Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n 33011 Oviedo, Spain.
Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain.
Int J Mol Sci. 2022 Jun 8;23(12):6425. doi: 10.3390/ijms23126425.
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.
几十年来，骨肉瘤的存活率并没有显著提高，部分原因是对当前系统治疗方法（如多柔比星）产生了耐药性。为了更好地了解介导耐药性的机制，我们生成了三株骨肉瘤和一株软骨肉瘤细胞系，具有稳定的多柔比星耐药表型，无论是在体外还是体内。这些耐药株包括从患者来源的软骨肉瘤系生成的先驱模型。耐药表型的特征是多柔比星处理后凋亡和 DNA 损伤的诱导较弱，迁移能力较低。此外，所有耐药系均表达更高水平的 ABC 泵；同时，在抗凋亡和干细胞相关因子的表达中没有发现明显的趋势。值得注意的是，在诱导耐药性后，骨肉瘤系的增殖潜力降低，但软骨肉瘤模型中的增殖潜力增强。耐药系对其他抗肿瘤药物的暴露显示，在某些模型中对顺铂和/或甲氨蝶呤的反应增加。最后，在骨肉瘤模型中证实了耐药表型在体内的保留能力。总之，这项工作证明了与骨肉瘤中多柔比星耐药性发展相关的常见和特定病例表型特征和机制的共存。
