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suppl 3

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Journal Article




A great deal of mental stress, depression, and anxiety often overwhelm cancer patients; those diagnosed with glioblastoma multiforme (GBM) are no exception. Different types of stress invariably impact what has been termed “the brain-adipocyte BDNF/leptin axis” (Dr. Cao and colleagues of the Comprehensive Cancer Center at The Ohio State University). For example, eustress (good stress) and distress (bad stress) both lead to increased sympathetic activity and adrenal gland stimulation, yet eustress reduces leptin levels and attenuates tumor growth while distress increases leptin levels and augments tumor growth. Complicating matters in GBM is that leptin and its receptor are expressed at much higher levels than in normal glial cells and provides a potential autocrine signaling pathway. In this study, we confirm that 200 ng/mL of leptin-conditioned media increases cell proliferation of the established GBM cell line T98G. We hypothesized that elevated sympathoadrenal activity would increase cell proliferation and be additive to leptin's effects. To the contrary, adding 300 pg/mL of epinephrine to leptin-conditioned media blocked leptin-mediated proliferation. Because beta3-adrenergic receptor stimulation suppresses leptin gene expression and release in adipocytes, we hypothesized that a beta3-adrenergic agonist would counteract leptin's effects on T98G cell proliferation. Use of the beta3-adrenergic agonist BRL 37344 did not only counteract leptin's effects but also significantly reduced T98G cell proliferation in unconditioned media. This has immediate translational value in that treating GBM with a beta3-adrenergic agonist may reduce tumor proliferation through receptor activation and by blocking the leptin-leptin receptor autocrine loop. Moreover, recent reports indicate that beta3-adrenergic agonists capable of crossing the blood-brain barrier (like SR 58611A) may be beneficial for anxiety and depression, further improving the quality of life for brain tumor patients.