ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer

Abstract

Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl(-)2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells.

The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo

“…ABC294640 treatment of ovarian cancer cells, which failed to induce apoptosis as a single agent, led to activation of caspase-9 when used in combination with paclitaxel (42). Recently, ABC294640 was reported to enhance the anti-tumor effects of TRAIL in non-small lung cancer (43). Similar results have been observed in colon cancer cells (CVJ, unpublished observation).…”

Recent advances in the development of sphingosine kinase inhibitors

“…ABC294640 has been used extensively in vivo where it has shown some efficacy in animal models of solid tumours [50,98,113,114,116,118,124,125], blood cancers [36,37,121], and inflammatory conditions such as osteoarthritis [126], transplantation [120], stroke/ischemia [122,127] and colitis [128,129] (Table 2). It has been shown to dose-dependently decrease circulating S1P in mice [50] and S1P levels in xenograft tumours [50,112].…”

Sphingolipid in Lung Cancer Pathogenesis and Therapy

“…Another study shows that ABC294640 sensitized NSCLC cells to cell death induced by TNF-related apoptosis-inducing ligand (TRAIL) [56]. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect [57].…”