Abstract
High progression and resistance to chemoimmunotherapies is the challenge in treatment of TP53 mutated patients. Para-nitric oxide releasing-acetylic salicylic acid (para-NO-ASA) has been shown to possess antineoplastic properties in CLL, but features an insufficient therapeutic index and a low efficacy against TP53 mutated CLL cells. Therefore, the para-NO-ASA was modified and the effect of these newly developed compounds in vitro and in vivo was investigated. Three of the synthesized derivatives effectively induced apoptosis with a high selectivity on CLL cells. This antineoplastic effect was independent of the TP53 mutation status. Derivative B9 demonstrated good tolerability and a strong anti-tumor efficacy in the xenograft mouse with a maximal tumor inhibition rate of 65%. Phosphorylation of the NFκB p65 subunit was significantly reduced by 10 M B9 and B13 by around 75%, while 20 M NO-aspirin could not induce significant reduction. The same applies to the reduction of translocation of NFκB p65 subunit to the nucleus. In addition, expressions of the NF-κB target genes BCL-2, CFLAR and BTK were clearly shut down after incubation with each substance. These results show arresting features of three newly developed derivatives making them promising compounds for high-risk CLL therapy.
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More From: American Journal of Cancer Research and Clinical Oncology
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