Abstract
Multi-drug resistance (MDR) is a critical problem in cancer chemotherapy. MDR causes the overexpression of ATP-binding cassette (ABC) transporters and mutations in tumor suppressor genes and oncogenes. To tackle this issue, in this study, we focused on Nuphar plants, which have been traditionally used as food. Sesquiterpene alkaloids (1-3) were isolated from N. japonicum and dimeric sesquiterpene thioalkaloids (4-10) were isolated from N. pumilum. P-glycoprotein-overexpressing CEM/ADR5000 cells were cross-resistant to 6,6'-dihydroxythiobinupharidine (10). Using in silico molecular docking, we calculated the binding energies and simulated the interactions of these compounds with the corresponding amino acid residues at the binding site of P-gp. In addition, we investigated the cytotoxicity of these compounds towards cell lines overexpressing other ABC transporters (BCRP, ABCB5), cell lines with a knocked out tumor suppressor gene TP53 or cell lines overexpressing a deletion-activated EGFR oncogene. These cell lines were sensitive or only minimally cross-resistant to these compounds compared with their corresponding wild-type cell lines.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / pharmacology*
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Resistance, Neoplasm
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Molecular Docking Simulation
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasms
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Nuphar / chemistry*
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Plant Extracts / chemistry
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Plant Extracts / pharmacology*
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Sesquiterpenes / chemistry
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Sesquiterpenes / pharmacology*
Substances
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ABCB5 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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Alkaloids
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Antineoplastic Agents, Phytogenic
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Neoplasm Proteins
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Plant Extracts
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Sesquiterpenes
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dihydroxythiobinupharidine