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Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.

Xun C, Chen MB, Qi L, Tie-Ning Z, Peng X, Ning L, Zhi-Xiao C, Li-Wei W - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro.In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. caixunshanghai2@163.com.

ABSTRACT

Background: Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.

Results: Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.

Conclusions: Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

No MeSH data available.


Related in: MedlinePlus

The in vitro chemo-sensitization activity by ABC294640. HT-29 cells were treated with 5-FU (5 μM), cisplatin (5 μM), or together with ABC294640 (0.3 μM) for 72 hours, cell growth was tested by MTT assay (a), and cell death was evaluated by LDH release assay (b). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing groups with or without ABC294640 co-treatment. *P < 0.05
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Fig5: The in vitro chemo-sensitization activity by ABC294640. HT-29 cells were treated with 5-FU (5 μM), cisplatin (5 μM), or together with ABC294640 (0.3 μM) for 72 hours, cell growth was tested by MTT assay (a), and cell death was evaluated by LDH release assay (b). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing groups with or without ABC294640 co-treatment. *P < 0.05

Mentions: Chemoresistance is major problem in current CRC treatment [1, 2]. The results above showed that ABC294640 treatment induced SphK2 and AKT-mTOR inactivation, S1P depletion, and ceramide accumulation in CRC cells. All these should favor a chemo-sensitization consequence [1, 2]. Thus, we tested the potential effect of ABC294640 on 5-fluorouracil (5-FU) and cisplatin, two widely utilized anti-CRC chemo-drugs, in CRC cells [1, 2]. As shown in Fig. 5a, 5-FU or cisplatin alone at tested concentration only induced moderate growth inhibition in HT-29 cells, co-administration with a low concentration of ABC294640 (0.3 μM) dramatically enhanced their sensitivities (Fig. 5a). Meanwhile, LDH results showed that ABC294640 remarkably facilitated 5-FU and cisplatin-induced HT-29 cell death (Fig. 5b). Note that similar chemo-sensitization effect by ABC294640 was also reproduced in two other CRC cell lines (HCT-116 and DLD-1) (Data not shown). These results demonstrate the 5-FU/cisplatin sensitization effect by ABC294640 in cultured CRC cells.Fig. 5


Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.

Xun C, Chen MB, Qi L, Tie-Ning Z, Peng X, Ning L, Zhi-Xiao C, Li-Wei W - J. Exp. Clin. Cancer Res. (2015)

The in vitro chemo-sensitization activity by ABC294640. HT-29 cells were treated with 5-FU (5 μM), cisplatin (5 μM), or together with ABC294640 (0.3 μM) for 72 hours, cell growth was tested by MTT assay (a), and cell death was evaluated by LDH release assay (b). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing groups with or without ABC294640 co-treatment. *P < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559903&req=5

Fig5: The in vitro chemo-sensitization activity by ABC294640. HT-29 cells were treated with 5-FU (5 μM), cisplatin (5 μM), or together with ABC294640 (0.3 μM) for 72 hours, cell growth was tested by MTT assay (a), and cell death was evaluated by LDH release assay (b). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing groups with or without ABC294640 co-treatment. *P < 0.05
Mentions: Chemoresistance is major problem in current CRC treatment [1, 2]. The results above showed that ABC294640 treatment induced SphK2 and AKT-mTOR inactivation, S1P depletion, and ceramide accumulation in CRC cells. All these should favor a chemo-sensitization consequence [1, 2]. Thus, we tested the potential effect of ABC294640 on 5-fluorouracil (5-FU) and cisplatin, two widely utilized anti-CRC chemo-drugs, in CRC cells [1, 2]. As shown in Fig. 5a, 5-FU or cisplatin alone at tested concentration only induced moderate growth inhibition in HT-29 cells, co-administration with a low concentration of ABC294640 (0.3 μM) dramatically enhanced their sensitivities (Fig. 5a). Meanwhile, LDH results showed that ABC294640 remarkably facilitated 5-FU and cisplatin-induced HT-29 cell death (Fig. 5b). Note that similar chemo-sensitization effect by ABC294640 was also reproduced in two other CRC cell lines (HCT-116 and DLD-1) (Data not shown). These results demonstrate the 5-FU/cisplatin sensitization effect by ABC294640 in cultured CRC cells.Fig. 5

Bottom Line: Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro.In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai, Hongkou District, 200080, China. caixunshanghai2@163.com.

ABSTRACT

Background: Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.

Results: Here we demonstrated that ABC294640, a novel SphK2 inhibitor, induced growth inhibition and apoptosis in transformed and primary CRC cells. The SphK activity was remarkably inhibited by ABC294640, accompanied by sphingosine-1-phosphate (S1P) depletion and ceramide incensement in CRC cells. Exogenously-added S1P inhibited ABC294640-induced HT-29 cell lethality. While C6 ceramide and SphK1 inhibitor SKI-II facilitated ABC294640-induced cytotoxicity against HT-29 cells. ABC294640 inhibited AKT-S6K1, but activated JNK signaling in transformed and primary CRC cells. JNK inhibitors (SP600125 and JNKi-II) alleviated ABC294640-induced CRC cell apoptosis. Moreover, a low concentration of ABC294640 sensitized the activity of 5-FU and cisplatin in vitro. In vivo, ABC294640 oral administration dramatically inhibited HT-29 xenografts growth in nude mice.

Conclusions: Targeting of SphK2 by ABC294640 potently inhibits CRC cell growth both in vitro and in vivo, ABC294640 could be developed as a novel therapeutic for the treatment of CRC.

No MeSH data available.


Related in: MedlinePlus