In:
Cancer Science, Wiley, Vol. 109, No. 9 ( 2018-09), p. 2801-2810
Abstract:
CD 44v9 is expressed in cancer stem cells ( CSC ) and stabilizes the glutamate‐cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species ( ROS ). This mechanism confers ROS resistance to CSC and CD 44v9‐expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD 44v9 and xCT in hepatocellular carcinoma ( HCC ) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization ( HAIC ) therapy with cisplatin ( CDDP ); and (ii) whether combination of CDDP with sulfasalazine ( SASP ), an inhibitor of xCT , was more effective on tumor cells than CDDP alone by inducing ROS ‐mediated apoptosis. Twenty non‐pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD 44v9 and xCT expression. Human HCC cell lines HAK ‐1A and HAK ‐1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD 44v9 positivity was significantly higher in HAIC ‐treated tissues (5/7) than in non‐pretreated tissues (2/30), suggesting the involvement of CD 44v9 in the resistance to HAIC . xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD 44v9‐harboring HAK ‐1B cells through ROS ‐mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS ‐mediated apoptosis in CDDP ‐treated HCC cells, in which the CD 44v9‐ xCT system functioned. As CD 44v9 is typically expressed in HAIC ‐resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance.
Type of Medium:
Online Resource
ISSN:
1347-9032
,
1349-7006
DOI:
10.1111/cas.2018.109.issue-9
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2115647-5
detail.hit.zdb_id:
2111204-6
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