Title:Drug Repurposing Screen Identifies Novel Classes of Drugs with Anticancer Activity in Mantle Cell Lymphoma
Volume: 22
Issue: 7
Author(s): Chengwu Han, Xueying Yu, Chunxia Zhang, Ying Cai, Yongyue Cao, Sijie Wang and Jun Shen*
Affiliation:
- Department of Laboratory Medicine, China-Japan Friendship Hospital, Beijing 100029,China
Keywords:
Mantel cell lymphoma, high-throughput screening, approved drugs, drug repurposing, chemotherapy.
Abstract:
Aim and Objective: Mantle Cell Lymphoma (MCL) is typically an aggressive and rare
disease with poor prognosis, therefore new effective therapeutics are urgently needed. Drug
repurposing for cancer treatment is becoming increasingly more attractive as an alternative
approach to discover clinically approved drugs that demonstrate antineoplastic effect. The
objective of this study was to screen an approved drug library and identify candidate compounds
with an antineoplastic effect in MCL cells using High-Throughput Screening (HTS) technique.
Materials and Methods: Using the HTS technique, nearly 3,800 clinically approved drugs and
drug candidates were screened in Jeko and Mino MCL cell lines. We also demonstrated the
selectivity window of the candidate compounds in six normal cell lines. Further validations were
performed in caspase-3/7 apoptosis assay and three-dimensional (3D) multicellular aggregates
model using Z138 cell line.
Results: We identified 98 compounds showing >50% inhibition in either MCL cell line screened,
they were distributed across eight unique therapeutic categories and have different mechanisms of
action (MOA). We selected alisertib, carfilzomib, pracinostat and YM155 for further validation
based on their antiproliferative activity in two MCL cell lines, selectivity to normal cell lines, and
drug developing stages in terms of clinical research. Alisertib and carfilzomib showed
antiproliferative effect on MCL cell with EC50 = 6 nM and >100-fold selectivity to normal cell
lines, especially for alisertib which demonstrated >1000-fold selectivity to 5 out of 6 normal cell
lines. Pracinostat and YM155 had potency of 11 and 12 nM in MCL cell with >20-fold selectivity
to normal cell lines. All four compounds had been tested in caspase-dependent apoptosis assay. We
further validated and demonstrated their anti-MCL effect on cell proliferation and (3D)
multicellular aggregates model using Z138 cell line.
Conclusion: This is the first study to examine such a large library of clinically approved
compounds for the identification of novel drug candidates for MCL treatment, the results could be
rapidly translated into clinical practice in patients with MCL.
