Reversal effect of tyroservatide (YSV) tripeptide on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU.

Abstract

Tyroservatide (YSV) is an active, low-molecular-weight polypeptide that has been shown to have antitumor effects on human hepatocellular carcinoma BEL-7402 cells in vitro and in vivo. Multi-drug resistance (MDR) represents a major obstacle to the success of cancer chemotherapy. To enhance the chemosensitivity of tumor cells, attention has been focused on MDR modulators. In this study, we evaluated the reversal effect of YSV on MDR, and explored its mechanism of action in vitro. Administration of YSV reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. The intracellular accumulation of doxorubicin and Rhodamine-123 (Rh123) were increased, which implied that the function of the P-glycoprotein (P-gp) efflux pump was inhibited by YSV. Moreover, the mRNA and protein expression of multi-drug resistance gene (MDR1) were also decreased by YSV. We observe that lung-resistance protein (LRP) and multi-drug resistance-associated protein (MRP1) each contribute to MDR in BEL-7402/5-FU cells as well. The mRNA and protein expression of LRP were decreased by YSV. No significant change was observed in mRNA expression of MRP1. However, we observe that the MRP1 protein level was reduced after treatment with YSV. These data demonstrate that YSV effectively reverses MDR in BEL-7402/5-FU cells, and that its mechanism of action is associated with the down-regulation of MDR1, MRP1 and LRP expression, as well as the inhibition of P-gp function.

• Authors: Lin-Xi Shi, Rui Ma, Rong Lu, Qiong Xu, Zhi-Feng Zhu, Li Wang, Chun-Lei Zhou, Xiao-Lei Li, Hua-Li Zhang, Zhi Yao
• Journal: Cancer letters (Cancer Lett) Vol. 269 Issue 1 Pg. 101-10 (Sep 28 2008) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 18538471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Multidrug Resistance-Associated Proteins
• Oligopeptides
• RNA, Messenger
• Vault Ribonucleoprotein Particles
• major vault protein
• tripeptide tyroservatide
• Rhodamine 123
• Doxorubicin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Doxorubicin (metabolism)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm
• Humans
• Liver Neoplasms (drug therapy)
• Multidrug Resistance-Associated Proteins (genetics)
• Oligopeptides (pharmacology)
• RNA, Messenger (analysis)
• Rhodamine 123 (metabolism)
• Vault Ribonucleoprotein Particles (genetics)