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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 cytotoxic effect of ABC294640 in primary human CRC cells. Ex vivo cultured primary cancer cells derived from three different colon cancer patients (−1, male, 47 yeas old; −2, female, 62 years old; −3, male, 55 years old) were treated with or without ABC294640 (1 μM) for 72 hours, cell growth and cell death were tested by MTT assay (b) and LDH release assay (c), respectively. Expression of SphK2 and tubulin in above cells was also shown (a). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05
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Fig3: The cytotoxic effect of ABC294640 in primary human CRC cells. Ex vivo cultured primary cancer cells derived from three different colon cancer patients (−1, male, 47 yeas old; −2, female, 62 years old; −3, male, 55 years old) were treated with or without ABC294640 (1 μM) for 72 hours, cell growth and cell death were tested by MTT assay (b) and LDH release assay (c), respectively. Expression of SphK2 and tubulin in above cells was also shown (a). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05

Mentions: The activity of ABC294640 on patient-derived primary cancer cells was tested. We successfully cultured primary cancer cells from 3 different colon cancer patients. Their corresponding in vitro growth curve and doubling time were presented in Additional file 1: Figure S1A and B. As shown in Fig. 3a, these primary cancer cells showed differential expression of SphK2 expression. Patient-2-derived cancer cells had highest level of SphK2, these cells were extremely sensitive to ABC294640-induced growth inhibition (Fig. 3b) and cell death (Fig. 3c). On the other hand, patient-1-derived cancer cells had lowest SphK2 level (Fig. 3a), the cytotoxic effect of ABC29464 was also relatively weak in those cells (Fig. 3b and c). Thus, ABC294640 is cytotoxic to the tested primary cancer cells, and its activity is negatively associated with SphK2 expression level. The morphology of these primary cancer cells before and after ABC294640 treatment was shown in Additional file 1: Figure S1C.Fig. 3


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 cytotoxic effect of ABC294640 in primary human CRC cells. Ex vivo cultured primary cancer cells derived from three different colon cancer patients (−1, male, 47 yeas old; −2, female, 62 years old; −3, male, 55 years old) were treated with or without ABC294640 (1 μM) for 72 hours, cell growth and cell death were tested by MTT assay (b) and LDH release assay (c), respectively. Expression of SphK2 and tubulin in above cells was also shown (a). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: The cytotoxic effect of ABC294640 in primary human CRC cells. Ex vivo cultured primary cancer cells derived from three different colon cancer patients (−1, male, 47 yeas old; −2, female, 62 years old; −3, male, 55 years old) were treated with or without ABC294640 (1 μM) for 72 hours, cell growth and cell death were tested by MTT assay (b) and LDH release assay (c), respectively. Expression of SphK2 and tubulin in above cells was also shown (a). Mean values ± SD of three independent experiments were reported. Statistical analysis was performed comparing treatment groups with vehicle control group (“C”). *P < 0.05
Mentions: The activity of ABC294640 on patient-derived primary cancer cells was tested. We successfully cultured primary cancer cells from 3 different colon cancer patients. Their corresponding in vitro growth curve and doubling time were presented in Additional file 1: Figure S1A and B. As shown in Fig. 3a, these primary cancer cells showed differential expression of SphK2 expression. Patient-2-derived cancer cells had highest level of SphK2, these cells were extremely sensitive to ABC294640-induced growth inhibition (Fig. 3b) and cell death (Fig. 3c). On the other hand, patient-1-derived cancer cells had lowest SphK2 level (Fig. 3a), the cytotoxic effect of ABC29464 was also relatively weak in those cells (Fig. 3b and c). Thus, ABC294640 is cytotoxic to the tested primary cancer cells, and its activity is negatively associated with SphK2 expression level. The morphology of these primary cancer cells before and after ABC294640 treatment was shown in Additional file 1: Figure S1C.Fig. 3

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