Synergistic oncolytic effects of temozolomide and oncomagnetic therapies in glioblastoma

Abstract The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) and other cancer cells while sparing normal developing neurons and astrocytes in vitro. We have reported that brief 2 – 6 h of daily Oncomagnetic brain stimulation causes >30% reduction of contrast-enhanced tumor (CET) volume in an end-stage recurrent GBM patient after a ~30-day treatment. We have evidence that the spinning oscillating magnetic fields (sOMF) generated by this device disrupts electron transport in the mitochondrial respiratory chain, at least in part by inhibiting the activity of Complex II succinate dehydrogenase, leading to a marked increase in reactive oxygen species (ROS) and consequent cancer cell death. Here, we further studied the cellular effects of sOMF treatment alone and in combination with Temozolomide (TMZ) on GBM cell lines with other methods and investigated the response to Oncomagnetic monotherapy (OMT) in a mouse GBM model. We treated LN229 and U87 GBM cells with sOMF with and without a sub-therapeutic dose of TMZ. To study the anticancer effect of sOMF in vivo, we developed syngeneic GBM tumors in BALB/c mice by stereotactic intracranial injection of GL261WT cells. Our results show that cytotoxic effects of sOMF or TMZ alone, as measured by the MTT assay and reduced cell survival, are significantly potentiated by combining the two treatments. OMT of tumor-bearing mice using a whole-body sOMF stimulation method causes substantial retardation of tumor growth and reduction of the CET volume in 9.4 T MRI scans. To study the molecular pathways involved in the treatment response we are mapping alterations in various key biomarkers in treated tumor tissues and comparing them with those in untreated controls. These experiments will unravel the molecular mechanism of action underlying the response to OMT in GBM and help develop a sound rationale for an effective therapeutic protocol.