Transcriptional Modulation by Idelalisib Synergizes with Bendamustine in Chronic Lymphocytic Leukemia

Cancers

EricD. J. Bouchard¹  EdgardM. Mejia²  AaronJ. Marshall²  Marina Mostafizar³  Versha Banerji⁴  SpencerB. Gibson⁴  JamesB. Johnston⁴  Ali Saleh⁴  Sachin Katyal⁴  SaraE. F. Kost⁴ 

[1] Department of Environmental Health and Safety, Simon Fraser University, Burnaby, BC V5A 1S6, Canada;Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0V9, Canada;Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada;

关键词: chronic lymphocytic leukemia;    bendamustine;    idelalisib;    drug combination therapy;    dna damage;    transcriptional regulation;   

DOI  :  10.3390/cancers11101519

来源: DOAJ

【 摘 要 】

The phosphatidyl-inositol 3 kinase (PI3K) δ inhibitor, idelalisib (IDE), is a potent inhibitor of the B-cell receptor pathway and a novel and highly effective agent for the treatment of chronic lymphocytic leukemia (CLL). We evaluated the activities of IDE in comparison to bendamusine (BEN), a commonly used alkylating agent, in primary CLL cells ex vivo. In contrast to BEN, IDE was cytotoxic to cells from extensively-treated patients, including those with a deletion (del)17p. Cross-resistance was not observed between BEN and IDE, confirming their different modes of cytotoxicity. Marked synergy was seen between BEN and IDE, even in cases that were resistant to BEN or IDE individually, and those with deletion (del) 17p. CD40L/interleukin 4 (IL4) co-treatment mimicking the CLL microenvironment increased resistance to IDE, but synergy was retained. PI3Kδ-deficient murine splenic B cells were more resistant to IDE and showed reduced synergy with BEN, thus confirming the importance of functional PI3Kδ protein. Although IDE was observed to induce γH2AX, IDE did not enhance activation of the DNA damage response nor DNA repair activity. Interestingly, IDE decreased global RNA synthesis and was antagonistic with 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB), an inhibitor of transcription. These findings add to the increasingly complex cellular effects of IDE, and B cell receptor (BCR) inhibitors in general, in CLL.

【 授权许可】

Unknown