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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

ABC294640 inhibits HT-29 cell growth in vivo. The volumes of HT-29 xenograft tumors in nude mice administrated with ABC294640 (ABC, 5 or 20 mg/kg, p.o., daily) or vehicle (0.375 % Polysorbate-80) control were recorded weekly (n = 10 for each group) (a). Tumor weights (b) and mice body weights (c) at week-6 were also presented. Statistical analysis was performed comparing treatment groups with vehicle control group. *P < 0.05
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Fig6: ABC294640 inhibits HT-29 cell growth in vivo. The volumes of HT-29 xenograft tumors in nude mice administrated with ABC294640 (ABC, 5 or 20 mg/kg, p.o., daily) or vehicle (0.375 % Polysorbate-80) control were recorded weekly (n = 10 for each group) (a). Tumor weights (b) and mice body weights (c) at week-6 were also presented. Statistical analysis was performed comparing treatment groups with vehicle control group. *P < 0.05

Mentions: At last, we studied the anti-CRC activity of ABC294640 in vivo. HT-29 tumor bearing nude mice model was applied. Established, sized-matched HT-29 tumors were divided into three groups: low-dose ABC294640 (5 mg/kg, daily, p.o.) treatment group (n = 10), high-dose ABC294640 (20 mg/kg, daily, p.o.) treatment group (n = 10), and the vehicle (0.375 % Polysorbate-80) control group (n = 10). Tumor growth curve results in Fig. 6a showed that oral administration of ABC294640 (5 or 20 mg/kg) dramatically inhibited HT-29 xenograft growth in nude mice. The weights ABC294640-treated tumors were remarkably lower than that of vehicle-treated group (Fig. 6b). Mice body weights were not affected by ABC294640 administration throughout the experiment duration (see the data of week-6 in Fig. 6c). Nor did we noticed any signs of system toxicity or wasting. Thus, in line with the in vitro results, oral administration of ABC294640 dramatically inhibits HT-29 cell growth in vivo.Fig. 6


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)

ABC294640 inhibits HT-29 cell growth in vivo. The volumes of HT-29 xenograft tumors in nude mice administrated with ABC294640 (ABC, 5 or 20 mg/kg, p.o., daily) or vehicle (0.375 % Polysorbate-80) control were recorded weekly (n = 10 for each group) (a). Tumor weights (b) and mice body weights (c) at week-6 were also presented. Statistical analysis was performed comparing treatment groups with vehicle control group. *P < 0.05
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Related In: Results  -  Collection

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Fig6: ABC294640 inhibits HT-29 cell growth in vivo. The volumes of HT-29 xenograft tumors in nude mice administrated with ABC294640 (ABC, 5 or 20 mg/kg, p.o., daily) or vehicle (0.375 % Polysorbate-80) control were recorded weekly (n = 10 for each group) (a). Tumor weights (b) and mice body weights (c) at week-6 were also presented. Statistical analysis was performed comparing treatment groups with vehicle control group. *P < 0.05
Mentions: At last, we studied the anti-CRC activity of ABC294640 in vivo. HT-29 tumor bearing nude mice model was applied. Established, sized-matched HT-29 tumors were divided into three groups: low-dose ABC294640 (5 mg/kg, daily, p.o.) treatment group (n = 10), high-dose ABC294640 (20 mg/kg, daily, p.o.) treatment group (n = 10), and the vehicle (0.375 % Polysorbate-80) control group (n = 10). Tumor growth curve results in Fig. 6a showed that oral administration of ABC294640 (5 or 20 mg/kg) dramatically inhibited HT-29 xenograft growth in nude mice. The weights ABC294640-treated tumors were remarkably lower than that of vehicle-treated group (Fig. 6b). Mice body weights were not affected by ABC294640 administration throughout the experiment duration (see the data of week-6 in Fig. 6c). Nor did we noticed any signs of system toxicity or wasting. Thus, in line with the in vitro results, oral administration of ABC294640 dramatically inhibits HT-29 cell growth in vivo.Fig. 6

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