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Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment.

Wang E, Bussom S, Chen J, Quinn C, Bedognetti D, Lam W, Guan F, Jiang Z, Mark Y, Zhao Y, Stroncek DF, White J, Marincola FM, Cheng YC - BMC Med Genomics (2011)

Bottom Line: Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures.PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy.Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

View Article: PubMed Central - HTML - PubMed

Affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT

Background: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

Methods: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.

Results: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.

Conclusions: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

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Immune network predominantly affected by the neoplastic process compared to normal tissues (a) and the effect of PHY906 (b), CPT-11 (c), CPT-11+PHY906 (d) or the differential effect of CPT+PHY906 over CPT-11 alone (e) (the analysis performed at low stringency for gene enrichment; t test p-value cutoff < 0.05).
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Figure 4: Immune network predominantly affected by the neoplastic process compared to normal tissues (a) and the effect of PHY906 (b), CPT-11 (c), CPT-11+PHY906 (d) or the differential effect of CPT+PHY906 over CPT-11 alone (e) (the analysis performed at low stringency for gene enrichment; t test p-value cutoff < 0.05).

Mentions: Class comparison between tumors from mice treated with PBS or CPT-11 identified 570 genes differentially expressed at a Student t-test cut-off p-value of < 0.001 (pt test p-value < 0.001) of which 557 had an annotated function (Table 1). Congregation of genes into functional networks identified the NF-kB family, master regulator of innate immune responses and apoptosis, as the top target of CPT-11 (score 45, focus molecules 28, Figure 3). A dichotomy was noted in the expression of NF-kB-dependent genes with a general down-regulation of the transcripts associated with innate immune responses including interferon regulatory factor (IRF)-1 and upregulation of genes regulating apoptosis including mitochondrial fatty acid oxidation [13]. Overlay of the effects of PHY906 alone demonstrated that the herbal extract had no direct effects on this pathway. However, when PHY906 was given in combination with CPT-11, a remarkable reversal of the anti-inflammatory effects induced by CPT-11 was observed. To better illustrate this point, enrichment of genes affected by CPT-11 compared to PBS was performed focusing on the immune regulatory aspects of the treatments (cutoff < 0.05), which identified 2,630 transcripts (2,513 with annotated function for IPA, Additional file 3, Figure. S3b). Compared to the constitutive expression of immune related networks in the tumor microenvironment (Figure 4a), CPT-11 had an ambivalent effect with down regulation of several pro-apoptotic/pro-inflammatory transcripts including IRF-1 and, down-stream of it several interferon stimulated genes (Figure 4c). This is an important observation because IRF-1 is the master regulator of the acute inflammatory switch with powerful pre-inflammatory/pro-apoptotic [14] and anti-angiogenic properties [15]. Side by side comparison of immune pathways between PHY906 and CPT-11 treated animals revealed that the latter had a mixed effect compared with the immune suppressing effects of the former (Figure 2c).


Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment.

Wang E, Bussom S, Chen J, Quinn C, Bedognetti D, Lam W, Guan F, Jiang Z, Mark Y, Zhao Y, Stroncek DF, White J, Marincola FM, Cheng YC - BMC Med Genomics (2011)

Immune network predominantly affected by the neoplastic process compared to normal tissues (a) and the effect of PHY906 (b), CPT-11 (c), CPT-11+PHY906 (d) or the differential effect of CPT+PHY906 over CPT-11 alone (e) (the analysis performed at low stringency for gene enrichment; t test p-value cutoff < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117677&req=5

Figure 4: Immune network predominantly affected by the neoplastic process compared to normal tissues (a) and the effect of PHY906 (b), CPT-11 (c), CPT-11+PHY906 (d) or the differential effect of CPT+PHY906 over CPT-11 alone (e) (the analysis performed at low stringency for gene enrichment; t test p-value cutoff < 0.05).
Mentions: Class comparison between tumors from mice treated with PBS or CPT-11 identified 570 genes differentially expressed at a Student t-test cut-off p-value of < 0.001 (pt test p-value < 0.001) of which 557 had an annotated function (Table 1). Congregation of genes into functional networks identified the NF-kB family, master regulator of innate immune responses and apoptosis, as the top target of CPT-11 (score 45, focus molecules 28, Figure 3). A dichotomy was noted in the expression of NF-kB-dependent genes with a general down-regulation of the transcripts associated with innate immune responses including interferon regulatory factor (IRF)-1 and upregulation of genes regulating apoptosis including mitochondrial fatty acid oxidation [13]. Overlay of the effects of PHY906 alone demonstrated that the herbal extract had no direct effects on this pathway. However, when PHY906 was given in combination with CPT-11, a remarkable reversal of the anti-inflammatory effects induced by CPT-11 was observed. To better illustrate this point, enrichment of genes affected by CPT-11 compared to PBS was performed focusing on the immune regulatory aspects of the treatments (cutoff < 0.05), which identified 2,630 transcripts (2,513 with annotated function for IPA, Additional file 3, Figure. S3b). Compared to the constitutive expression of immune related networks in the tumor microenvironment (Figure 4a), CPT-11 had an ambivalent effect with down regulation of several pro-apoptotic/pro-inflammatory transcripts including IRF-1 and, down-stream of it several interferon stimulated genes (Figure 4c). This is an important observation because IRF-1 is the master regulator of the acute inflammatory switch with powerful pre-inflammatory/pro-apoptotic [14] and anti-angiogenic properties [15]. Side by side comparison of immune pathways between PHY906 and CPT-11 treated animals revealed that the latter had a mixed effect compared with the immune suppressing effects of the former (Figure 2c).

Bottom Line: Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures.PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy.Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

View Article: PubMed Central - HTML - PubMed

Affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT

Background: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

Methods: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.

Results: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.

Conclusions: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

Show MeSH
Related in: MedlinePlus