Gibberellin derivative GA-13315 sensitizes multidrug-resistant cancer cells by antagonizing ABCB1 while agonizes ABCC1.

Abstract

PURPOSE:

GA-13315 is a gibberellin derivative that reveals antitumor and antineoplastic effects both in vitro and in vivo. In the present study, the chemosensitizing effects of GA-13315 in multidrug-resistant cell lines were examined and the underlying mechanisms were investigated.

METHODS:

Cytotoxicity and chemosensitizing effects of GA-13315 were determined by MTT assay. Function of ABC transporter was analyzed by measuring intracellular drug accumulation of doxorubicin and rhodamine 123 and by determining the ATPase activity of ABC transporter. Expression levels of apoptosis regulators were analyzed using real-time quantitative PCR and Western blot.

RESULTS:

GA-13315 selectively killed MCF-7/adr cells that overexpress P-glycoprotein (ABCB1) over the parent MCF-7 cells. In combination with conventional chemotherapeutic agents, GA-13315 at sub-toxic concentrations reversed the multidrug resistance mediated by ABCB1 but exacerbated the resistance conferred by multidrug resistance-associated protein 1 (ABCC1). GA-13315 increased intracellular accumulation of doxorubicin and rhodamine 123 in MCF-7/adr cells and in ABCB1-transfected HEK293 cells but facilitated drug flush-out from cells that overexpress ABCC1. GA-13315 inhibited the ATPase activity of ABCB1 while stimulated that of ABCC1. Moreover, the downregulated expression of Bax in MCF-7/adr cells was restored by GA-13315 markedly.

CONCLUSION:

These data suggest that GA-13315 sensitizes multidrug-resistant cells at least partially by impeding the efflux function of ABCB1. The upregulation of Bax by GA-13315 may also contribute to the sensitizing action. The opposite effects of GA-13315 on different ATP-binding cassette transporters and their implications in overcoming drug resistance require further investigation.

• Authors: Jiao Mo, Min Kang, Jun-Xian Ye, Jing-Bo Chen, Hong-Bin Zhang, Chen Qing
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 78 Issue 1 Pg. 51-61 (07 2016) ISSN: 1432-0843 [Electronic] Germany
• PMID: 27160689 (Publication Type: Journal Article)

Chemical References

• 13-chlorine-3,15-dioxy-gibberellic acid methyl ester
• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• BAX protein, human
• Gibberellins
• Multidrug Resistance-Associated Proteins
• bcl-2-Associated X Protein
• Rhodamine 123
• Doxorubicin
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacokinetics, pharmacology)
• Blotting, Western
• Down-Regulation (drug effects)
• Doxorubicin (pharmacokinetics)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Gibberellins (administration & dosage, pharmacology)
• HEK293 Cells
• Humans
• MCF-7 Cells
• Multidrug Resistance-Associated Proteins (agonists)
• Real-Time Polymerase Chain Reaction
• Rhodamine 123 (pharmacokinetics)
• Up-Regulation (drug effects)
• bcl-2-Associated X Protein (genetics)