Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells

Abstract

Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells. In this study, we found that cervical cancer cells were insensitive to DCA. Furthermore, we for the first time revealed that DCA could upregulate COX2 which impeded the chemosensitivity of DCA in cervical cancer cells. Mechanistic study showed that DCA reduced the level of RNA binding protein quaking (QKI), leading to the decay suppression of COX2 mRNA and the subsequent elevation of COX2 protein. Inhibition of COX2 using celecoxib could sensitize DCA in repressing the growth of cervical cancer cells both in vitro and in vivo. These results indicate that COX2 is a novel resistance factor of DCA, and combination of celecoxib with DCA may be beneficial to the treatment of cervical cancer.

Effect of sodium dichloroacetate as single agent or in combination with cisplatin in normal and human cervical cancer cell lines

“…It has been reported that the IC50 values of DCA in HeLa and SiHa were 7.98x10 4 µM and 8.95 x10 4 µM [23]. Similar to our results, the DCA at 3x10 3 µM to 3x10 4 µM moderately decreased the PBMC viability [24,25].…”

Combination of EP 4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells

“…61 Interestingly, we observed modest single-agent activity with MF-766, which is consistent with previous reports demonstrating elicitation of partial responses in 4T1 breast and Pan02 pancreatic syngeneic tumors following treatment with the E-7046 EP 4 inhibitor, as well as in a phase I clinical trial. 41 The importance of NSAIDs as adjuvants to current chemotherapy/radiation regimens has been reported, 30,32,62 and serves as a rationale for the evaluation of EP 4 antagonism in combination with chemotherapy or other immune-based therapies. Evaluation of preoperative radiotherapy and E-7046 in rectal cancer is currently being conducted (NCT03152370, https://clinicaltrials.gov/ct2/show/ NCT03152370?term=E-7046&draw=2&rank=2).…”

“…27,28 Inhibition of COX-2/PGE 2 was shown to decrease the incidence of colorectal adenoma, 29 improve chemotherapy resistance in bladder cancer, metastatic breast cancer, NSCLC, and cervical cancer, and enhance sensitization of other anti-tumor drugs in renal cell carcinoma (RCC) and melanoma. [30][31][32] Additionally, the combination of COX-2 inhibitors and anti-PD-1 monoclonal antibodies has been shown to improve anti-tumor activity in preclinical models of cancer. 33,34 However, dose-limiting toxicities and adverse effects, such as gastric ulcers and myocardial infarction have been observed.…”

Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt‑PI3K signaling pathway in lung cancer cells

“…In the present study, cotreatment with CAY10404 and sesamin downregulated the levels of these molecules, indicating that COX2 is an important target of sesamin in lung cancer and that downregulated COX2 can improve the antitumor effect of sesamin. Li et al (28) observed that increased COX2 expression was associated with chemosensitivity and poor prognosis in cervical cancer, and that upregulated COX2 impeded chemosensitivity to dichloroacetate (DCA), while the combination of the COX2 inhibitor celecoxib with DCA enhanced the chemosensitivity to DCA in cervical cancer cells. Other studies have suggested that knocking down COX2 expression effectively increases the chemosensitivity of human gastric cancer cells (29) and laryngeal carcinoma cells (27).…”