JPH203, an L-Type Amino Acid Transporter 1–Selective Compound, Induces Apoptosis of YD-38 Human Oral Cancer Cells

Yun, Dae-Woong; Lee, Seul Ah; Park, Min-Gyeong; Kim, Jae-Sung; Yu, Sun‐Kyoung; Park, Mi‐Ra; Kim, Su-Gwan; Oh, Ji‐Su; Kim, Chun Sung; Kim, Heung-Joong; Kim, Jin-Soo; Chun, Hong Sung; Kanai, Yoshikatsu; Endou, Hitoshi; Wempe, Michael F.; Kim, Do Kyung

doi:10.1254/jphs.13154fp

Cited by 63 publications

(64 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It suppressed the growth of YD-38 human oral cancer cells expressing LAT1 and 4F2hc [93]. In this case, JPH203 completely inhibited L-leucine uptake in YD-38 cells, showing a superior activity than BCH.…”

Section: Lat1 Inhibitorsmentioning

confidence: 87%

See 1 more Smart Citation

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Jin¹,

Jin²,

Hong³

2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

Section: Lat1 Inhibitorsmentioning

confidence: 87%

“…The activity of JPH203 was reported as a potent LAT1 selective inhibitor in vitro and in vivo [93,94]. It suppressed the growth of YD-38 human oral cancer cells expressing LAT1 and 4F2hc [93].…”

Section: Lat1 Inhibitorsmentioning

confidence: 99%

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Jin¹,

Jin²,

Hong³

2015

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…Leucine is a well-known activator of mTOR signaling (12), and pharmacologic inhibition of SLC7A5 transport function suppresses mTOR signaling and tumor growth in a number of model systems (13)(14)(15)(16). But how does SLC7A5, an obligatory exchanger, mediate the entry of leucine into cancer cells to impact on mTOR?…”

Section: Amino Acid Transporters In Cancermentioning

confidence: 99%

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

et al. 2015

View full text Add to dashboard Cite

Tumor cells have an increased demand for amino acids because of their rapid proliferation rate. In addition to their need in protein synthesis, several amino acids have other roles in supporting cancer growth. There are approximately two-dozen amino acid transporters in humans, and tumor cells must upregulate one or more of these transporters to satisfy their demand for amino acids. If the transporters that specifically serve this purpose in tumor cells are identified, they can be targeted for the development of a brand new class of anticancer drugs; the logical basis of such a strategy would be to starve the tumor cells of an important class of nutrients. To date, four amino acid transporters have been found to be expressed at high levels in cancer: SLC1A5, SLC7A5, SLC7A11, and SLC6A14. Their induction occurs in a cancer typespecific manner with a direct or indirect involvement of the oncogene c-Myc. Further, these transporters are functionally coupled, thus maximizing their ability to promote cancer growth and chemoresistance. Progress has been made in preclinical studies, exploiting these transporters as drug targets in cancer therapy. These transporters also show promise in development of new tumor-imaging probes and in tumor-specific delivery of appropriately designed chemotherapeutic agents. Cancer Res; 75(9);

show abstract

“…Recently, a selective LAT1 inhibitor named JPH203 [(S)-2-amino-3-(4-((5-amino-2-phenylbenzo [d] oxazol-7-yl) methoxy)-3, 5-dichlorophenyl) propanoic acid] has been created [18][19][20] . JPH203 inhibits the function of the LAT1 in many types of cancer cells, which functions through the mTOR signaling pathway to block their migration/invasion activities and induce apoptosis 13,21 .…”

mentioning

confidence: 99%

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma

Maimaiti

Sakamoto

Yamada

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.Bladder cancer (BC) is the ninth most common malignant tumour worldwide, with 430 000 patients newly diagnosed and 165 000 deaths annually 1 . The pathological type of BC is mainly urothelial cancer ( > 90%) and approximately 70% of patients had non-muscle-invasive BC at diagnosis 2 . These patients have a favorable prognosis with transurethral resection and subsequent intravesical injection therapy, whereas the survival rate of patients with locally advanced and metastatic BC is poor 3 . For metastatic BC patients, platinum-based systematic chemotherapy is the classical treatment, while immunotherapy targeting programmed cell death ligand 1 (PD-L1) blocking antibody was recently approved in Japan 4 . However, drug resistance will occur, and the survival benefit of these agents is not adequate. Their limited efficacy is due to side effects and challenges of drug resistance, leading to treatment failure and require additional treatment options 5 . Therefore, more effective and less toxic therapeutic strategies are needed for the treatment of metastatic BC. Additionally, there are presently no useful diagnostic markers for BC. The urine cytology test is a non-invasive examination, but its sensitivity remains low. Cystoscopy is an essential diagnostic tool but is invasive for patients 5 . Thus, a novel therapeutic approach and biomarker candidates for BC remain a major issue.

show abstract

JPH203, an L-Type Amino Acid Transporter 1–Selective Compound, Induces Apoptosis of YD-38 Human Oral Cancer Cells

Cited by 63 publications

References 30 publications

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma

Contact Info

Product

Resources

About