A new research paper was published in Oncotarget’s Volume 15, on March 14, 2024, titled, “ABT199/venetoclax Synergy with Thiotepa Enhances Fludarabine, Cladribine, and Busulfan Cytotoxicity in AML Cells.”
ABT199/venetoclax, an inhibitor of the pro-survival protein BCL-2, has improved the treatment of AML. Its effectiveness in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapy drugs, has not been thoroughly investigated. In this new study, 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 demonstrate the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells.
“The results may provide relevant information for the design of clinical trials using these drugs to bypass recognized drug resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogeneic HSCT.”
Caspase 3, PARP1, and HSP90 cleavage, as well as increased Annexin V positivity, suggest strong activation of apoptosis by this two-drug combination. increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19), and P-SMC1 (S957) indicate an enhanced DNA damage response. Similarly, increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) indicate enhanced activation of stress signaling pathways. These molecular cues were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, clotribine, and busulfan.
The five-drug combination reduced the levels of BCL-2, BCL-xL, and MCL-1, suggesting its potential clinical relevance in addressing ABT199/venetoclax resistance. In addition, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced apoptosis activation was observed in cell samples derived from leukemia patients exposed to the five-drug combination, suggesting a clinical relevance.
“The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a regimen for AML patients undergoing HSCT.”
Source:
Journal Reference:
Valdez, BC et al. (2024). ABT199/venetoclax synergy with thiotepa enhances the cytotoxicity of fludarabine, clandribine and busulfan in AML cells. Oncotarget. doi.org/10.18632/oncotarget.28563.
