Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide. Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma. 1. Introduction Drug resistance poses a major obstacle in the treatment of human cancers. Several mechanisms responsible for resistance to chemotherapy have previously been described. Drug-resistant cells may express one or more energy-dependent transporters like the multidrug resistance gene (mdr1) which detect and eject anticancer drugs from cells [1, 2]. Mechanisms including secondary mutations in drug targets or parallel pathways, insensitivity to drug-induced apoptosis [3, 4], and induction of drug-detoxifying proteins also play a role in acquired multidrug resistance (MDR). Numerous attempts have been made to target these pathways and reverse drug resistance. Although some attempts were successful in vitro, these strategies were not successfully implemented in vivo [5]. These data suggest there are additional, perhaps unknown mechanisms, which need to be identified and targeted for successful reversal or prevention of drug resistance. Our laboratory has hypothesized a cytoprotective relationship between drug-resistant and drug-sensitive cells within drug-resistant tumors. We
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