Anti-proliferative activity and suppression of P-glycoprotein by (-)-antofine, a natural phenanthroindolizidine alkaloid, in paclitaxel-resistant human lung cancer cells.

Abstract

Multidrug resistance (MDR) is a major obstacle in effective chemotherapy for cancer patients. The expression of P-glycoprotein (P-gp) in cancer cells is highly correlated with resistance to chemotherapeutic drugs. (-)-Antofine, a phenanthroindolizidine alkaloid derived from Cynanchum paniculatum, inhibits the growth of various human cancer cells. In this study, we further explored the potential of (-)-antofine to overcome the resistance induced by anti-cancer drugs. To this end, we established the paclitaxel-resistant human lung cancer cell line A549-PA by gradually exposing A549 cells to increasing concentrations of paclitaxel. As a result, the A549-PA cells acquired resistance against paclitaxel treatment and had an IC50 that was more than 200 times that of the parental A549 cells. (-)-Antofine, however, effectively suppressed the growth of both the parental and drug-resistant cells. Additional studies revealed that the anti-proliferative activity of (-)-antofine in A549-PA cells is accompanied by a down-regulation of P-gp mRNA and protein expression. The effect of reversing the multidrug resistance of A549-PA cells via (-)-antofine treatment was demonstrated an increase in intracellular rhodamine-123 accumulation, measured using FACS analysis. These findings suggest an additional chemotherapeutic value of (-)-antofine, that is, regulation of cancer cell drug resistance, in addition to its antitumor effect.

• Authors: Eun-Hye Kim, Hye-Young Min, Hwa-Jin Chung, Jayoung Song, Hyen-Joo Park, Sanghee Kim, Sang Kook Lee
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 50 Issue 3-4 Pg. 1060-5 (Mar 2012) ISSN: 1873-6351 [Electronic] England
• PMID: 22120505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• DNA Primers
• Indoles
• Phenanthrolines
• antofine
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Base Sequence
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Primers
• Drug Resistance, Neoplasm
• Humans
• Indoles (pharmacology)
• Lung Neoplasms (pathology)
• Paclitaxel (pharmacology)
• Phenanthrolines (pharmacology)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction