Related Experiment Video
Updated: Jul 1, 2025
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
BRD4-targeting PROTACs Synergize With Chemotherapeutics Against Osteosarcoma Cell Lines
Clemens Lang1, Sandra Stickler2, Barbara Rath2
1Department of Trauma Surgery, Hospital Donaustadt, Vienna, Austria.
Background/Aim:
Osteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles. This work aimed to investigate the efficacy of BETi, such as JQ1, dBET57, and MZ1 PROTACs in combination with cytotoxic drugs against osteosarcoma cell lines.
Materials And Methods:
Chemosensitivity of the osteosarcoma cell lines HOS, Saos-2, MG-63, and G292 were tested with BET-directed agents alone or in combination with cytotoxic drugs comprising cisplatin, doxorubicin, topotecan, and gemcitabine using cell viability assays.
Results:
The BET degraders exhibited highest toxicity to HOS cells and showed synergistic activity in combination with the chemotherapeutics, except for the degrader - topotecan/gemcitabine combinations. Highest synergy between BET agents and chemotherapeutics were found for the more chemoresistant Saos-2 cells and potentiation of toxicity in MG-63 cells for the BET agents - doxorubicin combinations and the MZ1-topotecan pair. HOS and Saos-2 cell lines had reduced protein expression of AXL, BCL-X, e-cadherin, CAIX, EpCAM, ErbB2, and vimentin in response to JQ1, MZ1, and BET57.
Conclusion:
The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials.
Insights
Novel bromodomain inhibitors (BETi) PROTACs show synergistic effects with chemotherapy against osteosarcoma cells. This combination therapy, particularly with BET agents and doxorubicin, offers a promising new treatment strategy for advanced osteosarcoma.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Advanced osteosarcoma has a poor prognosis, necessitating novel targeted therapies, especially for metastatic disease.
- Bromodomain inhibitors (BETi) are epigenetic modulators with demonstrated antitumor effects.
- Proteolysis targeting chimeras (PROTACs) offer enhanced degradation of target proteins when combined with chemotherapeutics.
Purpose of the Study:
- To investigate the efficacy of BET inhibitors (BETi), including JQ1, dBET57, and MZ1 PROTACs, in combination with cytotoxic drugs against osteosarcoma cell lines.
- To evaluate the synergistic activity and toxicity of these combined treatments.
Main Methods:
- Chemosensitivity assays were performed on osteosarcoma cell lines (HOS, Saos-2, MG-63, G292).
- Cells were treated with BET-directed agents alone or in combination with cisplatin, doxorubicin, topotecan, and gemcitabine.
- Cell viability was assessed to determine drug efficacy and synergy.
Main Results:
- BET degraders showed significant toxicity, particularly in HOS cells.
- Synergistic activity was observed between BET agents and chemotherapeutics, especially in chemoresistant Saos-2 cells and MG-63 cells.
- Combinations of BET agents with doxorubicin and the MZ1-topotecan pair demonstrated potentiation of toxicity. Protein expression of AXL, BCL-X, and others was reduced by BET agents.
Conclusions:
- The combination of novel BET PROTACs with chemotherapeutics presents a potential new therapeutic strategy for osteosarcoma.
- This approach may improve treatment outcomes for osteosarcoma patients.
- The development of orally available PROTACs entering clinical trials supports this therapeutic avenue.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...