Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas
T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acut...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Leukemia Research Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213048923000389 |
| _version_ | 1797385225182904320 |
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| author | Carlos Murga-Zamalloa Shaun Webb John Reneau Alejandro Zevallos Pierina Danos-Diaz Vanessa Perez-Silos Mirna Rodriguez Guangyao Gao Wolf-Nicolas Fischer Bernd Jandeleit Ryan Wilcox |
| author_facet | Carlos Murga-Zamalloa Shaun Webb John Reneau Alejandro Zevallos Pierina Danos-Diaz Vanessa Perez-Silos Mirna Rodriguez Guangyao Gao Wolf-Nicolas Fischer Bernd Jandeleit Ryan Wilcox |
| author_sort | Carlos Murga-Zamalloa |
| collection | DOAJ |
| description | T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic β-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases. |
| first_indexed | 2024-03-08T21:51:05Z |
| format | Article |
| id | doaj.art-8998a2e3b96f4b23b775c3aba7f40590 |
| institution | Directory Open Access Journal |
| issn | 2213-0489 |
| language | English |
| last_indexed | 2024-03-08T21:51:05Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Leukemia Research Reports |
| spelling | doaj.art-8998a2e3b96f4b23b775c3aba7f405902023-12-20T07:34:28ZengElsevierLeukemia Research Reports2213-04892024-01-0121100398Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomasCarlos Murga-Zamalloa0Shaun Webb1John Reneau2Alejandro Zevallos3Pierina Danos-Diaz4Vanessa Perez-Silos5Mirna Rodriguez6Guangyao Gao7Wolf-Nicolas Fischer8Bernd Jandeleit9Ryan Wilcox10Department of Pathology, University of Illinois at Chicago, 840 S Wood Street, 260 CMET, Chicago, IL 60607, United States; Corresponding author.Department of Pathology, University of Illinois at Chicago, 840 S Wood Street, 260 CMET, Chicago, IL 60607, United StatesDepartment of Internal Medicine, Ohio State University, Columbus, OH 43210, United StatesDepartment of Pathology, University of Illinois at Chicago, 840 S Wood Street, 260 CMET, Chicago, IL 60607, United StatesDepartment of Pathology, University of Illinois at Chicago, 840 S Wood Street, 260 CMET, Chicago, IL 60607, United StatesDepartment of Pathology, University of Illinois at Chicago, 840 S Wood Street, 260 CMET, Chicago, IL 60607, United StatesQuadriga BioSciences, Inc., Los Altos CA 94022, United StatesAcme Bioscience, Inc., Palo Alto, CA 94303, United StatesQuadriga BioSciences, Inc., Los Altos CA 94022, United StatesQuadriga BioSciences, Inc., Los Altos CA 94022, United StatesDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, United StatesT-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic β-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases.http://www.sciencedirect.com/science/article/pii/S2213048923000389SLC7A5LAT1T-cell lymphomasQBS10072SQBS10096S |
| spellingShingle | Carlos Murga-Zamalloa Shaun Webb John Reneau Alejandro Zevallos Pierina Danos-Diaz Vanessa Perez-Silos Mirna Rodriguez Guangyao Gao Wolf-Nicolas Fischer Bernd Jandeleit Ryan Wilcox Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas Leukemia Research Reports SLC7A5 LAT1 T-cell lymphomas QBS10072S QBS10096S |
| title | Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas |
| title_full | Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas |
| title_fullStr | Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas |
| title_full_unstemmed | Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas |
| title_short | Successful anti-tumor effects with two novel bifunctional chemotherapeutic compounds that combine a LAT1 substrate with cytotoxic moieties in aggressive T-cell lymphomas |
| title_sort | successful anti tumor effects with two novel bifunctional chemotherapeutic compounds that combine a lat1 substrate with cytotoxic moieties in aggressive t cell lymphomas |
| topic | SLC7A5 LAT1 T-cell lymphomas QBS10072S QBS10096S |
| url | http://www.sciencedirect.com/science/article/pii/S2213048923000389 |
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