Abstract
The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. In some cell lines, such as SF-295 glioma cells, schweinfurthins elicit cytotoxicity at nanomolar concentrations. However, other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations. At this time, the precise mechanism of action and target for these compounds is unknown. Here, we employ RNA sequencing of cells treated with 50 nM schweinfurthin analog TTI-3066 for 6 and 24 h to elucidate potential mechanisms and pathways which may contribute to schweinfurthin sensitivity and resistance. The data was analyzed via an interaction model to observe differential behaviors between sensitive SF-295 and resistant A549 cell lines. We show that metabolic and stress-response pathways were differentially regulated in the sensitive SF-295 cell line as compared with the resistant A549 cell line. In contrast, A549 cell had significant alterations in response genes involved in translation and protein metabolism. Overall, there was a significant interaction effect for translational proteins, RNA metabolism, protein metabolism, and metabolic genes. Members of the Hedgehog pathway were differentially regulated in the resistant A549 cell line at both early and late time points, suggesting a potential mechanism of resistance. Indeed, when cotreated with the Smoothened inhibitor cyclopamine, A549 cells became more sensitive to schweinfurthin treatment. This study therefore identifies a key interplay with the Hedgehog pathway that modulates sensitivity to the schweinfurthin class of compounds.
Highlights
The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo
National Cancer Institute (NCI)-60 sensitivity data are available for cell lines treated with methyl-schweinfurthin G (MG) (Fig. 1A), where sensitivity is described as the half maximal growth inhibitory 50 concentration (GI50) (Fig. 2A)
The data are presented as Δlog GI50, which is calculated as the difference between the mean log GI50, − 6.745, and the log GI50 for each cell line
Summary
The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. Other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations At this time, the precise mechanism of action and target for these compounds is unknown. Some cell lines are insensitive to schweinfurthins even at high (micromolar) concentrations, whereas others experience profound cytotoxicity at low nanomolar concentrations[2] This highly differential activity suggests that schweinfurthins may exploit certain sensitivities to elicit cell death in cancer cells, while sparing other cells, possibly including normal tissue. The mechanism of action by which schweinfurthins elicit cytotoxicity is poorly understood, and a molecular target has not yet been identified Far, these compounds have been implicated in: oxysterol binding protein activity, lipid profiles, disruption of the Golgi and endoplasmic reticulum, and cholesterol trafficking, among other p rocesses[2,13,14,15,16,17,18]. The consensus of the data is that lipid membrane structures may be compromised by schweinfurthin treatment, though the cause of this is not yet clear
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