Neuroblastoma, a
malignancy of neuroectoderrmal origin, accounts for 15% of childhood
cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric
cancers to treat. A major obstacle in the effective treatment of
neuroblastoma is the development of multidrug resistance (MDR). There is thus a compelling demand for new treatment strategies for this
cancer that can bypass such resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various
cancer cell lines, ex vivo patient samples and in vivo
cancer models. In this study we examined the ability of two members,
PBOX-6 and -15, to exhibit anti-
cancer effects in a panel of
drug sensitive and MDR
neuroblastoma cell lines. The PBOX compounds potently reduced the viability of all
neuroblastoma cells examined and exhibited a lower fold resistance in MDR cells when compared to standard chemotherapeutics. In addition, the PBOX compounds synergistically enhanced apoptosis induced by
etoposide,
carboplatin and
doxorubicin. Exposure of
drug sensitive and resistant cell lines to PBOX-6/
carboplatin induced cleavage of Bcl-2, a downregulation of Mcl-1 and a concomitant increase in Bak. Furthermore, activation of
caspase-3, -8 and -9 was demonstrated. Finally, gene silencing of Mcl-1 by
siRNA was shown to sensitise both
drug sensitive and multidrug resistant cells to
carboplatin-induced apoptosis demonstrating the importance of Mcl-1 downregulation in the apoptotic pathway mediated by the PBOX compounds in
neuroblastoma. In conclusion, our findings indicate the potential of the PBOX compounds in enhancing chemosensitivity in
neuroblastoma.