, our studies suggest that the anti-invasive and anti-proliferative effects of Dex that have been observed previously in both xenograft and genetically-engineered models of PDAC (2, 44) could be mediated, in part, by inhibition of a DUOX2-related cascade of pro-inflammatory ROS, thereby significantly reducing the local production of pro-angiogenic factors that play an essential role in pancreatic tumor cell growth.…”

“…In view of the pleiotropic effects of Dex on the inflammatory/immune response (25), there are several potential explanations for our in vivo observations beyond an effect on the DUOX2 promoter. Although conflicting reports exist (48), recent studies support the observation that Dex produces little, if any, change in the proliferation rate of PDAC cell lines in vitro (29,44,45). These reports support the hypothesis that the growth inhibition we found in vivo may be related to one or more effects of Dex on the interaction between BxPC-3 xenografts and their ecosystem, interactions that could occur even within the immunocompromised context of the athymic nude mice used for our experiments (49).…”

“…We have also demonstrated that several cytokines known to play an important role in tumor-associated inflammation upregulate DUOX2 expression in PDAC cells (21). Because Dex significantly decreased the growth rate of xenografts developed from the AsPC-1 human PDAC cell line (44) and a patient-derived xenograft (PDX) model (28), as well as post-surgical recurrence and invasiveness in other PDAC animal models (45), we examined whether Dex altered DUOX2 expression in human PDAC cells and xenografts. In vitro, Dex significantly inhibited the increase in DUOX2 expression produced by a wide variety of pro-inflammatory molecules (including IFN-γ, LPS, IL-4, IL-17A, and IFN-β); Dex administration in vivo significantly decreased the growth of BxPC-3 xenografts.…”

Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction

“…Dexamethasone is a glucocorticoid used as an antiemetic in cancer patients and has a well-established safety profile [ 12 , 13 ]. Notably, previous studies demonstrated that glucocorticoids sensitize non-cancer stem cells of several types of cancers, such as colorectal, breast, lung, liver, and pancreatic cancer, to chemotherapy [ 14 , 15 , 16 , 17 ]. We also reported that dexamethasone targets pancreatic CSCs and sensitizes pancreatic CSCs to chemotherapeutic agents, such as gemcitabine, by suppressing the expression of survivin [ 18 ].…”

Dexamethasone Suppresses Radicular Pain Through Targeting the L‐PGDS/PI3K/Akt Pathway in Rats With Lumbar Disc Herniation

“…Dexamethasone is a common clinical glucocorticoid with potent anti‐inflammatory and analgesic effects. It reduces nerve root edema by inhibiting phospholipase A2 and activating the glucocorticoid receptor 9,10 . The use of dexamethasone for radicular pain in LDH, which started in 1975, demonstrated that it confers prompt relief of pain caused by LDH and may obviate the need for surgery in most patients 11 .…”