Abstract
Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation.
Highlights
Osteosarcoma (OS) is the most common malignant tumor of bone, which accounts for about 5% of childhood and adolescence neoplasms
Our study focused on a group of DNA repair genes and kinases, which we found to be upregulated in our panel of CDDP-resistant human OS cell lines, in order to verify whether they could be considered as new candidate therapeutic targets
In high-grade OS, when patients fail to respond to first-line treatment and relapse, therapeutic options and drugs effective for rescue chemotherapy protocols are scarce, because resistance mechanisms developed against first-line chemotherapeutic drugs can be responsible for reduced responsiveness to the agents used in the subsequent regimens
Summary
Osteosarcoma (OS) is the most common malignant tumor of bone, which accounts for about 5% of childhood and adolescence neoplasms. High-grade OS is usually treated with neoadjuvant chemotherapy protocols based on cisplatin (CDDP), doxorubicin, methotrexate, and ifosfamide. Despite this aggressive approach, 35–45% of patients still recur and experience an unfavorable outcome [1,2,3,4,5]. Three out of the four conventional drugs, which are most commonly used in first-line chemotherapy for high-grade OS, induce DNA damages either directly (CDDP and ifosfamide) or indirectly (doxorubicin). Resistance mechanisms related to DNA damage response can significantly impact on OS chemotherapy unresponsiveness. Among these drugs, CDDP is the agent which has most extensively been studied in relation to DNA repair. A consistent body of evidence is showing that the onset of clinical unresponsiveness to CDDP usually creates further therapeutic complications, because patients can become cross-resistant to the other DNA damaging chemotherapeutic drugs used in first- or rescue treatment protocols [4, 6]
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