Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment
Ena Wang, Scott Bussom, Jinguo Chen, Courtney Quinn, Davide Bedognetti, Wing Lam, Fulan Guan, Zaoli Jiang, Yichao Mark, Yingdong Zhao, David F Stroncek, Jeffrey White, Francesco M Marincola, Yung-Chi Cheng, Ena Wang, Scott Bussom, Jinguo Chen, Courtney Quinn, Davide Bedognetti, Wing Lam, Fulan Guan, Zaoli Jiang, Yichao Mark, Yingdong Zhao, David F Stroncek, Jeffrey White, Francesco M Marincola, Yung-Chi Cheng
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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References
- Manheimer E, Wieland S, Kimbrough E, Cheng K, Berman BM. Evidence from the Cochrane Collaboration for Traditional Chinese Medicine therapies. J Altern Complement Med. 2009;15:1001–1014. doi: 10.1089/acm.2008.0414.
- Efferth T, Li PC, Konkimalla VS, Kaina B. From traditional Chinese medicine to rational cancer therapy. Trends Mol Med. 2007;13:353–361. doi: 10.1016/j.molmed.2007.07.001.
- Lee DC, Yang CL, Chik SC, Li JC, Rong JH, Chan GC, Lau AS. Bioactivity-guided identification and cell signaling technology to delineate the immunomodulatory effects of Panax ginseng on human promonocytic U937 cells. J Transl Med. 2009;7:34. doi: 10.1186/1479-5876-7-34.
- Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu S-H, Cheng Y-C. The four-herb chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Science Transl Med. 2010;2:45ra59.
- Callaway E. How an 1,800-year-old herbal mix heals the gut. Nature News. 2011.
- Yen Y, So S, Rose M, Saif MW, Chu E, Liu SH, Foo A, Jiang Z, Su T, Cheng YC. Phase I/II study of PHY906/capecitabine in advanced hepatocellular carcinoma. Anticancer Res. 2009;29:4083–4092.
- Saif MW, Lansigan F, Ruta S, Lamb L, Mezes M, Elligers K, Grant N, Jiang ZL, Liu SH, Cheng YC. Phase I study of the botanical formulation PHY906 with capecitabine in advanced pancreatic and other gastrointestinal malignancies. Phytomedicine. 2010;17:161–169. doi: 10.1016/j.phymed.2009.12.016.
- Tilton R, Paiva A, Guan J, Marathe R, Jiang Z, van Eindhoven W, Prusoff Z, Bjoraker J, Wang H, Liu SH, Cheng YC.. A comprehensive platform for quality control of botanical drugs (Phytomics QC) - A case study of Huanggi Tang (HGT) and PHY906. Chinese Medicine. 2010;5:30. doi: 10.1186/1749-8546-5-30.
- Zhang W, Saif MW, Dutschman GE, Li X, Lam W, Bussom S, Jiang Z, Ye M, Chu E, Cheng YC. Identification of chemicals and their metabolites from PHY906, a Chinese medicine formulation, in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass Spectrometry (LC/MS/MS) J Chromatogr A. 2010;1217:5785–5793. doi: 10.1016/j.chroma.2010.07.045.
- Wang E, Miller L, Ohnmacht GA, Liu E, Marincola FM. High fidelity mRNA amplification for gene profiling using cDNA microarrays. Nature Biotech. 2000;17:457–459.
- Simon R, Lam A, LI MC, Ngan M, Menenzes S, Zhao Y. Analysis of Gene Expression Data Using BRB-Array Tools. Cancer Inform. 2007;3:11–17.
- Kummar S, Copur MS, Rose M, Wadler S, Stephenson J, O'Rourke M, Brenckman W, Tilton R, Liu S-H, Jiang Z, Cheng YC, Chu E, A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer. Clin Colorec Cancer. 2010. in press .
- Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovsky DA, Wipf P, Kochanek PM, Greenberger JS, Pitt B, Shvedova AA, Borisenko G. Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med. 2009;46:1439–1453. doi: 10.1016/j.freeradbiomed.2009.03.004.
- Suk K, Chang I, Kim YH, Kim S, Kim JY, Kim H, Lee MS. Interferon gamma (IFNgamma) and tumor necrosis factor alpha synergism in ME-180 cervical cancer cell apoptosis and necrosis. IFNgamma inhibits cytoprotective NF-kappa B through STAT1/IRF-1 pathways. J Biol Chem. 2001;276:13153–13159. doi: 10.1074/jbc.M007646200.
- Lee JH, Chun T, Park SY, Rho SB. Interferon regulatory factor-1 (IRF-1) regulates VEGF-induced angiogenesis in HUVECs. Biochim Biophys Acta. 2008;1783:1654–1662. doi: 10.1016/j.bbamcr.2008.04.006.
- Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434:243–249. doi: 10.1038/nature03308.
- Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 2003;63:6424–6431.
- Barnes BJ, Kellum MJ, Field AE, Pitha PM. Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. Mol Cell Biol. 2002;22:5721–5740. doi: 10.1128/MCB.22.16.5721-5740.2002.
- Jin P, Zhao Y, Ngalame Y, Panelli MC, Nagorsen D, Monsurro' V, Smith K, Hu N, Su H, Taylor PR, Marincola FM, Wang E. Selection and validation of endogenous reference genes using a high throughput approach. BMC Genomics. 2004;5:55. doi: 10.1186/1471-2164-5-55.
- Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59–73. doi: 10.1038/nri2216.
- Jassar AS, Suzuki E, Kapoor V, Sun J, Silverberg MB, Cheung L, Burdick MD, Strieter RM, Ching LM, Kaiser LR, Albelda SM. Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. Cancer Res. 2005;65:11752–11761. doi: 10.1158/0008-5472.CAN-05-1658.
- Roberts ZJ, Goutagny N, Perera PY, Kato H, Kumar H, Kawai T, Akira S, Savan R, van ED, Fitzgerald KA, Young HA, Ching LM, Vogel SN. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J Exp Med. 2007;204:1559–1569. doi: 10.1084/jem.20061845.
- Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, Monsurró V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM. Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facets of oncolytic therapy. BMC Genomics. 2009;10:301. doi: 10.1186/1471-2164-10-301.
- Panelli MC, Wang E, Phan G, Puhlman M, Miller L, Ohnmacht GA, Klein H, Marincola FM. Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol. 2002;3:RESEARCH0035.
- Panelli MC, Stashower M, Slade HB, Smith K, Norwood C, Abati A, Fetsch PA, Filie A, Walters SA, Astry C, Aricó E, Zhao Y, Selleri S, Wang E, Marincola FM. Sequential gene profiling of basal cell carcinomas treated with Imiquimod in a placebo-controlled study defines the requirements for tissue rejection. Genome Biol. 2006;8:R8.
- Dong XE, Ito N, Lotze MT, Demarco RA, Popovic P, Shand SH, Watkins S, Winikoff S, Brown CK, Bartlett DL, Zeh HJ. High mobility group box I (HMGB1) release from tumor cells after treatment: implications for development of targeted chemoimmunotherapy. J Immunother. 2007;30:596–606. doi: 10.1097/CJI.0b013e31804efc76.
- Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S, André F, Tursz T, Kroemer G, Zitvogel L. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 2007;220:47–59. doi: 10.1111/j.1600-065X.2007.00573.x.
- Suk K, Kim YH, Chang I, Kim JY, Choi YH, Lee KY, Lee MS. IFNalpha sensitizes ME-180 human cervical cancer cells to TNFalpha-induced apoptosis by inhibiting cytoprotective NF-kappaB activation. FEBS Lett. 2001;495:66–70. doi: 10.1016/S0014-5793(01)02335-3.
- Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535–584. doi: 10.1146/annurev.immunol.26.021607.090400.
- Hu G, Mancl ME, Barnes BJ. Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death. Cancer Res. 2005;65:7403–7412. doi: 10.1158/0008-5472.CAN-05-0583.
- Wang E, Worschech A, Marincola FM. The immunologic constant of rejection. Trends Immunol. 2008;29:256–262. doi: 10.1016/j.it.2008.03.002.
- Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006;6:644–658. doi: 10.1038/nri1900.
- Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM, Fitzgerald KA, Golenbock DT. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. J Biol Chem. 2005;280:17005–17012. doi: 10.1074/jbc.M412584200.
- Pandey AK, Yang Y, Jiang Z, Fortune SM, Coulombe F, Behr MA, Fitzgerald KA, Sassetti CM, Kelliher MA. NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis. PLoS Pathog. 2009;5:e1000500. doi: 10.1371/journal.ppat.1000500.
- Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T, Honda K. Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem Biophys Res Commun. 2007;354:1045–1051. doi: 10.1016/j.bbrc.2007.01.090.
- Krausgruber T, Saliba D, Ryzhakov G, Lanfrancotti A, Blazek K, Udalova IA. IRF5 is required for late-phase TNF secretion by human dendritic cells. Blood. 2010.
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