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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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Macrophage infiltration signatures in tumors treated with PHY906 and/or CPT-11. Macrophage infiltration in colon 38 tumors treated with PBS (a), CPT-11 (b), PHY906 (c) or Ininotecan+PHY906 (d). MCP-1 RNA alteration in tumors induced by various treatments (e)
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Figure 5: Macrophage infiltration signatures in tumors treated with PHY906 and/or CPT-11. Macrophage infiltration in colon 38 tumors treated with PBS (a), CPT-11 (b), PHY906 (c) or Ininotecan+PHY906 (d). MCP-1 RNA alteration in tumors induced by various treatments (e)

Mentions: The previous analysis suggested that the colon 38 tumors are characterized by moderate inflammation compared with normal tissues and that this can be modulated by the anti-inflammatory effects of PHY906 alone and the pro-inflammatory effects of CPT-11 and even further by the combination of the two. Thus, we looked at the presence of macrophages in tumors as a general marker of the inflammatory process. In particular we were interested in macrophage infiltration in the combination treatment in which IRF-5 was found strongly up regulated. IRF-5 serves an integral role in the gene induction program activated by Toll-like receptor signaling [16] while playing a potent role as mediator of cell cycle arrest and cell death [17]. Among various pro-inflammatory activities, IRF-5 expressed in mice by activated macrophages can induce the production of several chemokines including CCL-1/I-309, CCL-2/monocyte chemotactic protein 1 (MCP-1), CCL-4/macrophage inflammatory protein 1 β (MIP-1β), CCL-5/Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) and CXCL-8/IL-8 [18] that can further recruit inflammatory cells in areas of inflammation. CCL-2/MCP-1 (Figure 5e) and CCL-5/RANTES were indeed significantly up-regulated by the combination PHY906+CPT-11 compared to CPT-11 alone. Therefore, to compare the localization of immune cells in the tumors suggested by gene expression analysis, we analyzed the presence of macrophages in histologically prepared whole tumor cross-sections. As shown in Figure 5, tumors harvested 3 days post treatment had an increase in the number of F4/80 antibody positive cells in the CPT-11 and CPT-11+PHY906 treated tumors compared with the PBS control group indicating extensive macrophage infiltration. The comparison of CPT-11+PHY906 with CPT-11 alone revealed a strongly enhanced macrophage infiltration corroborating the transcriptional signatures. In contrast, PHY906 alone treatment demonstrated reduced macrophage infiltration compared with PBS alone confirming the anti-inflammatory effects of the herb when given alone. Thus, PHY906 carries opposite effects in the tumor microenvironment by reducing inflammation when given alone but enhancing acute pro-inflammatory processes within the tumor when given in combination with CPT-11.


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)

Macrophage infiltration signatures in tumors treated with PHY906 and/or CPT-11. Macrophage infiltration in colon 38 tumors treated with PBS (a), CPT-11 (b), PHY906 (c) or Ininotecan+PHY906 (d). MCP-1 RNA alteration in tumors induced by various treatments (e)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Macrophage infiltration signatures in tumors treated with PHY906 and/or CPT-11. Macrophage infiltration in colon 38 tumors treated with PBS (a), CPT-11 (b), PHY906 (c) or Ininotecan+PHY906 (d). MCP-1 RNA alteration in tumors induced by various treatments (e)
Mentions: The previous analysis suggested that the colon 38 tumors are characterized by moderate inflammation compared with normal tissues and that this can be modulated by the anti-inflammatory effects of PHY906 alone and the pro-inflammatory effects of CPT-11 and even further by the combination of the two. Thus, we looked at the presence of macrophages in tumors as a general marker of the inflammatory process. In particular we were interested in macrophage infiltration in the combination treatment in which IRF-5 was found strongly up regulated. IRF-5 serves an integral role in the gene induction program activated by Toll-like receptor signaling [16] while playing a potent role as mediator of cell cycle arrest and cell death [17]. Among various pro-inflammatory activities, IRF-5 expressed in mice by activated macrophages can induce the production of several chemokines including CCL-1/I-309, CCL-2/monocyte chemotactic protein 1 (MCP-1), CCL-4/macrophage inflammatory protein 1 β (MIP-1β), CCL-5/Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) and CXCL-8/IL-8 [18] that can further recruit inflammatory cells in areas of inflammation. CCL-2/MCP-1 (Figure 5e) and CCL-5/RANTES were indeed significantly up-regulated by the combination PHY906+CPT-11 compared to CPT-11 alone. Therefore, to compare the localization of immune cells in the tumors suggested by gene expression analysis, we analyzed the presence of macrophages in histologically prepared whole tumor cross-sections. As shown in Figure 5, tumors harvested 3 days post treatment had an increase in the number of F4/80 antibody positive cells in the CPT-11 and CPT-11+PHY906 treated tumors compared with the PBS control group indicating extensive macrophage infiltration. The comparison of CPT-11+PHY906 with CPT-11 alone revealed a strongly enhanced macrophage infiltration corroborating the transcriptional signatures. In contrast, PHY906 alone treatment demonstrated reduced macrophage infiltration compared with PBS alone confirming the anti-inflammatory effects of the herb when given alone. Thus, PHY906 carries opposite effects in the tumor microenvironment by reducing inflammation when given alone but enhancing acute pro-inflammatory processes within the tumor when given in combination with CPT-11.

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