Therapeutic Impact of P-PENT, P-HEX and 5CLSS (IV) Platinum (IV) complexes on Acute Myeloid Leukemia in vitro and in vivo

Abstract

Platinum (II)-based complexes, such as cisplatin and carboplatin, are widely known for their anticancer activity against various types of cancers. While resistance has limited their efficacy, a growing interest in platinum (IV) complexes has recently grown to overcome this challenge. The present study investigates the anti-leukemic potential of three platinum (IV) complexes, PPENT, P-HEX, and 5CLSS(IV) in vitro and in vivo. The cytotoxic activity of P-PENT, P-HEX, and 5CLSS(IV) against WEHI-3 cells was assessed using MTS-PMS kit. All three complexes caused significant cytotoxicity with IC50 values of 0.12, 0.070, and 0.12 μM for 5CLSS(IV), PPENT, and P-HEX, respectively. A significant increase in ROS production was also observed upon cell treatment with the complexes. Flow cytometry analysis revealed that treatment with any of the platinum (IV) complexes induced apoptosis. Western blots analysis confirmed the involvement of an intrinsic apoptotic pathway (BAX/BCL2, procaspase 3, full length PARP )and inhibition of the MAPK pathway (P-ERK/ERK) . An advanced and early-stage leukemic mice models were established using WEHI-3 cells inoculation. Initiating treatment of animals 10 days post inoculation (advanced stage) showed improved mice survival with any of the platinum IV complexes treatment mainly at the 5 mg/kg and 15 mg/kg doses. While no additional benefit was observed with increasing the dose to 15 mg/kg, P-HEX at the 5 mg/kg dose exhibited the best mice survival among all groups including the positive controls (cytarabine or cispaltin). Initiating animal treatment 4 days post inoculation (early stage) using P-PENT or P-HEX at 5 mg/kg once or twice per week revealed similar engagement of animal survival rate compared to negative control. Both complexes significantly reduced spleen weight and CD11B expression compared to untreated leukemic controls. Collectively, these findings suggest that all platinum (IV) complexes, especially P-HEX exhibit promising anti-leukemic activity in vitro and in vivo, highlighting their potential as effective therapeutic agents against AML.