Overcoming Chemoresistance in Neuroblastoma Cells




Panchoo, Marlyn
Sabnis, Nirupama


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Background: The development of multi-drug resistance (MDR) in tumor cells continues to be a major challenge to effective cancer therapeutics. Regarding neuroblastoma (NB), a large proportion of the cases (~40%), designated as high risk NB (HRNB), present with a poor prognosis, with death occurring within 2-3 years of diagnosis. Most of these HRNB tumors become resistant and thus unresponsive during extended treatment, leading to the exceedingly poor prognosis. MDR is often due to the efflux (pumping out) of the drugs from the malignant cells via the ATP Binding Cassette (ABC) transporters. Hypothesis: The design of this study is based on the concept that the incorporation of the drug doxorubicin (Dox) into reconstituted high density lipoprotein (rHDL) nanoparticles will overcome MDR during treatment. This hypothesis also proposes a mechanism where delivery of Dox via the scavenger receptor type B1 (SR-B1), directly into the cytosol, will allow the drug to bypass the membrane MDR efflux pump and thus limit or eliminate drug resistance. Methods and Results: Drug resistance was induced in SMS-KCNR neuroblastoma cells by incubating the cells with 50 ng/ml of interleukin-6 (IL- 6) for five days. The IL-6 treated cells showed a 5 fold increase in resistance compared to the untreated cells. To evaluate the Dox encapsulated in rHDL (rHDL-Dox nanoparticles) for its ability to overcome MDR, the cytotoxicity of the free Dox vs. the encapsulated Dox was compared against resistant cells. The results showed that the rHDL-Dox formulation was more effective in killing the drug resistant cells than the free Dox (IC50 = 0.08 µg/ml vs. 0.52 µg/ml). These findings show that the rHDL-Dox formulation is indeed effective in limiting drug resistance. Conclusion: We anticipate that the increased sensitivity of MDR cells to rHDL-Dox nanoparticles, shown by these studies, could be extended to other drugs. Consequently, we also anticipate that these rHDL nanoparticle formulations could provide a safe and effective treatment for HRNB patients that otherwise would be resistant to therapy. Future plans will include screening of drug resistant NB cells for the expression of the SR-B1 receptor, monitoring of downstream events such as apoptosis, cell migration, and localization of the drug to document cytosolic delivery, in addition to studies with tumor carrying mice.