This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), doxorubicin (Doxo) and bortezomib showed no antagonism. Our study highlights the potential role of the tumour microenvironment in modulating the activity of this drug class.
Summary Jasmonates, plant stress hormones, have been demonstrated to be effective in killing various types of cancer cells. We therefore tested if methyljasmonate ( MJ ) has activity against multiple myeloma ( MM ) in vitro and in vivo . MM cell lines and primary MM tumour cells responded to MJ in vitro at concentrations that did not significantly affect normal haematopoietic cells, without stroma‐mediated resistance. Brief MJ exposures of MM cells caused release of H exokinase 2 ( HK 2) from mitochondria, rapid ATP depletion, perturbation of major intracellular signalling pathways, and ensuing mainly apoptotic cell death. Sensitivity to MJ correlated with lower cellular glucose consumption and lactate production, as well as lower intracellular protein levels of HK 2, phosphorylated V oltage‐dependent anion channel 2/3 (p VDAC 2/3) and A ldo‐keto reductase family 1 member C 1 ( AKR 1 C 1), which represent potential biomarkers of responsiveness to MJ treatment, especially as AKR 1 C 1 transcript levels also correlate with clinical outcome in bortezomib‐ or dexamethasone‐treated MM patients. Interestingly, MJ synergized with bortezomib in vitro and prolonged survival of immunocompromised mice harbouring diffuse lesions of MM .1 S cells compared to vehicle‐treated mice ( P = 0·0046). These studies indicate that jasmonates represent a new, promising strategy to treat MM .
