Idelalisib and bendamustine combination is synergistic and increases DNA damage response in chronic lymphocytic leukemia cells.

Abstract

Idelalisib is a targeted agent that potently inhibits PI3Kδ which is exclusively expressed in hematological cells. Bendamustine is a well-tolerated cytotoxic alkylating agent which has been extensively used for treatment of chronic lymphocytic leukemia (CLL). Both these agents are FDA-approved for CLL. To increase the potency of idelalisib and bendamustine, we tested their combination in primary CLL lymphocytes. While each compound alone produced a moderate response, combination at several concentrations resulted in synergistic cytotoxicity. Idelalisib enhanced the bendamustine-mediated DNA damage/repair response, indicated by the phosphorylation of ATM, Chk2, and p53. Each drug alone activated γH2AX but combination treatment further increased the expression of this DNA damage marker. Compared with the control, idelalisib treatment decreased global RNA synthesis, resulting in a decline of early-response and short-lived MCL1 transcripts. In concert, there was a decline in total Mcl-1 protein in CLL lymphocytes. Isogenic mouse embryonic fibroblasts lacking MCL1 had higher sensitivity to bendamustine alone or in combination compared to MCL1 proficient cells. Collectively, these data indicate that bendamustine and idelalisib combination therapy should be investigated for treating patients with CLL.

• Authors: Prexy Modi, Kumudha Balakrishnan, Qingshan Yang, William G Wierda, Michael J Keating, Varsha Gandhi
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 10 Pg. 16259-16274 (Mar 07 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28187444 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Purines
• Quinazolinones
• Bendamustine Hydrochloride
• idelalisib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bendamustine Hydrochloride (pharmacology)
• Cell Line
• Cell Survival (drug effects, genetics)
• Cells, Cultured
• DNA Damage
• Dose-Response Relationship, Drug
• Drug Synergism
• Embryo, Mammalian (cytology)
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Immunoblotting
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism, pathology)
• Mice, Knockout
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Purines (pharmacology)
• Quinazolinones (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured