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Synthesis of a dual functional anti-MDR tumor agent PH II-7 with elucidations of anti-tumor effects and mechanisms.

Su Y, Cheng X, Tan Y, Hu Y, Zhou Y, Liu J, Xu Y, Xie Y, Wang C, Gao Y, Wang J, Cheng T, Yang C, Xiong D, Miao H - PLoS ONE (2012)

Bottom Line: It also significantly inhibited the resistant xenograft tumor growth in mouse model.By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells.Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People's Republic of China.

ABSTRACT
Multidrug resistance mediated by P-glycoprotein in cancer cells has been a major issue that cripples the efficacy of chemotherapy agents. Aimed for improved efficacy against resistant cancer cells, we designed and synthesized 25 oxindole derivatives based on indirubin by structure-activity relationship analysis. The most potent one was named PH II-7, which was effective against 18 cancer cell lines and 5 resistant cell lines in MTT assay. It also significantly inhibited the resistant xenograft tumor growth in mouse model. In cell cycle assay and apoptosis assay conducted with flow cytometry, PH II-7 induced S phase cell cycle arrest and apoptosis even in resistant cells. Consistently revealed by real-time PCR, it modulates the expression of genes related to the cell cycle and apoptosis in these cells, which may contributes to its efficacy against them. By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells. Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators. Taken together, PH II-7 is a dual-functional compound that features both the cytotoxicity against cancer cells and the inhibitory effect on P-gp mediated drug efflux.

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Related in: MedlinePlus

Schematic illustration of the process that leads to the discovery of PH II-7.From Danggui Longhui Wan to Indigo naturalis, then to indirubin, the anti-cancer bioactivity was finally attributed to oxindole, the effector moiety of indirubin, which was kept intact in the further modifications that lead to 3 kinds of compounds. Based on compound II, 25 candidates were generated by different modifications, among them PH II-7 was finally screened out by structure-activity relationship analysis and MTT assay.
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pone-0032782-g001: Schematic illustration of the process that leads to the discovery of PH II-7.From Danggui Longhui Wan to Indigo naturalis, then to indirubin, the anti-cancer bioactivity was finally attributed to oxindole, the effector moiety of indirubin, which was kept intact in the further modifications that lead to 3 kinds of compounds. Based on compound II, 25 candidates were generated by different modifications, among them PH II-7 was finally screened out by structure-activity relationship analysis and MTT assay.

Mentions: Indirubin is composed of two structural units connected by a 2-3′ δ-bond, one is an indigoid and the other one is an indigoid isomer (Fig. 1). Indigo, with no bioactivity for tumor inhibition, is composed of two identical indigoid structural units connected by a 2-2′ δ-bond, indicating the bioactivity does not come with the indigoid, but with the indigoid isomer. We kept the indigoid isomer intact and modified the indigoid to generate three derivatives: I, II, and III. Through SAR and MTT analysis, we screened out compound II. Based on it we then synthesized 25 derivatives (Table S1) , among which PH II-7 was recognized as the most potent by further SAR analysis and MTT assay (Table S1,Fig. 1).


Synthesis of a dual functional anti-MDR tumor agent PH II-7 with elucidations of anti-tumor effects and mechanisms.

Su Y, Cheng X, Tan Y, Hu Y, Zhou Y, Liu J, Xu Y, Xie Y, Wang C, Gao Y, Wang J, Cheng T, Yang C, Xiong D, Miao H - PLoS ONE (2012)

Schematic illustration of the process that leads to the discovery of PH II-7.From Danggui Longhui Wan to Indigo naturalis, then to indirubin, the anti-cancer bioactivity was finally attributed to oxindole, the effector moiety of indirubin, which was kept intact in the further modifications that lead to 3 kinds of compounds. Based on compound II, 25 candidates were generated by different modifications, among them PH II-7 was finally screened out by structure-activity relationship analysis and MTT assay.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293869&req=5

pone-0032782-g001: Schematic illustration of the process that leads to the discovery of PH II-7.From Danggui Longhui Wan to Indigo naturalis, then to indirubin, the anti-cancer bioactivity was finally attributed to oxindole, the effector moiety of indirubin, which was kept intact in the further modifications that lead to 3 kinds of compounds. Based on compound II, 25 candidates were generated by different modifications, among them PH II-7 was finally screened out by structure-activity relationship analysis and MTT assay.
Mentions: Indirubin is composed of two structural units connected by a 2-3′ δ-bond, one is an indigoid and the other one is an indigoid isomer (Fig. 1). Indigo, with no bioactivity for tumor inhibition, is composed of two identical indigoid structural units connected by a 2-2′ δ-bond, indicating the bioactivity does not come with the indigoid, but with the indigoid isomer. We kept the indigoid isomer intact and modified the indigoid to generate three derivatives: I, II, and III. Through SAR and MTT analysis, we screened out compound II. Based on it we then synthesized 25 derivatives (Table S1) , among which PH II-7 was recognized as the most potent by further SAR analysis and MTT assay (Table S1,Fig. 1).

Bottom Line: It also significantly inhibited the resistant xenograft tumor growth in mouse model.By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells.Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People's Republic of China.

ABSTRACT
Multidrug resistance mediated by P-glycoprotein in cancer cells has been a major issue that cripples the efficacy of chemotherapy agents. Aimed for improved efficacy against resistant cancer cells, we designed and synthesized 25 oxindole derivatives based on indirubin by structure-activity relationship analysis. The most potent one was named PH II-7, which was effective against 18 cancer cell lines and 5 resistant cell lines in MTT assay. It also significantly inhibited the resistant xenograft tumor growth in mouse model. In cell cycle assay and apoptosis assay conducted with flow cytometry, PH II-7 induced S phase cell cycle arrest and apoptosis even in resistant cells. Consistently revealed by real-time PCR, it modulates the expression of genes related to the cell cycle and apoptosis in these cells, which may contributes to its efficacy against them. By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells. Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators. Taken together, PH II-7 is a dual-functional compound that features both the cytotoxicity against cancer cells and the inhibitory effect on P-gp mediated drug efflux.

Show MeSH
Related in: MedlinePlus