Reversal of multidrug resistance in vitro and in vivo by 5-N-formylardeemin, a new ardeemin derivative.

Abstract

Because multidrug resistance (MDR) is a serious impediment to the use of chemotherapy in treating cancer patients, great efforts have been made to search for effective MDR-reversing agents. We have developed a brand new synthetic ardeemin derivative, 5-N-formylardeemin, and investigated the activity of which in reversing MDR in MDR cancer cell lines derived from human breast cancer (MCF-7-R) or lung cancer (A549-R). 5-N-formylardeemin strongly enhanced the anti-cancer efficacy of doxorubicin, vincristine through potentiation of apoptosis in both MCF-7-R and A549-R at relatively noncytotoxic concentrations in vitro. Mechanistic studies showed that 5-N-formylardeemin inhibited the expression of MDR-1 (P-gp) and increased the intracellular accumulation of cytotoxic drugs in the MDR cells, suggesting that 5-N-formylardeemin reverses MDR activities through inhibiting MDR-1 expression. Interestingly, 5-N-formylardeemin also sensitized the parent wild-type cancer cells toward these chemotherapeutic agents to various extents. Importantly, in vivo studies demonstrated that 5-N-formylardeemin significantly improved the therapeutic effects of doxorubicin in nude mice bearing A549-R xenografts, which was associated with reduced expression of MDR-1 protein level and increased apoptosis in tumor tissues. These results underscore 5-N-formylardeemin as a potential sensitizer for chemotherapy against multidrug resistant cancers.

• Authors: Xuelian Zheng, Daoxia Li, Chen Zhao, Qiong Wang, Hao Song, Yong Qin, Linchuan Liao, Lin Zhang, Yong Lin, Xia Wang
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 8 Pg. 1293-300 (Aug 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24858827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Indole Alkaloids
• ardeemin
• formylardeemin
• Vincristine
• Doxorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Heterografts
• Humans
• Indole Alkaloids (chemistry, pharmacology)
• Male
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Vincristine (pharmacology)