Differential interactions of cytochalasins with P-glycoprotein.

Abstract

Cytochalasins are a family of structurally related natural product cytotoxins that selectively depolymerize microfilaments. In this study, the interaction between several cytochalasins and the drug transporter P-glycoprotein was investigated. Dihydrocytochalasin B and cytochalasin E consistently sensitized P-glycoprotein-overexpressing human breast carcinoma cells (MCF-7/ADR) to daunomycin, vinblastine, and actinomycin D without affecting the cytotoxicity of cisplatin. These compounds did not affect the sensitivities of the parental MCF-7 cells to anticancer drugs, indicating that their effects are due to P-glycoprotein inhibition. Effects of dihydrocytochalasin B and cytochalasin E were observed at concentrations as low as 2.5 and 5 microM, respectively. In contrast, cytochalasins A, B, C, D, H, and J did not sensitize MCF-7/ADR cells to any of the drugs. The accumulation of [3H]-vinblastine by MCF-7/ADR cells and by drug-resistant human ovarian carcinoma cells (SKVLB1) was increased to the greatest extent by verapamil, followed by dihydrocytochalasin B > cytochalasin E > cytochalasin B, whereas cytochalasins A, C, D, H, and J did not alter intracellular accumulation of the drug. Similarly to verapamil, dihydrocytochalasin B significantly stimulated the ATPase activity of P-glycoprotein, while other cytochalasins were ineffective. These results demonstrate that very closely related compounds can differentially interact with P-glycoprotein. For example, the only difference between cytochalasin B and dihydrocytochalasin B is the saturation of a carbon-carbon double bond in dihydrocytochalasin B. These structural differences may provide important insight into chemical determinants for drug interaction with P-glycoprotein.

• Authors: J T Zilfou, C D Smith
• Journal: Oncology research (Oncol Res) Vol. 7 Issue 9 Pg. 435-43 ( 1995) ISSN: 0965-0407 [Print] United States
• PMID: 8835287 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Cytochalasins
• Dactinomycin
• Vinblastine
• Verapamil
• Adenosine Triphosphatases
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects, metabolism)
• Adenosine Triphosphatases (metabolism)
• Cell Death (drug effects)
• Cell Membrane (metabolism)
• Cisplatin (toxicity)
• Cytochalasins (chemistry, toxicity)
• Dactinomycin (toxicity)
• Drug Resistance, Multiple
• Humans
• Models, Molecular
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Verapamil (toxicity)
• Vinblastine (metabolism)