Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells

SIMPLE SUMMARY: Osteosarcoma represents the most common bone tumor, and it is the second most fatal cancer in children and young adults. However, despite the clinical benefit of chemotherapy, osteosarcoma patients still have a poor prognosis due to the common onset of drug resistance, as well as the disease’s growth and metastasis frequency. Thus, understanding the processes underlying the phenomenon of resistance represents a challenge in the field of oncology and may lead to new approaches to overcome resistance. This study highlights a different mitochondrial phenotype in doxorubicin-resistant cancer cells and suggests targeting the altered pathway to re-sensitize the resistant clones to the drug. Taken together, these results contribute to identifying the mitochondrial metabolism changes and to developing combined approaches with the final goal of overcoming doxorubicin resistance in osteosarcoma. ABSTRACT: Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects.