Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi)

Abstract

For reversal of MDR1 gene-dependent multidrug resistance (MDR), two small interfering RNA (siRNA) constructs were designed to inhibit MDR1 expression by RNA interference. SiRNA duplexes were used to treat human pancreatic carcinoma (EPP85-181RDB) and gastric carcinoma (EPG85-257RDB) cells. In both cellular systems, siRNAs could speci¢-cally inhibit MDR1 expression up to 91% at the mRNA and protein levels. Resistance against daunorubicin was decreased to 89% (EPP85-181RDB) or 58% (EPG85-257RDB). The data indicate that this approach may be applicable to cancer patients as a speci¢c means to reverse tumors with a P-glycoproteindependent MDR phenotype back to a drug-sensitive one. ß

Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells

“…12 Finally, the successful use of small interfering RNAs (siRNAs) to downregulate gene expression in several model systems [13][14][15][16][17][18] has led to many attempts to explore this methodology in potentially therapeutic settings. 19,20 Along this line, several recent studies have documented: (a) successful downregulation of BCR-ABL expression, resulting in increased apoptosis and decreased proliferation, in chronic myeloid leukemia cells; 21,22 (b) the MDR1 downregulation followed by chemosensitization of human pancreatic and gastric cell lines; 23 (c) combined inhibition of Bcl-2 and Raf-1 in human myeloid leukemia cells resulting in induction of apoptosis and chemosensitization. 24 Bearing in mind that RNAi is feasible in MCF-7 cell line [25][26][27] and that these cells are known to be relatively resistant to etoposide and doxorubicin, 28,29 the purpose of this study was to investigate if specific downregulation of bcl-2 or xIAP gene expression by RNAi sensitized MCF-7 cells to those chemotherapeutic drugs.…”

Using attenuated salmonella typhi as tumor targeting vector for MDR1 siRNA delivery: An experimental study

“…21,22 In some recent studies, RNA interference was used to suppress P-gp expression by tumor cells, effectively reversing multidrug-resistance in an array of tumor cells. [10][11][12] RNA interference technology is more efficient and specific than antisense nucleic acids; hence, it shows bright promise for clinical application. However, it is imperative to increase the in vivo transfer efficiency and targeting of siRNA before RNA interference can become a viable clinical alternative, a problem common to Salmonella typhi is an intracellular parasitic bacterium that mainly invades mucosa-associated lymphoid tissue (MALT) through M cells in the intestinal mucosa and is phagocytized by macrophages and dendritic cells, in which the bacteria can proliferate.…”

“…8,9 An array of research has confirmed that MDR1 siRNA can effectively suppress P-gp expression and reverse multidrug-resistance of tumor cells. [10][11][12] However, there are still many obstacles to the in vivo application of siRNA, thus it is imperative to increase the in vivo transfer efficiency and targeting of siRNA. Based on a study of targeted infection of tumor cells with attenuated Salmonella typhi, 13 we have established a cisplatin-resistant human tongue squamous cell cancer cell line and associated tumor-bearing nude mouse model and then investigated the feasibility of using attenuated Salmonella typhi as an in vivo delivery vector of MDR1 siRNA.…”

Non-Coding RNAs: A Dynamic and Complex Network of Gene Regulation

“…Endogenous cellular microRNAs that target viral RNAs have been reported as well. The siRNAs have been used to decrease the drug resistance of cells in vitro by inhibiting the repression of MDR1, a multidrug resistance complex [154]. The drawbacks of siRNA include off-target effects, elicitation of the interferonresponse and their interference with microRNA biogenesis, hampering its use as a therapeutic.…”