Different antitumor effects of JPH 203 in gastrointestinal cancer cells

[Speaker] Yasuhide Muto:1,2
[Co-author] Tomomi Furihata:1, Kentarou Okunishi:1, Yoshie Reien:1, Hanae Morio:1, Kousuke Higuchi:1, Sinichi Sakamoto:1, Hisahiro Matsubara:2, Naohiko Anzai:1
1:Department of Pharmacology, Chiba University Graduate School of Medicine, Japan, 2:Department of frontier surgery, Chiba University Graduate School of Medicine, Japan

[Introduction] L-type amino acid transporter 1 (LAT1) is responsible for cellular uptake of large neutral amino acids including several essential amino acids. Since LAT1 expression levels are significantly increased in various cancer tissues, it has long been acknowledged as a promising molecular target for cancer therapy. In this context, JPH203, a selective LAT1 inhibitor, has been developed, and its anti-cancer effects has been demonstrated in several cancer cell lines. However, since pharmacological characterization of JPH203 remains limited, it is important to clarify what types of cancer cells are sensitive or insensitive to this agent. Therefore, in this study, we aimed at characterizing its anti-cancer properties in several colon, esophagus, and stomach cancer cell lines, and also tried to identify determinant factors for the effects.
[Methods] Colon (Lovo and HT29), esophagus (TE5, TE6, TE14 and TE15), and stomach (MKN1 and MKN45) cancer cells were used and cultured in a conventional method. Cytotoxic effects of JPH203 (uM, 72 hr) were examined by WST-8 assay. Dimethyl sulfoxide was used as a control. LAT1 mRNA expression levels were determined by quantitate real-time PCR.
[Results] The results of cytotoxic assay showed that the viabilities of MKN1 and MKN45 cells, as well as Lovo and HT29 cells, were significantly reduced upon JPH203 treatment (50.4 ± 12.8%, 42.8 ± 1.5%, 17.3 ± 11.6%, and 61.5 ± 17.8%, compared to those of the control, respectively). In contrast, all TE cells were highly resistant to the treatment (91.1 ± 11.6%, 99.1 ± 11.6%, 79.8 ± 10.5%, 93.9 ± 5.8%, respectively), indicating that there is a significant difference in responsive profiles against JPH203 among cancer cells. To try to address a factor behind the difference, LAT1 expression levels of these cells were determined. The results showed that LAT1 mRNA expression were clearly observed in all cells examined, but these levels apparently did not correspond to their cytotoxic profiles.
[Conclusion] Our results have demonstrated that cytotoxic effects of JPH203 are obviously cell-type dependent. Since the reason for this dependence does not seem to be solely explained by LAT1 expression levels, there should be unidentified factors determining JPH203 efficacy.

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