Biochemical mechanism of modulation of human P-glycoprotein by stemofoline.

Abstract

The resistance to chemotherapeutic drugs by cancer cells is considered to be one of the major obstacles for success in the treatment of cancer. A major mechanism underlying this multidrug resistance is the overexpression of P-glycoprotein (P-gp), resulting in insufficient drug delivery to the tumor sites. A previous study has shown that stemofoline, an alkaloid isolated from Stemona burkillii, could enhance the sensitivity of chemotherapeutics in a synergistic fashion. In the present study, we have focused on the effect of stemofoline on the modulation of P-gp function in a multidrug resistant human cervical carcinoma cell line (KB-V1). The effects of stemofoline on a radiolabeled drug, [(3)H]-vinblastine, and fluorescent P-gp substrates, rhodamine 123 and calcein-AM accumulation or retention were investigated to confirm this finding. Stemofoline could increase the accumulation or retention of radiolabeled drugs or fluorescent P-gp substrates in a dose-dependent manner. For additional studies on drug-P-gp binding, P-gp ATPase activity was stimulated by stemofoline in a concentration-dependent manner. More evidence was offered that stemofoline inhibits the effect on photoaffinity labeling of P-gp with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner. These data indicate that stemofoline may interact directly with P-gp and inhibit P-gp activity, whereas stemofoline has no effect on P-gp expression. Taken together, the results exhibit that stemofoline possesses an effective MDR modulator, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells.

• Authors: Wisinee Chanmahasathien, Shinobu Ohnuma, Suresh V Ambudkar, Pornngarm Limtrakul
• Journal: Planta medica (Planta Med) Vol. 77 Issue 18 Pg. 1990-5 (Dec 2011) ISSN: 1439-0221 [Electronic] Germany
• PMID: 21786221 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Azides
• Fluoresceins
• Fluorescent Dyes
• Heterocyclic Compounds, 4 or More Rings
• Photoaffinity Labels
• calcein AM
• Rhodamine 123
• stemofoline
• Vinblastine
• azidoprazosin
• Adenosine Triphosphatases
• Prazosin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (chemistry, drug effects)
• Adenosine Triphosphatases (chemistry)
• Animals
• Antineoplastic Agents (pharmacology)
• Azides (pharmacology)
• Binding Sites
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Flow Cytometry
• Fluoresceins (chemistry)
• Fluorescent Dyes (chemistry)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Insecta (chemistry)
• Membranes (drug effects)
• Photoaffinity Labels (chemistry)
• Plant Roots (chemistry)
• Prazosin (analogs & derivatives, pharmacology)
• Protein Binding
• Rhodamine 123 (chemistry)
• Stemonaceae (chemistry)
• Vinblastine (pharmacology)