ABT199/venetoclax synergism with thiotepa enhances cytotoxicity of chemo medicine in AML cells

A brand new analysis paper was revealed in Oncotarget’s Volume 15 on March 14, 2024, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.”

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML remedy. Its efficacy in hematopoietic stem cell transplantation (HSCT), when mixed with different chemotherapeutic medicine, has not been totally investigated. In this new research, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta show the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. 

“The outcomes might present related data for the design of medical trials utilizing these medicine to avoid acknowledged drug-resistance mechanisms when used as a part of pre-transplant conditioning regimens for AML sufferers present process allogenic HSCT.”

Cleavage of Caspase 3, PARP1 and HSP90, in addition to elevated Annexin V positivity, counsel potent activation of apoptosis by this two-drug mixture; elevated ranges of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) point out an enhanced DNA harm response. Likewise, the elevated degree of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) counsel enhanced activation of stress signaling pathways. These molecular readouts had been synergistically enhanced when ABT199/venetoclax and Thio had been mixed with fludarabine, cladribine and busulfan. 

The five-drug mixture decreased the degrees of BCL-2, BCL-xL and MCL-1, suggesting its potential medical relevance in overcoming ABT199/venetoclax resistance. Moreover, this mixture is lively towards P53-negative and FLT3-ITD-positive cell strains. Enhanced activation of apoptosis was noticed in leukemia patient-derived cell samples uncovered to the five-drug mixture, suggesting a medical relevance. 

“The outcomes present a rationale for medical trials utilizing these two- and five-drug mixtures as a part of a conditioning routine for AML sufferers present process HSCT.”