Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models.
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| 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.
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| Authors | Borja Gallego, Dzohara Murillo, Verónica Rey, Carmen Huergo, Óscar Estupiñán, Aida Rodríguez, Juan Tornín, René Rodríguez |
| Journal | International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 12 (Jun 08 2022) ISSN: 1422-0067 [Electronic] Switzerland |
| PMID | 35742867 (Publication Type: Journal Article) |
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