A new Mixed-Backbone Oligonucleotide Against Glucosylceramide Synthase Sensitizes Multidrug-Resistant Tumors to Apoptosis
National Institutes of Health, Department of Defense Breast Cancer Research Program, United States Public Health Service/NIGMS, Louisiana Board of Regents
P20 RR16456,GM77391 (M.C.C), CA088932 (B.O), CA097132 (B.O.), LEQSF RD-A-19 (Q.Z.) DE016572 (B.O.),
Department of Biology
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 C18-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.
Patwardhan, G.. A.; Zhang, Qian-Jin; Yin, D.; Gupta, V.; Senkal, S. E.; Ogretmen, B.; Cabot, M. C.; Shah, G. V.; sylvester, P. W.; Jazwinski, S. M.; and Liu, Y. Y., "A new Mixed-Backbone Oligonucleotide Against Glucosylceramide Synthase Sensitizes Multidrug-Resistant Tumors to Apoptosis" (2009). Faculty and Staff Publications. 171.