title: Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function.
abstract: Inhibition of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an appealing method for decreasing the immunoresistance and augmenting T cell-mediated immunotherapy. A major impediment to this strategy is the impact of conventional PI3K/mTOR pathway inhibitors on T cell function. In particular, rapamycin, is a well-known immunosuppressant that can decrease the activity of the PI3K/mTOR pathway in tumor cells, but also has a profound inhibitory effect on T cells. Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. Specifically, we show that at doses sufficient to down-regulate levels of phospho-S6 and the negative immune regulator B7-H1 in tumor cells, Honokiol does not significantly impair T cell proliferation or proinflammatory cytokine production. In contrast to classic inhibitors, including LY294002, wortmannin, AKT inhibitor III and rapamycin, Honokiol specifically decreases the PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells. Collectively, our data define a unique application for Honokiol and provide the impetus to more fully elucidate the mechanism by which T cells are resistant to the effects of this particular inhibitor. Honokiol is clinically available for human testing and may serve to augment T cell-mediated cancer immunotherapy.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Crane
authors.forename: Amith
authors.initials: A
authors.lastname: Panner
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000628:therapy; D002277:Carcinoma / Q000276:immunology* / Q000628:therapy; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005910:Glioma / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000730:Androstadienes; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D002867:Chromones; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D020381:Interleukin-17; D017705:Lignans; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human