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Identification of effective anti-osteosarcoma agents via screening of an in-house NQO1-targeted compound library
Xiang Li1, Qijie Gong2, Jianglin Yu3
1Department of Orthopedics, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China.
Abstract:
Osteosarcoma is one of the most prevalent malignant bone tumors, and despite advances in treatment, significant improvements in survival rates for osteosarcoma patients remain elusive. There is an urgent need for developing novel molecules for the targeted treatment of osteosarcoma. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly overexpressed in osteosarcoma. Here, we evaluated a series of in-house NQO1-targeting compounds, including NQO1 substrates and β-lap prodrugs, through phenotypic screening using NQO1-positive methylnitronitrosoguanidine-induced human osteosarcoma cells (MNNG) and NQO1-negative normal human umbilical vein endothelial cells (HUVEC), aiming to identify novel candidate compounds for osteosarcoma therapy. As a result, compound 21, an NQO1 substrate, was identified as a potent anti-osteosarcoma agent that promotes apoptosis and induces cell cycle arrest in osteosarcoma cells in vitro, while significantly inhibiting tumor growth in vivo. These findings suggest that compound 21 holds promise as a candidate for osteosarcoma treatment. Moreover, NQO1-targeting substrates present a promising pathway for the discovery of novel anti-osteosarcoma agents.
Insights
A novel compound, targeting NAD(P)H:quinone oxidoreductase 1 (NQO1), shows significant promise for osteosarcoma treatment. This NQO1 substrate effectively inhibits tumor growth and induces cancer cell death, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma remains a prevalent bone cancer with limited survival improvements despite treatment advances.
- There is a critical need for novel therapeutic molecules targeting osteosarcoma.
- NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequently overexpressed in osteosarcoma, presenting a potential therapeutic target.
Purpose of the Study:
- To identify novel anti-osteosarcoma compounds by evaluating NQO1-targeting agents.
- To assess the efficacy of NQO1 substrates and prodrugs in osteosarcoma models.
- To discover new therapeutic candidates for osteosarcoma treatment.
Main Methods:
- Phenotypic screening of NQO1-targeting compounds using NQO1-positive human osteosarcoma cells (MNNG) and NQO1-negative HUVEC cells.
- Evaluation of compound activity in vitro, including apoptosis induction and cell cycle arrest.
- Assessment of anti-tumor efficacy in vivo through tumor growth inhibition studies.
Main Results:
- Compound 21, an NQO1 substrate, demonstrated potent anti-osteosarcoma activity.
- In vitro studies showed compound 21 promotes apoptosis and induces cell cycle arrest in osteosarcoma cells.
- In vivo studies revealed significant inhibition of tumor growth by compound 21.
Conclusions:
- Compound 21 is a promising candidate for osteosarcoma therapy.
- NQO1-targeting substrates represent a viable strategy for developing novel anti-osteosarcoma agents.
- Further investigation into compound 21 and NQO1-targeting agents is warranted for osteosarcoma treatment.
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