Abstract
The use of celecoxib is associated with a significant decrease in breast cancer risk. However, the long-term use of high-dose celecoxib might be limited owing to cardiovascular side effects. In this study, we found that acetylbritannilactone (ABL), extract from a Chinese medicinal herb, could reduce celecoxib dose and potentiate the growth-inhibitory effect in breast cancer cells. ABL enhanced the apoptotic effect of celecoxib in COX-2-expressing cells, but had little effect in COX-2-negative cells. The apoptosis induced by the combination treatment disappeared when COX-2 was knocked down, whereas the lack of apoptotic effects in COX-2-negative cells was reversed after COX-2 transfection. However, the combination treatment induced a G0/G1 phase arrest independent of whether or not the cells expressed COX-2. The G0/G1 arrest was attributed to a decreased expression of cyclinD1, cyclinE, CDK2 and CDK6, especially the upregulation of p21. In addition, inhibition of Akt and p38 signaling pathways was required by the synergism, as the constitutively active Akt and p38 protected cells against apoptosis and cell cycle arrest induced by the combination treatment. In vivo, administration of celecoxib and ABL were more effective than the individual agents against xenograft tumor growth. Thus, our data suggested that the combinatorial approach of celecoxib and ABL might be helpful for breast cancer treatment.
Highlights
IntroductionMany lines of evidence from in vitro studies and animal models indicated that celecoxib exerted its effect by preventing COX-2 protein expression and prostaglandin E2 (PGE2) synthesis.[9,10] other studies suggested that celecoxib might suppress cell proliferation and carcinogenesis by downregulating multidrug resistance-associated protein expression[12] or inhibiting nuclear factor-kappa B (NF-kB) activation.[13,15]
The exact molecular mechanisms involved are not yet defined
Three cell lines (MDA-MB231, MDA-MB-468 and MCF-7) that differ in the COX-2 status (Supplementary Figure S1A) were used to elucidate whether the effects depend on COX-2 expression levels
Summary
Many lines of evidence from in vitro studies and animal models indicated that celecoxib exerted its effect by preventing COX-2 protein expression and prostaglandin E2 (PGE2) synthesis.[9,10] other studies suggested that celecoxib might suppress cell proliferation and carcinogenesis by downregulating multidrug resistance-associated protein expression[12] or inhibiting nuclear factor-kappa B (NF-kB) activation.[13,15]. To do mathematical analysis by the median effect method, MDA-MB-231 cells were treated with both celecoxib and ABL simultaneously at fixed 1: 5 and 1:10 dose ratio for 48 h. Combination index (CI) values were calculated as described previously.[28] the CI values of the concentration were less than 1, indicating that ABL synergistically enhances celecoxib-induced growth inhibition in MDAMB-231 cells. Celecoxib and ABL may be an effective combination for cell growth inhibition due to their synergistic efficacy
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