JPH203, a newly developed anti-cancer drug, shows a preincubation inhibitory effect on L-type amino acid transporter 1 function

Okunushi, Kentaro; Furihata, Tomomi; Morio, Hanae; Muto, Yasuhide; Higuchi, Kosuke; Kaneko, Meika; Otsuka, Yusuke; Ohno, Yuta; Watanabe, Yasuhiro; Reien, Yoshie; Nakagawa, Kiyoshi; Sakamoto, Shinichi; Wakashin, Hidefumi; Shimojo, Naoki; Anzai, Naohiko

doi:10.1016/j.jphs.2020.06.006

Cited by 26 publications

(20 citation statements)

References 22 publications

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“…HT-29 CRC xenografts in vivo 114,115 . Although JPH203 blocks the influx of many neutral amino acids, including glutamine, it is now in phase I and advancing to phase II clinical studies 116 .…”

Section: Glutamine Metabolismmentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

637

402

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Before Sidney Farber published his seminal paper in 1948 in The New England Journal of Medicine describing anti-folate-induced remissions 1 , childhood acute lymphocytic leukaemia (ALL) was universally fatal. Thirty years before this article was published, Otto Warburg's determination to conquer cancer led him to discover that many tumours used aerobic glycolysis (also known as the Warburg effect) to convert almost all glucose to lactate even in the presence of oxygen 2 . Aerobic glycolysis, however, has never been successfully exploited clinically, particularly as the use of 2-deoxyglucose, which inhibits glycolysis, was proved to have undesirable side effects and limited efficacy in humans 3 . Farber noted the clinical 'accelerated phenomenon' among 11 children treated with an active form of folate, pteroyltriglutamic acid, which was thought to have broad anticancer activity, and thus sought folate antagonists as therapeutic agents. Working with chemist Yellapragada Subbarow, the anti-folate aminopterin was synthesized, and Farber was able to induce remissions in children with ALL, thus providing the foundation for cancer chemotherapy 4 . Today, another folate antagonist, methotrexate, is still used in the multi-chemotherapy treatment of childhood ALL and, used together with l-asparaginase, induces a remarkable 90% cure rate. Indeed, many anti-metabolite drugs, particularly those targeting nucleotide metabolism, have been approved and used in the clinic (Table 1). The recent approval of drugs that target mutant isocitrate dehydrogenases in acute myeloid leukaemias (AMLs) (Table 1) provides a milestone in targeting cancer metabolism with precision and establishes that metabolic therapy can be highly effective.Warburg's and Farber's ideas were conceptually displaced in the 1980s as oncogenes and tumour suppressors became recognized as targets in human cancer treatments. Molecular biology took centre stage, and the drive to target oncogenes began with vigour, resulting in many effective anticancer kinase drugs that displaced interest in targeting metabolism. However, the links between oncogenes, tumour suppressors and metabolism began to emerge in the 1990s, ushering in a resurgence of interest in cancer metabolism [5][6][7] . More recently, the success of immunotherapy underscores the importance of non-cancer-cell autonomous components of the tumour immune microenvironment (TIME) [8][9][10] , which is a neoplastic hub of metabolically active cells comprising tumour cells, immune cells, stromal cells and blood and lymph vessel cells, all of which are involved in tumour growth. In this regard, targeting cancer metabolism must be based on a thorough understanding of how inhibiting specific metabolic pathways affects the TIME cells, which can either dampen or promote tumour progression. In this Review, we cover the fundamentals of cancer metabolism and focus on recent small-molecule drug discovery efforts to target cancer.

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Section: Glutamine Metabolismmentioning

confidence: 99%

Targeting cancer metabolism in the era of precision oncology

Stine¹,

Schug

Salvino

et al. 2021

Nat Rev Drug Discov

637

402

View full text Add to dashboard Cite

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“…JPH203 interferes with constitutive activation of mTORC1 and Akt, reduces c-MyC expression, and triggers a folding protein response mediated by CHOP transcription factors associated with cell death [ 116 ]. Since then, several studies have confirmed that JPH203 has an impressive inhibitory effect on the growth of common tumor cells, such as colon cancer [ 115 , 117 ], gastric carcinoma [ 64 ], medulloblastoma [ 118 ], osteosarcoma [ 119 ], thyroid cancer [ 120 , 121 ], endocrine-resistant breast cancer [ 122 ], pituitary tumor [ 123 ], head and neck cancer cells [ 124 ], and T-cell Acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells [ 116 ], etc.…”

Section: Inhibitors Of Lat1/4f2hc and Targeted Therapymentioning

confidence: 99%

Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

Zhao

Sakamoto

Maimaiti

et al. 2022

Cancers

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Tumor cells are known for their ability to proliferate. Nutrients are essential for rapidly growing tumor cells. In particular, essential amino acids are essential for tumor cell growth. Tumor cell growth nutrition requires the regulation of membrane transport proteins. Nutritional processes require amino acid uptake across the cell membrane. Leucine, one of the essential amino acids, has recently been found to be closely associated with cancer, which activate mTOR signaling pathway. The transport of leucine into cells requires an L-type amino acid transporter protein 1, LAT1 (SLC7A5), which requires the 4F2 cell surface antigen heavy chain (4F2hc, SLC3A2) to form a heterodimeric amino acid transporter protein complex. Recent evidence identified 4F2hc as a specific downstream target of the androgen receptor splice variant 7 (AR-V7). We stressed the importance of the LAT1-4F2hc complex as a diagnostic and therapeutic target in urological cancers in this review, which covered the recent achievements in research on the involvement of the LAT1-4F2hc complex in urinary system tumors. In addition, JPH203, which is a selective LAT1 inhibitor, has shown excellent inhibitory effects on the proliferation in a variety of tumor cells. The current phase I clinical trials of JPH203 in patients with biliary tract cancer have also achieved good results, which is the future research direction for LAT1 targeted therapy drugs.

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“…We also found the decreased phosphorylation of Akt and mTOR in LAT1 knockdown A400 and H1299 cells (Figure 2C). In addition to RNA interference, we also used JPH203, the small molecule inhibitor of LAT1 [20], to inhibit LAT1 activity. The formation of tumorspheres in A400 and H1299 cells was decreased by JPH203 treatment in a dose-dependent manner (Figure 3A).…”

Section: The Inhibition Of Lat1 Suppresses Csc Activity In Nsclc Cellsmentioning

confidence: 99%

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells

Liu

Shen

et al. 2021

IJMS

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The l-type amino acid transporter 1 (LAT1) is a membranous transporter that transports neutral amino acids for cells and is dysregulated in various types of cancer. Here, we first observed increased LAT1 expression in pemetrexed-resistant non-small cell lung cancer (NSCLC) cells with high cancer stem cell (CSC) activity, and its mRNA expression level was associated with shorter overall survival in the lung adenocarcinoma dataset of the Cancer Genome Atlas database. The inhibition of LAT1 by a small molecule inhibitor, JPH203, or by RNA interference led to a significant reduction in tumorsphere formation and the downregulation of several cancer stemness genes in NSCLC cells through decreased AKT serine/threonine kinase (AKT)/ mammalian target of rapamycin (mTOR) activation. The treatment of the cell-permeable leucine derivative promoted AKT/mTOR phosphorylation and reversed the inhibitory effect of JPH203 in the reduction of CSC activity in pemetrexed-resistant lung cancer cells. Furthermore, we observed that LAT1 silencing caused the downregulation of programmed cell death 1 ligand 1 (PD-L1) on lung cancer cells. The PD-L1+/LAT1+ subpopulation of NSCLC cells displayed great CSC activity with increased expression of several cancer stemness genes. These data suggest that LAT1 inhibitors can serve as anti-CSC agents and could be used in combination with immune checkpoint inhibitors in lung cancer therapy.

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JPH203, a newly developed anti-cancer drug, shows a preincubation inhibitory effect on L-type amino acid transporter 1 function

Cited by 26 publications

References 22 publications

Targeting cancer metabolism in the era of precision oncology

Targeting cancer metabolism in the era of precision oncology

Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells

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