Found 1 Presentation For Request "11P"
11P - Novel HDAC6 inhibitors show anti-lymphoma activity alone and in combination with venetoclax and copanlisib
- Afua A. Mensah (Bellinzona, Switzerland)
- Afua A. Mensah (Bellinzona, Switzerland)
- Giulio Sartori (Bellinzona, Switzerland)
- Chiara Falzarano (Bellinzona, Switzerland)
- Werner Tueckmantel (New York, NY, United States of America)
- Alan Kozikowski (New York, NY, United States of America)
- Francesco Bertoni (Bellinzona, Switzerland)
Abstract
Background
Diffuse large B cell lymphomas (DLBCL) are aggressive tumours with frequent aberrations in epigenetic proteins. Histone deacetylase inhibitors (HDACi) are epigenetic agents with pre-clinical and clinical efficacy in lymphomas. Here we investigated the in vitro anti-lymphoma activities of eight novel HDAC6 inhibitors (HDAC6i) in DLBCL.
Methods
MTT assay was used to assess the anti-proliferative activities of HDAC6i: SS-2-08, SS-5-55, SW- 101, SW-113, SW-114, SW-115, SW-117 and WT-36-87, alone or combined with venetoclax or copanlisib (72 hours [h] ) in DLBCL cells: DOHH2, OCI-LY-18 (BCL2 and MYC translocated); SU-DHL-4, OCI-LY-1 (BCL2 translocated and MYC amplified). The Chou-Talalay combination index (CI) determined additive effect (CI 0.9-1.1), synergism (CI 0.3-0.9) and antagonism (CI > 1.1). For cell cycle analysis by flow cytometry, cells were fixed in 70% ethanol then stained with 7-AAD. Western blotting determined levels of acetylated α-tubulin.
Results
Median IC50 values for the eight HDAC6i ranged from 0.6 μM to 19.3 μM. SW-101, SW-117, SS-2-08 and WT-36-87 showed the strongest anti-proliferative activities. SW-117 was the most potent (range 0.2 - 2 μM; median 0.6 μM). DLBCLs treated with median IC50s of SW-101, SW-117, SS-2-08 and WT-36-87 for 72 h underwent G1 arrest and cell death. The most potent HDAC6i, SW-117 (with a potency of 0.3 nM for HDAC6), increased acetylated α-tubulin levels at 4 h and this upregulation persisted to 72 h. The three most active HDAC6i (SW-117, SW-101, WT-36-87), plus SW-113 that showed negligible activity as a single agent, were tested in combination with the PI3Kα/δ inhibitor copanlisib and the BCL2 inhibitor venetoclax, in DOHH2 and SU-DHL-4. All four HDAC6i showed enhanced anti-proliferative activity in at least one of the combinations tested. SW-117 and SW-101 showed similar benefit when combined with either copanlisib or venetoclax.
Conclusions
We observed robust in vitro anti-lymphoma activity of novel HDAC6i in DLBCL cells. Our results suggest that these agents are worthy of further pre-clinical investigation in DLBCL as single agents and in combination with other targeted anti-lymphoma drugs.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
W. Tueckmantel: Financial Interests, Personal, Member: Bright Minds Biosciences. A. Kozikowski: Financial Interests, Personal, Member of the Board of Directors: Bright Minds Biosciences. All other authors have declared no conflicts of interest.