Cellular diamine levels in cancer chemoprevention: modulation by ibuprofen and membrane plasmalogens

Abstract

BackgroundTo develop effective strategies in cancer chemoprevention, an increased understanding of endogenous biochemical mediators that block metastatic processes is critically needed. Dietary lipids and non-steroidal anti-inflammatory drugs (NSAIDs) have a published track record of providing protection against gastrointestinal malignancies. In this regard, we examined the effects of membrane plasmalogens and ibuprofen on regulation of cellular levels of diamines, polyamine mediators that are augmented in cancer cells. For these studies we utilized Chinese hamster ovary (CHO) cells and NRel-4 cells, a CHO cell line with defective plasmalogen synthesis.ResultsNRel-4 cells, which possess cellular plasmalogen levels that are 10% of control CHO cells, demonstrated 2- to 3-fold increases in cellular diamine levels. These diamine levels were normalized by plasmalogen replacement and significantly reduced by ibuprofen. In both cases the mechanism of action appears to mainly involve increased diamine efflux via the diamine exporter. The actions of ibuprofen were not stereospecific, supporting previous studies that cyclooxygenase (COX) inhibition is unlikely to be involved in the ability of NSAIDs to reduce intracellular diamine levels.ConclusionsOur data demonstrate that ibuprofen, a drug known to reduce the risk of colorectal cancer, reduces cellular diamine levels via augmentation of diamine efflux. Similarly, augmentation of membrane plasmalogens can increase diamine export from control and plasmalogen-deficient cells. These data support the concept that membrane transporter function may be a therapeutic point of intervention for dietary and pharmacological approaches to cancer chemoprevention.

Searching for Drug Synergy Against Cancer Through Polyamine Metabolism Impairment: Insight Into the Metabolic Effect of Indomethacin on Lung Cancer Cells

“…The main mode of action described for NSAIDs is the inhibition of the cyclooxygenase enzyme, which is involved in the inflammatory cascade. However, the overexpression of SSAT is described as a cyclooxygenase-independent effect, as shown for sulindac, acetylsalicylic acid, celecoxib, ibuprofen, and naproxen in several models of cancer (Babbar et al, 2003;Babbar et al, 2006a;Wood et al, 2011;Hughes et al, 2012;Xie et al, 2012). In this study, we demonstrated that indomethacin induced an increase in SSAT expression, with a metabolic impact on NSCLC cells.…”

Choline Plasmalogens Isolated from Swine Liver Inhibit Hepatoma Cell Proliferation Associated with Caveolin-1/Akt Signaling

“…Plasmalogens and Caceolin-1 are known to play important roles in cell membrane lipid homeostasis [12,13,38,39] and are both involved in cancer [15,19]. In the present study, it was shown that exogenous natural ChoPlas treatment activated Caveolin-1 expression in hepatoma CBRH7919 cells, indicating that exogenous ChoPlas-induced cell proliferation inhibition is dependent on caveolin-1 over-expression.…”

“…Recent studies showed that selective membrane plasmalogen enhancement was related to altered cellular cholesterol processing in vitro [13]. Since increased cholesterol levels are commonly found in cancers [14] and cell membrane plasmalogen levels have been associated with cancer [15], plasmalogens could potentially be involved in cancer cell proliferation.…”

Lipidome in colorectal cancer

“…Due to the anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered as chemopreventive and therapeutic drugs for CRC [83, 84]. For example, ibuprofen reduced the risk of CRC and cellular diamine levels via augmentation of diamine efflux [85]. NSAIDs prevented frequency of carcinogen-induced animal colonic tumors [86].…”