Co-suppression of MDR1 (multidrug resistance 1) and GCS (glucosylceramide synthase) restores sensitivity to multidrug resistance breast cancer cells by RNA interference (RNAi)

Abstract

Multidrug resistance (MDR) to chemotherapeutic agents is a major obstacle to successful treatment in patients with breast cancer. Besides overexpression of MDR1, the member of the ABC transporter family, glucosylceramide synthase (GCS) which allows cellular escape from ceramide-induced cellular apoptosis by mediating ceramide glycosylation was considered to be related with multidrug resistance (MDR) in breast cancer. To specifically and efficiently reverse MDR of breast carcinoma cells, two small interference RNA (siRNA) targeted multidrug resistance 1 (MDR1) and GCS mediated by plasmids were constructed and co-transfected into the MDR breast cancer cell line MCF-7/ADM. The results showed that both transient transfection and stable transfection of the two siRNA-expression plasmids could greatly decrease the relative expression of GCS mRNA and MDR1 mRNA, significantly lower than the controls (p < 0.01). Evaluation of chemosensitivity displayed a 96-fold reduction in drug resistance for Adriamycin. And the reversing effects could keep for a long period (at least 3 w). Our results demonstrated that co-inhibition of MDR1 and GCS could more effectively reverse MDR in drug resistant breast carcinoma cells in vitro.