Targeting Akt/NF-kappa beta for Pancreatic Cancer Therapy

Summary

Principal Investigator: Maha Hussain
Abstract: Pancreatic neoplasia is the fifth most common cancer in the United States. Its etiology is largely unknown and no curative treatment is presently available. Over-expression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of human pancreatic cancer. EGFR over-expression or activation leads to the activation of Akt and NF-kappaB signaling pathways, suggesting that these pathways are important therapeutic targets for pancreas cancer. Activation of Akt/NF-kappaB in pancreatic cancer induces downstream target genes, such as uPA, VEGF, IL-8 and Bcl-xl that may mediate its cardinal clinical features of locally aggressive growth, metastasis, and chemotherapy resistance. We have recently observed that genistein is a potent inhibitor of Akt/NF-kappaB pathway and inducer of apoptotic cell death. Our microarray data from cells treated with genistein showed inactivation of NF-kappaB downstream genes that are important in angiogenesis, invasion and metastasis (Cancer Letters 186:157, 2002). In addition, we have recently discovered a new cDNA that codes for ERRP. ERRP is believed to attenuate the EGFR function by sequestration of EGFR ligands, and that the ERRP could be upregulated by genistein treatment of pancreatic cancer cells. Our results also suggest that treatment of pancreatic cancer cells with either genistein or ERRP or their combinations may induce apoptotic cell death, and may also sensitize pancreatic cancer cells to commonly used chemotherapeutic agents, such as cisplatin and gemcitabine. Collectively, these findings strongly suggest that the inactivation of the EGFR/Akt/NF-kappaB pathways should be very important for devising therapeutic strategies for pancreatic cancer, which could be accomplished by our novel approach (genistein and ERRP treatment). Based on our preliminary data, we hypothesize that ERRP is a negative regulator of EGFR that inhibits proliferation and stimulates apoptosis by attenuating EGFR signaling. We further hypothesize that inactivation of Akt/NF-kappaB signaling, which is a downstream signaling pathway of EGFR, by genistein may potentiate the activity of ERRP treatment in pancreatic cancer cells, and may also sensitize these cells to cisplatin and/or gemcitabine. To test our hypothesis, we will determine how ERRP inactivates EGFR signaling, and also determine the effects of ERRP and genistein on cell growth inhibition and induction of apoptosis, and correlate these results with inactivation of Akt and NF-kappaB. Moreover, we will determine the cause and effect relationships between cell growth inhibition and apoptosis inducing activity of genistein and ERRP with Akt/NF-kappaB signaling, by gene transfection experiments. We will also test whether the inactivation of Akt/NF-kappaB by genistein and/or ERRP could sensitize pancreatic cancer cells to cisplatin and gemcitabine-induced apoptosis. Finally, we will test whether the treatment effects of these agents alone or in combinations with or without cisplatin and gemcitabine will inhibit tumor growth in SCID xenografts. These results will provide mechanistic as well as pre-clinical data in support of our hypotheses and may open new and novel avenues for the treatment of human pancreatic cancer.
Funding Period: 2003-08-01 - 2009-05-31
more information: NIH RePORT

Top Publications

  1. ncbi NF-kappaB: a potential target for cancer chemoprevention and therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Front Biosci 13:2950-9. 2008
  2. pmc Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy
    Bin Bao
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
    Curr Protoc Pharmacol . 2013
  3. pmc Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations
    Asfar S Azmi
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R St, Detroit, Michigan 48201, USA
    Mol Cancer Ther 9:3137-44. 2010
  4. pmc Targeting Notch signaling pathway to overcome drug resistance for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
    Biochim Biophys Acta 1806:258-67. 2010
  5. pmc Notch signaling proteins: legitimate targets for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 9374 Scott Hall, 540 E Canfield, Detroit, MI 48201, USA
    Curr Protein Pept Sci 11:398-408. 2010
  6. pmc Emerging roles of PDGF-D signaling pathway in tumor development and progression
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
    Biochim Biophys Acta 1806:122-30. 2010
  7. ncbi MDM2 inhibitors for pancreatic cancer therapy
    Asfar S Azmi
    Hematology and Oncology, Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, 732 HWCRC, 4100 John R Street, Detroit, MI 48201, USA
    Mini Rev Med Chem 10:518-26. 2010
  8. pmc MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function
    Asfar S Azmi
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
    Eur J Cancer 46:1122-31. 2010
  9. ncbi Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    J Cell Biochem 109:726-36. 2010
  10. pmc The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
    Curr Drug Targets 11:745-51. 2010

Scientific Experts

  • Maha Hussain
  • Zhiwei Wang
  • Ramzi Mohammad
  • Asfar S Azmi
  • Sanjeev Banerjee
  • David A Davis
  • PREM-VEER G REDDY
  • Fazlul H Sarkar
  • Yiwei Li
  • Shadan Ali
  • Dejuan Kong
  • Philip A Philip
  • Bin Bao
  • Yuxiang Zhang
  • Uzma Shamim
  • Timothy G VandenBoom
  • Shreelekha Adsule
  • Subhash Padhye
  • Basil F El-Rayes
  • G Prem Veer Reddy
  • Omer Kucuk
  • Adhip P N Majumdar
  • Aamir Ahmad
  • Sarmad Hanif
  • Abdulmajeed Albanyan
  • Frances W J Beck
  • Sheikh M Hadi
  • Ran Li
  • Sanila H Sarkar
  • Yi Wei Li
  • Liyue Zhang
  • Evelyn R Barrack
  • Q Ping Dou
  • Michael L Cher
  • Ifrah F Ali
  • Hu Xu
  • Ronald Pelley
  • Mingxin Che
  • James Abbruzzese
  • Amro Aboukameel
  • Nazmi V Adsay
  • Judith Abrams
  • Shijie Sheng
  • Mani Menon
  • James L Abbruzzese
  • Sudhir Kulkarni
  • Fakhara Ahmed
  • Dorota J Marciniak

Detail Information

Publications63

  1. ncbi NF-kappaB: a potential target for cancer chemoprevention and therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Front Biosci 13:2950-9. 2008
    ..In this brief review article, we will summarize the state of our knowledge for the role of NF-kappaB in relation to cancer prevention and therapy...
  2. pmc Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy
    Bin Bao
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
    Curr Protoc Pharmacol . 2013
    ..The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics...
  3. pmc Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations
    Asfar S Azmi
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R St, Detroit, Michigan 48201, USA
    Mol Cancer Ther 9:3137-44. 2010
    ....
  4. pmc Targeting Notch signaling pathway to overcome drug resistance for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
    Biochim Biophys Acta 1806:258-67. 2010
    ....
  5. pmc Notch signaling proteins: legitimate targets for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 9374 Scott Hall, 540 E Canfield, Detroit, MI 48201, USA
    Curr Protein Pept Sci 11:398-408. 2010
    ..Further, we summarize the role of several Notch inhibitors especially "natural agents" that could represent novel therapeutic strategies targeting Notch signaling toward better treatment outcome of patients diagnosed with cancer...
  6. pmc Emerging roles of PDGF-D signaling pathway in tumor development and progression
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
    Biochim Biophys Acta 1806:122-30. 2010
    ....
  7. ncbi MDM2 inhibitors for pancreatic cancer therapy
    Asfar S Azmi
    Hematology and Oncology, Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, 732 HWCRC, 4100 John R Street, Detroit, MI 48201, USA
    Mini Rev Med Chem 10:518-26. 2010
    ..This review summarizes recent advancements in the development of MDM2 inhibitors, their novel primary and secondary targets and highlights their potential as therapeutics for PaCa...
  8. pmc MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function
    Asfar S Azmi
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
    Eur J Cancer 46:1122-31. 2010
    ..In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53...
  9. ncbi Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    J Cell Biochem 109:726-36. 2010
    ..Our results further suggest that inactivation of Notch signaling pathways by innovative strategies could be a potential targeted approach for the treatment of metastatic prostate cancer...
  10. pmc The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
    Curr Drug Targets 11:745-51. 2010
    ....
  11. pmc Forkhead box M1 transcription factor: a novel target for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, 540 E Canfield, Detroit, MI 48201, USA
    Cancer Treat Rev 36:151-6. 2010
    ....
  12. pmc Signaling mechanism(s) of reactive oxygen species in Epithelial-Mesenchymal Transition reminiscent of cancer stem cells in tumor progression
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    Curr Stem Cell Res Ther 5:74-80. 2010
    ....
  13. pmc Cross-talk between miRNA and Notch signaling pathways in tumor development and progression
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
    Cancer Lett 292:141-8. 2010
    ..Further, we summarize how targeting miRNAs by natural agents could become a novel and safer approach for the prevention of tumor progression and treatment...
  14. pmc Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
    J Cell Biochem 112:78-88. 2011
    ....
  15. pmc Targeting miRNAs involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
    Drug Resist Updat 13:109-18. 2010
    ..A particular promising lead is the potential synergistic combination of natural compounds that affect critical miRNAs, such as curcumin or epigallocatechin-3-gallate (EGCG) with chemotherapeutic agents...
  16. pmc MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy
    A S Azmi
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Oncogene 30:117-26. 2011
    ..Therefore, use of supplemental zinc with MI-219 will benefit the overall efficacy of MIs and this potent combination warrants further investigation...
  17. pmc Aberrant epigenetic grooming of miRNAs in pancreatic cancer: a systems biology perspective
    Asfar S Azmi
    Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
    Epigenomics 3:747-59. 2011
    ....
  18. pmc Attenuation of multi-targeted proliferation-linked signaling by 3,3'-diindolylmethane (DIM): from bench to clinic
    Sanjeev Banerjee
    Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Mutat Res 728:47-66. 2011
    ..Therefore, DIM appears to be a promising chemopreventive agent or chemo-radio-sensitizer for the prevention of tumor recurrence and/or for the treatment of human malignancies...
  19. pmc Resveratrol-induced apoptosis is enhanced in low pH environments associated with cancer
    Uzma Shamim
    Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP, India
    J Cell Physiol 227:1493-500. 2012
    ..Our findings provide irrevocable proof that low pH environment can be turned into tumor weakness and assist in eradication of cancer cells by resveratrol...
  20. pmc Network modeling of MDM2 inhibitor-oxaliplatin combination reveals biological synergy in wt-p53 solid tumors
    Asfar S Azmi
    Department of Pathology, Wayne State University School of Medicine, MI, USA
    Oncotarget 2:378-92. 2011
    ..We anticipate that our MI219-oxaliplatin network blueprints can be clinically translated in the rationale design and application of this unique therapeutic combination in a genetically pre-defined subset of patients...
  21. ncbi Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy
    Zhiwei Wang
    Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Anticancer Res 31:1105-13. 2011
    ....
  22. ncbi Network perspectives on HDM2 inhibitor chemotherapy combinations
    Asfar S Azmi
    Department of Pathology, Karmanos Cancer Institute HWCRC Building 732, 4100 John R, Detroit, MI 48201, USA
    Curr Pharm Des 17:640-52. 2011
    ..We anticipate that in the near future such network-centric approaches will benefit clinical development of HDM2 inhibitors for genetically predefined subsets of cancer patients and this will be a step towards personalized medicine...
  23. pmc Review on molecular and therapeutic potential of thymoquinone in cancer
    Sanjeev Banerjee
    Department of Pathology and Internal Medicine, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    Nutr Cancer 62:938-46. 2010
    ..The results from such studies will be instrumental in advancing this field in support of initiating clinical trials for testing the effects of this ancient agent in cancer therapy...
  24. pmc Restoring sensitivity to oxaliplatin by a novel approach in gemcitabine-resistant pancreatic cancer cells in vitro and in vivo
    Sanjeev Banerjee
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Wayne State University, Detroit, MI, USA
    Int J Cancer 128:1240-50. 2011
    ....
  25. pmc miR-146a suppresses invasion of pancreatic cancer cells
    Yiwei Li
    Departments of Pathology and Internal Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 70:1486-95. 2010
    ..Our findings reveal DIM and isoflavone as nontoxic activators of a miRNA that can block pancreatic cancer cell invasion and metastasis, offering starting points to design novel anticancer agents...
  26. pmc TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    Cancer Res 69:2757-65. 2009
    ..Our data suggest that the observed antitumor activity of TW-37 is mediated through a novel pathway involving inactivation of Notch-1 and Jagged-1...
  27. pmc 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer
    Sanjeev Banerjee
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 69:5592-600. 2009
    ....
  28. pmc Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells
    Yiwei Li
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 69:6704-12. 2009
    ....
  29. pmc Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics
    Fazlul H Sarkar
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Cancer Treat Rev 35:597-607. 2009
    ....
  30. pmc Multi-targeted therapy of cancer by genistein
    Sanjeev Banerjee
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 110 E Warren, Detroit, MI 48201, USA
    Cancer Lett 269:226-42. 2008
    ....
  31. ncbi Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts
    Ramzi M Mohammad
    Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Cancer 106:1260-8. 2006
    ....
  32. pmc Cellular signaling perturbation by natural products
    Fazlul H Sarkar
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R, Detroit, MI 48201, USA
    Cell Signal 21:1541-7. 2009
    ..Therefore, non-toxic "natural agents" harvested from the bounties of nature could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies...
  33. pmc Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA
    Cancer Res 69:2400-7. 2009
    ....
  34. ncbi Exploitation of the Notch signaling pathway as a novel target for cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Anticancer Res 28:3621-30. 2008
    ..Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of Notch signaling, which could become a novel approach for cancer prevention and treatment...
  35. ncbi Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer
    Yiwei Li
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 66:4816-25. 2006
    ..From these results, we conclude that genistein could be a promising nontoxic agent to improve the treatment outcome of metastatic prostate cancer with docetaxel...
  36. ncbi Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer 106:2503-13. 2006
    ....
  37. ncbi Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer
    G Prem Veer Reddy
    Vattikuti Urology Institute, Henry Ford Hospital, Detroit, Michigan 48202, USA
    J Cell Biochem 98:1408-23. 2006
    ....
  38. ncbi The role of genistein and synthetic derivatives of isoflavone in cancer prevention and therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Mini Rev Med Chem 6:401-7. 2006
    ..These results suggest that genistein and synthetic structurally-modified derivatives of isoflavone may be promising agents for cancer chemoprevention and therapy either alone or in combination with existing chemotherapeutic agents...
  39. ncbi Using chemopreventive agents to enhance the efficacy of cancer therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 110 East Warren, Detroit, MI 48201, USA
    Cancer Res 66:3347-50. 2006
    ..In this article, we summarize the findings of recent investigations of chemopreventive agents in combination with cancer treatment regimens...
  40. ncbi Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 9374 Scott Hall, 540 East Canfield, Detroit, MI 48201, USA
    Mol Cancer Ther 5:483-93. 2006
    ..These findings suggest that Notch-1 down-regulation, especially by genistein, could be a novel therapeutic approach for the treatment of pancreatic cancer...
  41. ncbi Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 66:2778-84. 2006
    ....
  42. pmc Increased therapeutic potential of an experimental anti-mitotic inhibitor SB715992 by genistein in PC-3 human prostate cancer cell line
    David A Davis
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
    BMC Cancer 6:22. 2006
    ....
  43. ncbi Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer
    Yuxiang Zhang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University of Medicine, Detroit, MI 48201, USA
    Cancer Res 66:1025-32. 2006
    ..In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins...
  44. ncbi Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Int J Cancer 118:1930-6. 2006
    ..From these results, we conclude that the inhibition of Notch-1 and NF-kappaB activity and their cross talk provides a novel mechanism by which genistein inhibits cell growth and induces apoptotic processes in pancreatic cancer cells...
  45. ncbi Nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-XL, (-)-Gossypol, enhances biological effect of genistein against BxPC-3 human pancreatic cancer cell line
    Ramzi M Mohammad
    Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Pancreas 31:317-24. 2005
    ..Gossypol, a natural polyphenolic compound isolated from cottonseeds, is a dual and potent small-molecule inhibitor of Bcl-2 and Bcl-XL proteins, with a Ki value in the 300-600 nM range for both proteins...
  46. ncbi Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer
    Sanjeev Banerjee
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 65:9064-72. 2005
    ....
  47. ncbi Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells
    Yiwei Li
    Department of Pathology and Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    Cancer Res 65:6934-42. 2005
    ..Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers...
  48. ncbi Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer
    Zhiwei Wang
    Departments of Pathology and Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, 110 East Warren Avenue, Detroit, MI 48201, USA
    Cancer Res 66:7653-60. 2006
    ..We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer...
  49. ncbi Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB
    Basil F El-Rayes
    Division of Hematology Oncology, Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
    Cancer Res 66:10553-9. 2006
    ..Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein...
  50. ncbi PDGF-D signaling: a novel target in cancer therapy
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA
    Curr Drug Targets 10:38-41. 2009
    ..The functions of PDGF-D in human cancer progression are largely unknown. We discuss here the role of PDGF-D signaling pathway in cancer and how its deregulation is involved in tumor development and progression to metastatic disease...
  51. pmc Emerging role of Notch in stem cells and cancer
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 9374 Scott Hall, 540 E Canfield, Detroit, MI 48201, United States
    Cancer Lett 279:8-12. 2009
    ....
  52. pmc Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells
    Yiwei Li
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
    J Biol Chem 283:27707-16. 2008
    ..In conclusion, our data suggest that isoflavone could be useful for the prevention and/or treatment of PCa...
  53. pmc Synergistic effects of multiple natural products in pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States
    Life Sci 83:293-300. 2008
    ..The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways...
  54. pmc TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and invasion in pancreatic cancer
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
    Int J Cancer 123:958-66. 2008
    ..We also suggest that TW-37 could be further developed as a potential therapeutic agent for the treatment of pancreatic cancer...
  55. ncbi Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, 9374 Scott Hall, 540 East Canfield, Detroit, MI 48201, USA
    Cancer Res 67:11377-85. 2007
    ..e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis...
  56. ncbi Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells
    Zhiwei Wang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
    Cancer Res 67:8293-300. 2007
    ..These findings suggest that FoxM1 down-regulation could be a novel approach for the inhibition of pancreatic tumor progression...
  57. ncbi Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Acta Pharmacol Sin 28:1305-15. 2007
    ..Here, we have briefly reviewed the role of chemopreventive agents in cancer prevention, but most importantly, we have reviewed how they could be useful for cancer therapy in combination with conventional therapies...
  58. ncbi Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, Detroit, MI 48201, USA
    Mini Rev Med Chem 7:599-608. 2007
    ..In addition, we provide further evidence regarding the state of our knowledge toward the development of novel COX-2 targeting agents for the prevention and/or treatment of human cancers especially pancreatic cancer...
  59. pmc Pancreatic cancer: pathogenesis, prevention and treatment
    Fazlul H Sarkar
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 110 E Warren, Detroit, MI 48201, USA
    Toxicol Appl Pharmacol 224:326-36. 2007
    ..In this brief review, we will summarize the current knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer...
  60. ncbi In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer
    Sanjeev Banerjee
    Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
    Int J Cancer 120:906-17. 2007
    ....
  61. ncbi Epidermal growth factor receptor-related protein inhibits cell growth and induces apoptosis of BxPC3 pancreatic cancer cells
    Yuxiang Zhang
    Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Veterans Affairs Medical Center, Detroit, Michigan 48201, USA
    Cancer Res 65:3877-82. 2005
    ..We also suggest that ERRP could be a potential therapeutic agent for pancreatic cancer...