title: Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters.
abstract: Anti-cancer agents delivered to cancer cells often show multi-drug resistance (MDR) due to expulsion of the agents. One way to address this problem is to increase the accumulation of anti-cancer agents in cells via amino acid transporters. Thus, val-lapatinib and tyr-lapatinib were newly synthesized by adding valine and tyrosine moieties, respectively, to the parent anti-cancer agent lapatinib without stability issues in rat plasma. Val-lapatinib and tyr-lapatinib showed enhanced anti-cancer effects versus the parent lapatinib in various cancer cell lines, including human breast cancer cells (MDA-MB-231, MCF7) and lung cancer cells (A549), but not in non-cancerous MDCK-II cells. A glutamine uptake study revealed that both val-lapatinib and tyr-lapatinib, but not the parent lapatinib, inhibited glutamine transport in MDA-MB-231 and MCF7 cells, suggesting the involvement of amino acid transporters. In conclusion, val-lapatinib and tyr-lapatinib have enhanced anti-cancer effects, likely due to an increased uptake of the agents into cancer cells via amino acid transporters. The present data suggest that amino acid transporters may be an effective drug delivery target to increase the uptake of anti-cancer agents, leading to one method of overcoming MDR in cancer cells.
authors.affiliation: College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam, South Korea.
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.forename: Eun-Seo
authors.initials: ES
authors.lastname: Kim
authors.forename: Chieyeon
authors.initials: C
authors.lastname: Chough
authors.forename: Misuk
authors.initials: M
authors.lastname: Joung
authors.forename: Jee Woong
authors.initials: JW
authors.lastname: Lim
authors.forename: Chang-Koo
authors.initials: CK
authors.lastname: Shim
authors.forename: Won-Sik
authors.initials: WS
authors.lastname: Shim
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D000077341:Lapatinib; D061985:Madin Darby Canine Kidney Cells; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry*; D014633:Valine / Q000737:chemistry*
chemical_list: D026905:Amino Acid Transport Systems; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D005973:Glutamine; D000077341:Lapatinib; D014443:Tyrosine; D014633:Valine
keywords: amino acid transporters; cancer cells; lapatinib; multi-drug resistance (MDR); tyr-lapatinib; val-lapatinib