Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes

Chisato Inoue, Sayaka Sobue, Naoki Mizutani, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Toshiyuki Takeuchi, Fumihiko Hayakawa, Motoshi Suzuki, Tetsuro Ito, Yoshinori Nozawa, Takashi Murate

Research output: Contribution to journalArticle

Abstract

Resveratrol (RSV) has recently attracted keen interest because of its pleiotropic effects. It exerts a wide range of health-promoting effects. In addition to health-promoting effects, RSV possesses anti-carcinogenic activity. However, a non-physiological concentration is needed to achieve an anti-cancer effect, and its in vivo bioavailability is low. Therefore, the clinical application of phytochemicals requires alternative candidates that induce the desired effects at a lower concentration and with increased bioavailability. We previously reported a low IC50 of vaticanol C (VTC), an RSV tetramer, among 12 RSV derivatives (Ito T. et al, 2003). However, the precise mechanism involved remains to be determined. Here, we screened an in-house chemical library bearing RSV building blocks ranging from dimers to octamers for cytotoxic effects in several leukemia and cancer cell lines and their anti-cancer drug-resistant sublines. Among the compounds, VTC exhibited the highest cytotoxicity, which was partially inhibited by a caspase 3 inhibitor, Z-VAD-FMK. VTC decreased the expression of sphingosine kinase 1, sphingosine kinase 2 and glucosylceramide synthase by transcriptional or post-transcriptional mechanisms, and increased cellular ceramides/dihydroceramides and decreased sphingosine 1-phosphate (S1P). VTC-induced sphingolipid rheostat modulation (the ratio of ceramide/S1P) is thought to be involved in cellular apoptosis. Indeed, exogenous S1P addition modulated VTC cytotoxicity significantly. A combination of SPHK1, SPHK2, and GCS chemical inhibitors induced sphingolipid rheostat modulation, cell growth suppression, and cytotoxicity similar to that of VTC. These results suggest the involvement of sphingolipid metabolism in VTC-induced cytotoxicity, and indicate VTC is a promising prototype for translational research.

Original languageEnglish
Pages (from-to)261-280
Number of pages20
JournalNagoya journal of medical science
Volume82
Issue number2
DOIs
Publication statusPublished - 01-05-2020

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Inoue, C., Sobue, S., Mizutani, N., Kawamoto, Y., Nishizawa, Y., Ichihara, M., Takeuchi, T., Hayakawa, F., Suzuki, M., Ito, T., Nozawa, Y., & Murate, T. (2020). Vaticanol C, a phytoalexin, induces apoptosis of leukemia and cancer cells by modulating expression of multiple sphingolipid metabolic enzymes. Nagoya journal of medical science, 82(2), 261-280. https://doi.org/10.18999/nagjms.82.2.261