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Identification of Novel Therapeutic Agent Candidates Through High Throughput Screening With Chemical Library Based on
Hiroki Sakuma1, Hirotaka Tomiyasu1, Mari Takamiya2
1Laboratory of Veterinary Internal Medicine, Veterinary Clinical Science Unit, Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Tokyo, Japan.
Abstract:
Effective chemotherapy for canine histiocytic sarcoma (CHS) has yet to be established. In our previous study, CHS cell lines were subclassified into two groups based on their gene expression profiles: Group A and Group B. This study aimed to identify novel therapeutic agents that are effective against each CHS subgroup, and we performed high throughput screening, which examined the effects of 1824 chemical compounds on the 10 CHS cell lines. Among the compounds examined, 73 compounds were identified as candidates to show antiproliferative effects in all CHS cell lines examined, and the median IC50 values of 5-fluorouracil and sunitinib were 7.49 μM and 608 nM, respectively, across all CHS cell lines. While there was no compound that was specifically effective for Group B CHS cell lines, duvelisib was identified as a selective antitumor agent for CHS cell lines in Group A (median IC50 = 287 nM), with minimal effects on the other group (median IC50 > 5 μM) and normal peripheral blood mononuclear cells (IC50 = 7.46 μM). The amount of phosphorylated Akt protein decreased following duvelisib treatment in all eight CHS cell lines in Group A, but not in cell lines in Group B. Furthermore, duvelisib induced cell cycle arrest and increased cell death in a subset of Group A cell lines. These findings demonstrated that duvelisib exerted antiproliferative effects through inhibition of the Akt pathway in a subset of CHS cell lines while causing minimal cytotoxicity to normal cells.
Insights
Duvelisib shows promise as a targeted chemotherapy for canine histiocytic sarcoma (CHS) Group A by inhibiting the Akt pathway. This drug demonstrated selective antiproliferative effects on CHS Group A cell lines with minimal impact on normal cells.
Area of Science:
- Veterinary Oncology
- Cancer Pharmacology
Background:
- Canine histiocytic sarcoma (CHS) lacks established effective chemotherapy.
- Previous research subclassified CHS cell lines into Group A and Group B based on gene expression.
Purpose of the Study:
- To identify novel therapeutic agents effective against distinct CHS subgroups.
- To evaluate duvelisib's efficacy and mechanism of action in CHS.
Main Methods:
- High-throughput screening of 1824 chemical compounds against 10 CHS cell lines.
- Assessed antiproliferative effects, IC50 values, and Akt pathway inhibition.
- Evaluated duvelisib's impact on cell cycle and cell death.
Main Results:
- Duvelisib selectively inhibited Group A CHS cell lines (median IC50 = 287 nM) with minimal effect on Group B or normal cells.
- Duvelisib treatment reduced phosphorylated Akt in Group A CHS cells, inducing cell cycle arrest and death.
- 73 compounds showed antiproliferative effects across all CHS cell lines; 5-fluorouracil and sunitinib had median IC50 values of 7.49 μM and 608 nM, respectively.
Conclusions:
- Duvelisib is a potential targeted therapy for canine histiocytic sarcoma Group A.
- Inhibition of the Akt pathway is a key mechanism for duvelisib's antiproliferative effect in CHS.
- Duvelisib offers a selective treatment option with low cytotoxicity to normal canine cells.
