Targeting Cancer Cells With the Natural Compound Obtusaquinone

Cancer therapeutics are becoming increasingly effective in controlling tumor growth and progression, yet the chief challenge remains to selectively kill tumor cells while having little or no toxicity on their normal counterparts. In that context, compounds that target cancer-related genetic alterations offer a great alternative; however, due to the heterogeneity of tumors, these drugs are often limited to a selective group of patients and tumors can often circumvent their efficiency and become resistant (1). Another therapeutic approach consists of exploiting the biochemical changes in cancer. Tumor cells present particularly high levels of oxidative stress (2). This is generally caused by an increase in reactive oxygen species (ROS) production or a decrease in intracellular ROS scavengers (3). A marked increase in ROS is believed to promote cell survival and confer resistance to therapy (4). Given this different redox state between normal and tumor cells, it is believed that the latter has a greater reliance on their ROS-scavenging capacities. Thus, further increase in oxidative stress can overwhelm this stress response in tumor cells, leading to cell death. Through small molecule drug screening assay based on the secreted Gaussia luciferase bioluminescent reporter as a cell viability readout (5), we identified a natural compound, obtusaquinone (OBT) that exhibited substantial toxicity toward different glioblastoma (GBM) cell lines and primary cells as well as toward twelve different cancer cell lines. OBT is a quinone methide extracted from the heartwood of Dalbergia retusa (cocobolo) (6). This compound has been shown to present antifungal properties (7). Here we describe the antineoplastic activity of OBT and its selective killing of tumor cells through an ROS-dependent mechanism.