Replies to post #5803 on Therapeutic Solutions International Inc (TSOI)

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INTRODUCTION

The dismal outcome for glioblastoma (GBM) patients with current therapies [1] strongly motivates the exploration for new therapeutic approaches

Pterostilbene (trans-3, 5-dimethoxy-4'-hydroxystilbene) is chemically classified as a stilbenoid and biologically as a phytoalexin (a class of low molecular weight compounds synthesized by plants as part of their antimicrobial defense). It is considered a safe compound with no reported toxicities, and is found naturally in berries.

A recent large scale screen detected that pterostilbene might functionally interact with other compounds to suppress growth in GBM [4]. Two such tentative interacting partners were the serotonin reuptake inhibitor (SSRI) sertraline and the EGFR tyrosine kinase inhibitor gefitinib. Sertraline, while not intended as a cancer drug, effectively passes the blood brain barrier; it has been reported to have activity against GBM cells [7, 22], and is being considered for clinical evaluation in GBM patients [23]. The target of gefitinib, EGFR, is frequently altered in GBM, by point mutation, chromosomal aberration, or both [24, 25]. However, clinical trials of gefitinib have not shown a significant increase in GBM patient survival [26]. It is therefore interesting to consider pterostilbene as a possible modulator of clinical response to both sertraline and gefitinib.

We analyzed the effect of pterostilbene as a potentiating compound across a panel of glioblastoma cell (GC) cultures [7, 27, 28] established from patient surgical samples. By sampling GCs from several patients, we could assess variations in the level of functional interaction between pterostilbene, gefitinib and sertraline across a large and diverse sample of patient-derived cell cultures. Further, we explored how pterostilbene, singly or in combination, suppressed malignant phenotypes in GCs, such as migration and proliferation, and investigated the mechanism by which pterostilbene modulates sertraline and gefitinib. The results identify pterostilbene as a potentiator of two drugs with anti-GBM activity with possible implications for other malignancies.