title: Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.
abstract: P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.
authors: Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
authors: Guang-min
authors: GM
authors: Xi
authors: Bin
authors: B
authors: Sun
authors: Hui-Hui
authors: HH
authors: Jiang
authors: Feng
authors: F
authors: Kong
authors: Hui-qing
authors: HQ
authors: Yuan
authors: Hong-xiang
authors: HX
authors: Lou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004988:Ethers, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D020112:Rhodamine 123 / Q000378:metabolism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001632:Bibenzyls; D002396:Catechols; D004988:Ethers, Cyclic; D010647:Phenyl Ethers; D013267:Stilbenes; C459129:marchantin C; D020112:Rhodamine 123; D014750:Vincristine; D004317:Doxorubicin