Combination effects of amino acid transporter LAT1 inhibitor nanvuranlat and cytotoxic anticancer drug gemcitabine on pancreatic and biliary tract cancer cells

Abstract

Background Cytotoxic anticancer drugs widely used in cancer chemotherapy have some limitations, such as the development of side effects and drug resistance. Furthermore, monotherapy is often less effective against heterogeneous cancer tissues. Combination therapies of cytotoxic anticancer drugs with molecularly targeted drugs have been pursued to solve such fundamental problems. Nanvuranlat (JPH203 or KYT-0353), an inhibitor for L-type amino acid transporter 1 (LAT1; SLC7A5), has novel mechanisms of action to suppress the cancer cell proliferation and tumor growth by inhibiting the transport of large neutral amino acids into cancer cells. This study investigated the potential of the combined use of nanvuranlat and cytotoxic anticancer drugs. Methods The combination effects of cytotoxic anticancer drugs and nanvuranlat on cell growth were examined by a water-soluble tetrazolium salt assay in two-dimensional cultures of pancreatic and biliary tract cancer cell lines. To elucidate the pharmacological mechanisms underlying the combination of gemcitabine and nanvuranlat, we investigated apoptotic cell death and cell cycle by flow cytometry. The phosphorylation levels of amino acid-related signaling pathways were analyzed by Western blot. Furthermore, growth inhibition was examined in cancer cell spheroids. Results All the tested seven types of cytotoxic anticancer drugs combined with nanvuranlat significantly inhibited the cell growth of pancreatic cancer MIA PaCa-2 cells compared to their single treatment. Among them, the combined effects of gemcitabine and nanvuranlat were relatively high and confirmed in multiple pancreatic and biliary tract cell lines in two-dimensional cultures. The growth inhibitory effects were suggested to be additive but not synergistic under the tested conditions. Gemcitabine generally induced cell cycle arrest at the S phase and apoptotic cell death, while nanvuranlat induced cell cycle arrest at the G0/G1 phase and affected amino acid-related mTORC1 and GAAC signaling pathways. In combination, each anticancer drug basically exerted its own pharmacological activities, although gemcitabine more strongly influenced the cell cycle than nanvuranlat. The combination effects of growth inhibition were also verified in cancer cell spheroids. Conclusions Our study demonstrates the potential of first-in-class LAT1 inhibitor nanvuranlat as a concomitant drug with cytotoxic anticancer drugs, especially gemcitabine, on pancreatic and biliary tract cancers.

m6A modification mediates SLC3A2/SLC7A5 translation in 3-methylcholanthrene-induced uroepithelial transformation

“…STC-15 (S TORM Therapeutics, NCT05584111) has begun to be tested in the clinic, which is the first RNA epigenetic anti-cancer drug project moving into clinical trials in the world. Moreover, SLC7A5 inhibitors R-OKY-034F (PRN-jRCT2051200105, JPRN-UMIN000036395, JPRN-jRCT2051190003) and Nanvuranlat (JPRN-UMIN000016546, JPRN-UMIN000034080) are also under clinical development or have been completed clinical trials (Nishikubo et al 2023 ). Altogether, our data identify METTL3/ALKBH5 and SLC3A2/SLC7A5 as the potential therapeutic targets and pave the way for future development of therapy for bladder cancer related to PAHs.…”

L-type Amino Acid Transporter 1 as a Therapeutic Target in Pancreatic Cancer

“…In experimental models, it was shown that JPH203 (nanvuranlat), a selective inhibitor of LAT1, suppressed pancreatic cancer cell proliferation and tumor growth, alone and in combination with gemcitabine. 13 , 14 The results indicated that the inhibition of LAT1 downregulated global translation in pancreatic cancer cells through the amino acid signaling mediated by mTORC1 and general amino acid control (GAAC) pathways. In the clinical setting, JPH203 was tested in a phase 1 study involving 17 patients with solid tumors, including 4 with pancreatic cancer.…”