title: A new mixed-backbone oligonucleotide against glucosylceramide synthase sensitizes multidrug-resistant tumors to apoptosis.
abstract: Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C(18)-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent.
authors.affiliation: Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, Louisiana, United States of America.
authors.forename: Gauri A
authors.initials: GA
authors.lastname: Patwardhan
authors.forename: Qian-Jin
authors.initials: QJ
authors.lastname: Zhang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yin
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Bao
authors.forename: Can E
authors.initials: CE
authors.lastname: Senkal
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
authors.forename: Girish V
authors.initials: GV
authors.lastname: Shah
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
authors.forename: Yong-Yu
authors.initials: YY
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000494:pharmacology*
chemical_list: D009841:Oligonucleotides; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase