Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
Oncotarget. 2024 Mar 14;15:220-231. doi: 10.18632/oncotarget.28563.
ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent 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. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples 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 conditioning regimen for AML patients undergoing HSCT.
ABT199/venetoclax 是一种抗生存 BCL-2 蛋白的抑制剂，可改善 AML 的治疗效果。它与其他化疗药物联合用于造血干细胞移植 (HSCT) 的疗效尚未得到彻底研究。本研究表明，ABT199/venetoclax 与 DNA 烷化剂噻替派 (Thio) 在 AML 细胞中具有协同细胞毒性。Caspase 3、PARP1 和 HSP90 的切割以及 Annexin V 阳性增加表明这种双药联合可有效激活细胞凋亡；γ-H2AX、P-CHK1（S317）、P-CHK2（S19）和 P-SMC1（S957）水平升高表明 DNA 损伤反应增强。同样，P-SAPK/JNK（T183/Y185）水平升高和 P-PI3Kp85（Y458）水平降低表明应激信号通路的激活增强。当 ABT199/venetoclax 和 Thio 与氟达拉滨、克拉屈滨和白消安联合使用时，这些分子读数协同增强。五种药物联合降低了 BCL-2、BCL-xL 和 MCL-1 的水平，表明其在克服 ABT199/venetoclax 耐药性方面具有潜在的临床相关性。此外，该联合用药对 P53 阴性和 FLT3-ITD 阳性细胞系有效。在暴露于五种药物联合用药的白血病患者来源的细胞样本中观察到细胞凋亡的增强，提示其具有临床相关性。这些结果为使用这些二药和五药联合作为接受 HSCT 的 AML 患者预处理方案的一部分进行临床试验提供了依据。
