Peripheral T-cell lymphomas (PTCL) are malignancies derived from mature (post-thymic) T cells and natural killer cells. As a rare and aggressive type of non-Hodgkin’s lymphoma, PTCL affects mature T cells. In addition, this type of cancer is characterized by the abnormal growth of T cells, which can accumulate in the lymph nodes, spleen, bone marrow, and other organs, leading to a variety of symptoms. What’s worse, PTCLs are often difficult to diagnose and treat, and they have a poorer prognosis than other types of lymphoma. However, PTCLs represent 10% to 15% of all non-Hodgkin’s lymphomas worldwide, accounting for 6,000 to 9,000 cases annually in the United States. Hence, we will introduce a potent dihydrofolate reductasean (DHFR) inhibitor, Pralatrexate, which has the potential for relapsed/refractory T-cell lymphoma treatment.
Pralatrexate is a DHFR inhibitor (Ki=13.4 pM) for research of PTCL.
Moreover, Pralatrexate is a substrate for folylpolyglutamate synthetase with improved cellular uptake and retention.
In vitro, Pralatrexate (2-5.5 nM; 48-72 hours; H9, HH, P12 and PF382 cells) treatment induces potent apoptosis, and caspase-8 and caspase-9 activation. Moreover, Pralatrexate (3 nM; 16-48 hours; H9 and P12 cells) treatment clearly increases p27 levels and increases the accumulation of educed folate carrier type 1 (RFC-1) in cells. Further more, Pralatrexate (100 pM-200 μM; 48-72 hours; T-lymphoma cell lines) treatment exhibits concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines, such as H9 cells, P12 cells and ect.
In vivo, the addition of Pralatrexate (15 mg/kg; intraperitoneal injection; on days 1, 4, 8, and 11; SCID-beige mice) to Bortezomib (0.5 mg/kg) enhanced efficacy compared with either drug alone.
Besides, Pralatrexate also is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
All in all, Pralatrexate is a promising DHFR inhibitor for PTCL research and has potential for other studies.
Reference:
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