title: The glucosylceramide synthase inhibitor PDMP sensitizes pancreatic cancer cells to MEK/ERK inhibitor AZD-6244.
abstract: Here we show that d,l-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a glycosphingolipid biosynthesis inhibitor, increases the sensitivity of pancreatic cancer cells to the novel MEK-ERK inhibitor AZD-6244. AZD-6244 and PDMP co-administration induced massive pancreatic cancer cell death and apoptosis, more potently than either drug alone. We discovered that AZD-6244 induced ceramide production in pancreatic cancer cells, yet the excess ceramide was metabolically removed in the long-term (24-48h). PDMP facilitated AZD-6244-induced ceramide production, and ceramide level remained elevated up to 48h. Meanwhile, exogenously-added cell-permeable short chain ceramide (C2) similarly sensitized AZD-6244's activity, the two caused substantial pancreatic cancer cell death and apoptosis. At the molecular level, PDMP and AZD-6244 co-treatment inactivated ERK1/2 and AKT-mTOR signalings simultaneously in pancreatic cancer cells, while either agent alone only affected one signaling. In summary, PDMP significantly increased the sensitivity of AZD-6244 in pancreatic cancer cells. This appears to involve a sustained ceramide production as well as concurrent block of ERK and AKT-mTOR signalings.
authors.affiliation: Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Ma
authors.affiliation: Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China. Electronic address: huipingpingtr9@163.com.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Hui
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D002518:Ceramides; D004791:Enzyme Inhibitors; D009025:Morpholines; D047428:Protein Kinase Inhibitors; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
keywords: AZD-6244; Ceramide; Chemo-sensitization; PDMP; Pancreatic cancer