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Gene Expression Profiling and Pathway Network Analysis Predicts a Novel Antitumor Function for a Botanical-Derived Drug, PG2.

Kuo YL, Chen CH, Chuang TH, Hua WK, Lin WJ, Hsu WH, Chang PM, Hsu SL, Huang TH, Kao CY, Huang CY - Evid Based Complement Alternat Med (2015)

Bottom Line: The results showed that PG2 product batches were consistent and of high quality.Within the PG2 signature, there were five genes associated with doxorubicin: IL-8, MDM4, BCL2, PRODH2, and BIRC5.Moreover, the combination of PG2 and doxorubicin had a synergistic effect on induced cell death in HL-60 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan.

ABSTRACT
PG2 is a botanical drug that is mostly composed of Astragalus polysaccharides (APS). Its role in hematopoiesis and relieving cancer-related fatigue has recently been clinically investigated in cancer patients. However, systematic analyses of its functions are still limited. The aim of this study was to use microarray-based expression profiling to evaluate the quality and consistency of PG2 from three different product batches and to study biological mechanisms of PG2. An integrative molecular analysis approach has been designed to examine significant PG2-induced signatures in HL-60 leukemia cells. A quantitative analysis of gene expression signatures was conducted for PG2 by hierarchical clustering of correlation coefficients. The results showed that PG2 product batches were consistent and of high quality. These batches were also functionally equivalent to each other with regard to how they modulated the immune and hematopoietic systems. Within the PG2 signature, there were five genes associated with doxorubicin: IL-8, MDM4, BCL2, PRODH2, and BIRC5. Moreover, the combination of PG2 and doxorubicin had a synergistic effect on induced cell death in HL-60 cells. Together with the bioinformatics-based approach, gene expression profiling provided a quantitative measurement for the quality and consistency of herbal medicines and revealed new roles (e.g., immune modulation) for PG2 in cancer treatment.

No MeSH data available.


Related in: MedlinePlus

The effect of combining PG2 and doxorubicin on cell death in HL-60 cells. (a) The top 80 confidence interactions associated with doxorubicin were obtained from STITCH. Five of these (MDM4, IL-8, PRODH2, BCL2, and BIRC5) are derived from the PG2 signature and interact with doxorubicin (identified with arrows). Associated strength is represented by the thickness of the line. Protein-protein interactions are colored in blue, and chemical-protein interactions are colored in green. (b) Drug-target interactions between anthracyclines and PG2. Among these, daunorubicin and epirubicin are associated with only one interactor. HL-60 cells were treated with different concentrations of PG2 for 6 hr. (c) IL8, (d) MDM4, and (e) BIRC5 gene expressions were measured by Q-RT-PCR and normalized to β-actin (n = 3). (f) HL-60 cells were treated with various concentrations of PG2 in the presence or absence of doxorubicin (0.75 µg/mL). Cell viability was determined by the trypan blue exclusion assay. Data are expressed as the mean ± standard deviation (SD) of three repeats. A representative result from three independent experiments is shown (n = 5) (#P < 0.05; ##P < 0.01; ###P < 0.001 versus vehicle control group).
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fig4: The effect of combining PG2 and doxorubicin on cell death in HL-60 cells. (a) The top 80 confidence interactions associated with doxorubicin were obtained from STITCH. Five of these (MDM4, IL-8, PRODH2, BCL2, and BIRC5) are derived from the PG2 signature and interact with doxorubicin (identified with arrows). Associated strength is represented by the thickness of the line. Protein-protein interactions are colored in blue, and chemical-protein interactions are colored in green. (b) Drug-target interactions between anthracyclines and PG2. Among these, daunorubicin and epirubicin are associated with only one interactor. HL-60 cells were treated with different concentrations of PG2 for 6 hr. (c) IL8, (d) MDM4, and (e) BIRC5 gene expressions were measured by Q-RT-PCR and normalized to β-actin (n = 3). (f) HL-60 cells were treated with various concentrations of PG2 in the presence or absence of doxorubicin (0.75 µg/mL). Cell viability was determined by the trypan blue exclusion assay. Data are expressed as the mean ± standard deviation (SD) of three repeats. A representative result from three independent experiments is shown (n = 5) (#P < 0.05; ##P < 0.01; ###P < 0.001 versus vehicle control group).

Mentions: The anthracyclines are a class of antineoplastic drugs that damage DNA by intercalating into DNA strands in human cancer cells, particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Doxorubicin, daunorubicin, and epirubicin are anthracycline-based chemotherapeutic drugs and are most commonly used to treat these specific types of leukemia. In this study, STITCH was used to predict chemical-protein interactions between anthracyclines and the PG2 signature (Figure 1). Of these chemotherapeutic agents, doxorubicin had more interactions associated with PG2 than any other (Figures 4(a) and 4(b) and Supplementary Table S2). Additionally, multiple genes in the PG2 signature are associated with doxorubicin, including IL-8, MDM4, BCL2, PRODH2, and BIRC5. In addition to acute leukemia, doxorubicin is a well-known chemotherapeutic agent that is useful for treating various cancers, including non-Hodgkin's lymphoma, Kaposi's sarcoma, Ewing's sarcoma, Wilms' tumor, and breast cancer. Recent studies have shown that doxorubicin induces NF-κB through interleukin-8 (IL-8) [42], whereas p53 inactivation is associated with the overexpression of MDM2/MDM4 in AML cell lines [43]. MDM4 overexpression is associated with a poor prognosis in chronic lymphocytic leukemia [44]. Moreover, previous study showed that BIRC5 downregulation would help eradicate the chemotherapy resistant in ALL [45, 46]. Kuai et al. [47] reported that IL-8 plays an essential role in the adhesion, migration, invasion, and chemosensitivity of human gastric cancer cells. Interestingly, BIRC5 and MDM4 were downregulated and IL8 was upregulated in HL-60 cells treated with PG2 (Figures 4(c)–4(e)), which might enhance the response to chemotherapy.


Gene Expression Profiling and Pathway Network Analysis Predicts a Novel Antitumor Function for a Botanical-Derived Drug, PG2.

Kuo YL, Chen CH, Chuang TH, Hua WK, Lin WJ, Hsu WH, Chang PM, Hsu SL, Huang TH, Kao CY, Huang CY - Evid Based Complement Alternat Med (2015)

The effect of combining PG2 and doxorubicin on cell death in HL-60 cells. (a) The top 80 confidence interactions associated with doxorubicin were obtained from STITCH. Five of these (MDM4, IL-8, PRODH2, BCL2, and BIRC5) are derived from the PG2 signature and interact with doxorubicin (identified with arrows). Associated strength is represented by the thickness of the line. Protein-protein interactions are colored in blue, and chemical-protein interactions are colored in green. (b) Drug-target interactions between anthracyclines and PG2. Among these, daunorubicin and epirubicin are associated with only one interactor. HL-60 cells were treated with different concentrations of PG2 for 6 hr. (c) IL8, (d) MDM4, and (e) BIRC5 gene expressions were measured by Q-RT-PCR and normalized to β-actin (n = 3). (f) HL-60 cells were treated with various concentrations of PG2 in the presence or absence of doxorubicin (0.75 µg/mL). Cell viability was determined by the trypan blue exclusion assay. Data are expressed as the mean ± standard deviation (SD) of three repeats. A representative result from three independent experiments is shown (n = 5) (#P < 0.05; ##P < 0.01; ###P < 0.001 versus vehicle control group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: The effect of combining PG2 and doxorubicin on cell death in HL-60 cells. (a) The top 80 confidence interactions associated with doxorubicin were obtained from STITCH. Five of these (MDM4, IL-8, PRODH2, BCL2, and BIRC5) are derived from the PG2 signature and interact with doxorubicin (identified with arrows). Associated strength is represented by the thickness of the line. Protein-protein interactions are colored in blue, and chemical-protein interactions are colored in green. (b) Drug-target interactions between anthracyclines and PG2. Among these, daunorubicin and epirubicin are associated with only one interactor. HL-60 cells were treated with different concentrations of PG2 for 6 hr. (c) IL8, (d) MDM4, and (e) BIRC5 gene expressions were measured by Q-RT-PCR and normalized to β-actin (n = 3). (f) HL-60 cells were treated with various concentrations of PG2 in the presence or absence of doxorubicin (0.75 µg/mL). Cell viability was determined by the trypan blue exclusion assay. Data are expressed as the mean ± standard deviation (SD) of three repeats. A representative result from three independent experiments is shown (n = 5) (#P < 0.05; ##P < 0.01; ###P < 0.001 versus vehicle control group).
Mentions: The anthracyclines are a class of antineoplastic drugs that damage DNA by intercalating into DNA strands in human cancer cells, particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Doxorubicin, daunorubicin, and epirubicin are anthracycline-based chemotherapeutic drugs and are most commonly used to treat these specific types of leukemia. In this study, STITCH was used to predict chemical-protein interactions between anthracyclines and the PG2 signature (Figure 1). Of these chemotherapeutic agents, doxorubicin had more interactions associated with PG2 than any other (Figures 4(a) and 4(b) and Supplementary Table S2). Additionally, multiple genes in the PG2 signature are associated with doxorubicin, including IL-8, MDM4, BCL2, PRODH2, and BIRC5. In addition to acute leukemia, doxorubicin is a well-known chemotherapeutic agent that is useful for treating various cancers, including non-Hodgkin's lymphoma, Kaposi's sarcoma, Ewing's sarcoma, Wilms' tumor, and breast cancer. Recent studies have shown that doxorubicin induces NF-κB through interleukin-8 (IL-8) [42], whereas p53 inactivation is associated with the overexpression of MDM2/MDM4 in AML cell lines [43]. MDM4 overexpression is associated with a poor prognosis in chronic lymphocytic leukemia [44]. Moreover, previous study showed that BIRC5 downregulation would help eradicate the chemotherapy resistant in ALL [45, 46]. Kuai et al. [47] reported that IL-8 plays an essential role in the adhesion, migration, invasion, and chemosensitivity of human gastric cancer cells. Interestingly, BIRC5 and MDM4 were downregulated and IL8 was upregulated in HL-60 cells treated with PG2 (Figures 4(c)–4(e)), which might enhance the response to chemotherapy.

Bottom Line: The results showed that PG2 product batches were consistent and of high quality.Within the PG2 signature, there were five genes associated with doxorubicin: IL-8, MDM4, BCL2, PRODH2, and BIRC5.Moreover, the combination of PG2 and doxorubicin had a synergistic effect on induced cell death in HL-60 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Information Engineering, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan.

ABSTRACT
PG2 is a botanical drug that is mostly composed of Astragalus polysaccharides (APS). Its role in hematopoiesis and relieving cancer-related fatigue has recently been clinically investigated in cancer patients. However, systematic analyses of its functions are still limited. The aim of this study was to use microarray-based expression profiling to evaluate the quality and consistency of PG2 from three different product batches and to study biological mechanisms of PG2. An integrative molecular analysis approach has been designed to examine significant PG2-induced signatures in HL-60 leukemia cells. A quantitative analysis of gene expression signatures was conducted for PG2 by hierarchical clustering of correlation coefficients. The results showed that PG2 product batches were consistent and of high quality. These batches were also functionally equivalent to each other with regard to how they modulated the immune and hematopoietic systems. Within the PG2 signature, there were five genes associated with doxorubicin: IL-8, MDM4, BCL2, PRODH2, and BIRC5. Moreover, the combination of PG2 and doxorubicin had a synergistic effect on induced cell death in HL-60 cells. Together with the bioinformatics-based approach, gene expression profiling provided a quantitative measurement for the quality and consistency of herbal medicines and revealed new roles (e.g., immune modulation) for PG2 in cancer treatment.

No MeSH data available.


Related in: MedlinePlus