Abstract
Neuroblastoma (NB) is the most common childhood cancer arising from the nervous system. Many high-risk neuroblastoma (HRNB) patients develop relapse after initial response to induction treatment and overall long term survival remains poor (less than 60%), emphasizing the need for new therapeutic approaches and more effective treatments. Combination therapies present a favorable approach to improve efficacy, decrease toxicity, and reduce development of drug resistance. Difluoromethylornithine (DFMO) has shown promise in recent clinical trials as a therapeutic agent in treating HRNB. Proteasomes are known to play an important role in tumor cell growth. Bortezomib was the first proteasome inhibitor shown to have anticancer activity clinically. In this study we explore the mechanistic and therapeutic effects of the novel drug combination of DFMO and bortezomib in NB. Cell proliferation studies demonstrated synergistic inhibition of NB cell growth. Bortezomib induced cleaved caspase-3 apoptotic pathway whereas DFMO induced a cytostatic effect on NB cells. Western blot analyses demonstrated down regulation of MYCN, LIN28 and NF-kB in response to DFMO and bortezomib, pathways that are important in cancer stem cells. A decrease in ATP-per-cell when treated with combination therapy suggests inhibition of glycolytic metabolism in NB cells. DFMO as a single agent or in combination with bortezomib significantly reduced tumor growth in xenograft mice. Given the lack of effective treatments, DFMO coupled with bortezomib offers a potential new therapeutic treatment for children with NB.
Highlights
The most common extracranial solid pediatric tumor, neuroblastoma (NB), is a heterogeneous malignancy that develops throughout the sympathetic nervous system from neural crest stem cells, often in the adrenal glands [1]
Western blot analyses demonstrated down regulation of MYCN, LIN28 and NF-kB in response to DFMO and bortezomib, pathways that are important in cancer stem cells
Results of this study revealed that synergistic effect of DFMO and bortezomib was observed in cells overexpressing LIN28 and MYCN but not in cells with low LIN28 expression
Summary
The most common extracranial solid pediatric tumor, neuroblastoma (NB), is a heterogeneous malignancy that develops throughout the sympathetic nervous system from neural crest stem cells, often in the adrenal glands [1]. High incidence of metastatic disease and relapse in high-risk NB is hypothesized to be due to the presence of cancer stem cells (CSCs) that have capacity to self-renew and initiate new tumor formation [6] [7] [8]. New studies have shown that LIN28 has profound effects on normal and malignant stem cells through the posttranscriptional downregulation of the microRNA Let-7 via a double negative feedback loop [13] [14]. Due to the important role of the LIN28/Let-7 axis in glycolytic metabolism as well as the importance of glycolytic metabolic activity for the assembly of ATP in CSCs, manipulating the LIN28 and Let-7 pathway in cancer cells may provide novel therapeutic opportunities in cancer
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