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Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models
Borja Gallego1,2,3, Dzohara Murillo1,2, Verónica Rey1,2,3
1Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n 33011 Oviedo, Spain.
Abstract:
Bone sarcomas have not shown a significant improvement in survival for decades, due, in part, to the development of resistance to current systemic treatments, such as doxorubicin. To better understand those mechanisms mediating drug-resistance we generated three osteosarcoma and one chondrosarcoma cell lines with a stable doxorubicin-resistant phenotype, both in vitro and in vivo. These resistant strains include a pioneer model generated from a patient-derived chondrosarcoma line. The resistant phenotype was characterized by a weaker induction of apoptosis and DNA damage after doxorubicin treatment and a lower migratory capability. In addition, all resistant lines expressed higher levels of ABC pumps; meanwhile, no clear trends were found in the expression of anti-apoptotic and stem cell-related factors. Remarkably, upon the induction of resistance, the proliferation potential was reduced in osteosarcoma lines but enhanced in the chondrosarcoma model. The exposure of resistant lines to other anti-tumor drugs revealed an increased response to cisplatin and/or methotrexate in some models. Finally, the ability to retain the resistant phenotype in vivo was confirmed in an osteosarcoma model. Altogether, this work evidenced the co-existence of common and case-dependent phenotypic traits and mechanisms associated with the development of resistance to doxorubicin in bone sarcomas.
Insights
This study developed doxorubicin-resistant bone sarcoma models to investigate drug resistance mechanisms. Resistant cells showed altered apoptosis, DNA damage, and ABC pump expression, impacting treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Bone sarcomas exhibit poor survival rates due to resistance to systemic therapies like doxorubicin.
- Understanding the mechanisms of drug resistance is crucial for improving treatment outcomes in bone sarcomas.
Purpose of the Study:
- To generate and characterize doxorubicin-resistant osteosarcoma and chondrosarcoma cell lines.
- To elucidate the molecular mechanisms underlying doxorubicin resistance in bone sarcomas.
- To assess cross-resistance and sensitivity to other chemotherapeutic agents.
Main Methods:
- Generation of stable doxorubicin-resistant cell lines (osteosarcoma and chondrosarcoma) in vitro and in vivo.
- Assessment of apoptosis, DNA damage, migratory capability, proliferation, and ABC transporter expression.
- Evaluation of drug response to cisplatin and methotrexate in resistant cell lines.
Main Results:
- Resistant cell lines exhibited reduced apoptosis and DNA damage, and lower migratory potential.
- Increased expression of ATP-binding cassette (ABC) pumps was observed in all resistant lines.
- Proliferation decreased in resistant osteosarcoma but increased in resistant chondrosarcoma.
- Some resistant models showed enhanced sensitivity to cisplatin and/or methotrexate.
Conclusions:
- Doxorubicin resistance in bone sarcomas involves common and specific mechanisms.
- The resistant phenotype is stable in vivo.
- Findings provide insights into therapeutic strategies for overcoming drug resistance in bone sarcomas.
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