Inhibition of Sphingolipid Metabolism Enhances Resveratrol Chemotherapy in Human Gastric Cancer Cells

Abstract

Resveratrol, a chemopreventive agent, is rapidly metabolized in the intestine and liver via glucuronidation. Thus, the pharmacokinetics of resveratrol limits its efficacy. To improve efficacy, the activity of resveratrol was investigated in the context of sphingolipid metabolism in human gastric cancer cells. Diverse sphingolipid metabolites, including dihydroceramides (DHCer), were tested for their ability to induce resveratrol cytotoxicity. Exposure to resveratrol (100 μM) for 24 hr induced cell death and cell cycle arrest in gastric cancer cells. Exposure to the combination of resveratrol and dimethylsphingosine (DMS) increased cytotoxicity, demonstrating that sphingolipid metabolites intensify resveratrol activity. Specifically, DHCer accumulated in a resveratrol concentration-dependent manner in SNU-1 and HT-29 cells, but not in SNU-668 cells. LC-MS/MS analysis showed that specific DHCer species containing C24:0, C16:0, C24:1, and C22:0 fatty acids chain were increased by up to 30-fold by resveratrol, indicating that resveratrol may partially inhibit DHCer desaturase. Indeed, resveratrol mildly inhibited DHCer desaturase activity compared to the specific inhibitor GT-11 or to retinamide (4-HPR); however, in SNU-1 cells resveratrol alone exhibited a typical cell cycle arrest pattern, which GT-11 did not alter, indicating that inhibition of DHCer desaturase is not essential to the cytotoxicity induced by the combination of resveratrol and sphingolipid metabolites. Resveratrol-induced p53 expression strongly correlated with the enhancement of cytotoxicity observed upon combination of resveratrol with DMS or 4-HPR. Taken together, these results show that DHCer accumulation is a novel lipid biomarker of resveratrol-induced cytotoxicity in human gastric cancer cells.

Inhibitors of dihydroceramide desaturase 1: Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology

“…In gastric cancer SNU-1 cells, resveratrol mildly inhibited Des1 activity compared to the specific inhibitor GT-11 or to 4-HPR; however, resveratrol alone exhibited a typical cell cycle arrest pattern, which GT-11 did not alter, indicating that inhibition of Des1 is not essential to the cytotoxicity induced by the combination of resveratrol and sphingolipid metabolites (Shin et al, 2012). In contrast, inhibition of Des1 by resveratrol and the resulting increase in intracellular dhCer has been reported to be involved in autophagy induction in gastric cancer HGC27 cells (Signorelli et al, 2009).…”

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

“…The mechanisms by which resveratrol and ceramide induce apoptosis in ovarian cancer cells are partially overlapped and involve a COX-2-dependent pathway (Lin et al 2013). Resveratrol also increases dihydroceramide levels by reducing the activity of dihydroceramide synthases in gastric cancer cells (Shin et al 2012). There is also increasing evidence that resveratrol can induce autophagy by modulating sphingolipid levels in cancer cells.…”

Stearoyl-CoA Desaturase-1 Enzyme Inhibition by Grape Skin Extracts Affects Membrane Fluidity in Human Colon Cancer Cell Lines

“…Grape skin and grape seed extracts are made up of different polyphenolic compounds that elicit multiple beneficial biological activities [26]. The resveratrol is able to accumulate sphingolipids in cell membranes, leading to cell cycle arrest and apoptosis [27]. Furthermore, in the Caco2 cell line, resveratrol reduces the global content of unsaturated fatty acids, probably acting on SCD1 [28].…”