Abstract
Multidrug resistance (MDR) is a major obstacle to effective cancer therapy. The membrane transporter MDR-1 (P-gp, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, effluxes anti-cancer drugs from cancer cells. Increased activity of MDR-1 is known to be the main mechanism for multidrug resistance. MDR-1 is known to be localized in the cholesterol- and sphingolipid-enriched plasma membrane microdomains, known as lipid rafts. Disruption of lipid rafts by cholesterol depletion alters lipid raft functions, indicating that cholesterol is critical for raft function. Because ginsenosides are structurally similar to cholesterol, in this study, we investigated the effect of Rp1, a novel ginsenoside derivative, on drug resistance using drug-sensitive OVCAR-8 and drug-resistant NCI/ADR-RES and DXR cells. Rp1 treatment resulted in an accumulation of doxorubicin or rhodamine 123 by decreasing MDR-1 activity in doxorubicin-resistant cells. Rp1 synergistically induced cell death with actinomycin D in DXR cells. Rp1 appeared to redistribute lipid rafts and MDR-1 protein. Moreover, Rp1 reversed resistance to actinomycin D by decreasing MDR-1 protein levels and Src phosphorylation with modulation of lipid rafts. Addition of cholesterol attenuated Rp1-induced raft aggregation and MDR-1 redistribution. Rp1 and actinomycin D reduced Src activity, and overexpression of active Src decreased the synergistic effect of Rp1 with actinomycin D. Rp1-induced drug sensitization was also observed with several anti-cancer drugs, including doxorubicin. These data suggest that lipid raft-modulating agents can be used to inhibit MDR-1 activity and thus overcome drug resistance.
Original language | English |
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Pages (from-to) | 1441-1453 |
Number of pages | 13 |
Journal | Biochemical Pharmacology |
Volume | 85 |
Issue number | 10 |
DOIs | |
State | Published - 15 May 2013 |
Keywords
- Actinomycin D
- Ginsenosides
- Lipid rafts
- MDR-1
- Src