Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells
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Rachael A. Clark1,*, Sora Lee1,*, Jingbo Qiao1 and Dai H. Chung1
1 Department of Surgery, Division of Pediatric Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
* These authors contributed equally to this work
|Dai H. Chung,||email:||[email protected]|
Keywords: neuroblastoma; pralatrexate; N-myc; folate metabolism
Received: February 14, 2020 Accepted: July 07, 2020 Published: August 11, 2020
Introduction: Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase exhibiting high affinity for reduced folate carrier-1 with antineoplastic and immunosuppressive activities, similar to methotrexate. Despite advances in multi-modality treatment strategies, the survival rates for children with high-risk neuroblastoma have failed to improve. Therefore, the intense research continues in order to identify the ideal novel agent or combination of chemotherapy drugs to treat high-risk neuroblastoma.
Materials and Methods: Four human neuroblastoma cell lines were used to determine IC50 values of select chemotherapy agents. Antiproliferative effects of pralatrexate were assessed by adherent and non-adherent colony formation assays. Cell cycle arrest and apoptosis were measured by flow cytometry and immunoblotting. PDX tissue culture was used to assess ex vivo efficacy.
Results: Treatment with pralatrexate in all four neuroblastoma cell lines blocked cell growth in 2D and 3D culture conditions in a time-dependent manner. The potency of pralatrexate was ten-fold stronger than methotrexate, as measured by IC50. Pralatrexate-induced apoptosis was confirmed by caspase-3 activation and PARP cleavage. MYCN and SLC19A1 mRNA expressions were decreased with pralatrexate in MYCN-amplified neuroblastoma cells.
Conclusions: Pralatrexate demonstrated effective inhibition of cell growth and viability. The higher potency of pralatrexate compared to methotrexate, a drug with high levels of toxicity, suggests pralatrexate may be a safer alternative to methotrexate as an effective chemotherapeutic agent in the treatment of patients with high-risk neuroblastoma.
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