title: Sorafenib/regorafenib and phosphatidyl inositol 3 kinase/thymoma viral proto-oncogene inhibition interact to kill tumor cells.
abstract: The present studies were undertaken to determine whether the multikinase inhibitors sorafenib/regorafenib cooperated with clinically relevant , phosphatidyl inositol 3 kinase (PI3K)-thymoma viral proto-oncogene (AKT) inhibitors to kill tumor cells. In liver, colorectal, lung, breast, kidney, and brain cancer cells, at clinically achievable doses, sorafenib/regorafenib and the PI3K inhibitor acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester (PX-866) cooperated in a greater than additive fashion to kill tumor cells. Cells lacking phosphatase and tensin homolog were as sensitive to the drug combination as cells expressing the protein. Similar data were obtained using the AKT inhibitors perifosine and 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f] [1,6]naphthyridin-3(2H)-one hydrochloride (MK2206). PX-866 treatment abolished AKT/glycogen synthase kinase 3 (GSK3) phosphorylation, and cell killing correlated with reduced activity of AKT and mammalian target of rapamycin (mTOR). Expression of activated AKT and to a lesser extent activated mTOR reduced drug combination lethality. Expression of B-cell lymphoma-extra large or dominant negative caspase 9, but not cellular FLICE (FADD-like IL-1b-converting enzyme)-inhibitory protein short, protected cells from the drug combination. Treatment of cells with PX-866 increased protein levels of p62, lysosome-associated membrane protein 2 (LAMP2), and microtubule-associated protein light chain (LC) 3 and LC3II that correlated with a large increase in LC3-green fluorescent protein (GFP) vesicle numbers. Exposure of PX-866 treated cells to sorafenib reduced p62 and LAMP2 levels, decreased the ratio of LC3 to LC3II, and reduced LC3-GFP vesicle levels. Knockdown of Beclin1 or autophagy-related 5 suppressed drug toxicity by ∼40%. In vivo, sorafenib and PX-866 or regorafenib and MK2206 cooperated to suppress the growth of established HuH7 and HCT116 tumors, respectively. Collectively our data demonstrate that the combination of sorafenib family kinase inhibitors with inhibitors of the PI3K/AKT pathway kills tumor cells in vitro and in vivo.
authors.affiliation: Departments of Neurosurgery (G.B.S., H.A.H., N.C., L.B., S.T., J.S., P.D.) and Medicine (S.G., A.P.), Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Gangadharan B
authors.initials: GB
authors.lastname: Sajithlal
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.forename: Seyedmehrad
authors.initials: S
authors.lastname: Tavallai
authors.forename: Jahangir
authors.initials: J
authors.lastname: Syed
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006067:Gonanes / Q000008:administration & dosage; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib; D013945:Thymoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D013953:Thymus Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D006067:Gonanes; D009536:Niacinamide; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D000077157:Sorafenib; C000715470:MAS1 protein, human; C496788:PX-866; C559147:regorafenib