VITAMIN D ANALOGS AS ADJUVANTS IN CHEMOTHERAPY

Summary

Principal Investigator: GEORGE STUDZINSKI
Affiliation: New Jersey
Country: USA
Abstract: Acute and chronic myeloid leukemias are responsible for approximately 15,000 deaths in the USA every year. These diseases frequently afflict people in the prime of their lives, and substantially less than half of all achieve long-term remission with current therapies, Most treatment options are both intense and toxic, requiring anti-neoplastic poly-chemotherapy, and, in some cases, therapy as radical as allogeneic hematopoietic cell transplantation, with its attendant risks. The overall goal of this proposal is to develop differentiation therapy to supplement the treatment regimens for this group of diseases. We will focus on the identification of the most effective analogs (deltanoids) of the physiological form of vitamin D, 1,25- dihydroxyvitamin D3 (1,25D3) administered at low concentrations to leukemia cells in culture to study alterations in gene expression and other changes in cell physiology. The deltanoids and 1,25D3 will also be administered in combination with nontoxic substances currently used as food preservatives or additives, or with potential for such use, to maximize the differentiation activity of the deltanoids. Established lines of leukemia as well as samples of leukemic cells freshly obtained from patients will be used for studies of cell differentiation. Insight into differentiation control will be obtained by examination of signaling pathways with particular attention to MAPK pathways and into cell cycle regulation by the expression of cyclin-dependent kinases as well as their activators and inhibitors. This will be accomplished by adding pharmacological agents, antisense oligonucleotides, transcription factor decoys, and transfected plasmid constructs to study the molecular consequences of these manipulations, which will be determined by immunoblotting, Northern analysis, RT-PCR, coimmunoprecipitation, and other standard techniques. Differentiating cells will be monitored by determination of surface makers as well as the activity of various kinases as and as their expression. The information obtained in basic studies will be utilized to guide development of a new generation of deltanoids and deltanoid combinations with co-inducers, while translational studies on leukemic cells ex vivo will serve to identify subgroups of myeloid leukemias most suitable for the initiation of clinical trials.
Funding Period: 1987-06-01 - 2007-07-31
more information: NIH RePORT

Top Publications

  1. pmc Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1,25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling
    Farnaz Jamshidi
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey, USA
    Cell Cycle 7:917-24. 2008
  2. pmc Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor
    Edward Garay
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07103, USA
    J Cell Physiol 213:816-25. 2007
  3. ncbi ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey
    J Cell Physiol 229:856-67. 2014
  4. ncbi Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells
    Elzbieta Gocek
    Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
    Crit Rev Clin Lab Sci 51:125-37. 2014
  5. pmc Silibinin can induce differentiation as well as enhance vitamin D3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors
    Jing Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07103, USA
    Hematol Oncol 28:124-32. 2010
  6. pmc 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53
    Thelma Thompson
    Discovery Oncology, Roche Research Center, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Mol Cancer Ther 9:1158-68. 2010
  7. pmc Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants
    Thelma Thompson
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ, USA
    Cancer Biol Ther 10:344-50. 2010
  8. pmc Expression of MAP3 kinase COT1 is up-regulated by 1,25-dihydroxyvitamin D3 in parallel with activated c-jun during differentiation of human myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey, Medical School, Newark, NJ 07103, USA
    J Steroid Biochem Mol Biol 121:395-8. 2010
  9. pmc Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D₃
    Jing Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey, Medical School, Newark, NJ 07103, USA
    Exp Cell Res 317:117-30. 2011
  10. pmc Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07101 1709, USA
    J Cell Physiol 226:1232-40. 2011

Scientific Experts

  • GEORGE STUDZINSKI
  • Xuening Wang
  • Elzbieta Gocek
  • Michael Danilenko
  • Jing Zhang
  • Jonathan S Harrison
  • Edward Garay
  • Xiangwen Chen-Deutsch
  • Thelma Thompson
  • Yoav Sharoni
  • Joseph Levy
  • Ewa Marcinkowska
  • Hagar Sharabani
  • Qing Wang
  • Irene Bobilev
  • Victoria Novik
  • Philip J Hughes
  • Chang Gong Liu
  • Farnaz Jamshidi
  • Milan Uskokovic
  • Ayelet Shabtay
  • Milan R Uskokovic
  • Zeev Barvish
  • Michael Kafka
  • X Wang
  • Yingyu Zhang
  • Stella Pesakhov
  • Anargyros N Moulas
  • Andrzej Kutner
  • Xiuping Liu
  • Itai Levi
  • Ofer Shpilberg
  • Lyubomir Vassilev
  • Lyubomir T Vassilev
  • Michael Andreeff
  • Geoffrey Brown
  • Doron Amichay
  • Rahul Patel
  • Robert Donnelly
  • Hubert Maehr
  • John H White
  • Gary H Posner
  • Stanislaw Marczak
  • Pawel Jankowski
  • Tian Tian Wang
  • Paulo Lizano
  • Luciano Adorini
  • T T Wang
  • Rita Kreinin
  • Agnieszka Chrobak
  • Michael Steiner
  • J H White
  • Eugene Izumchenko
  • Hagar Salman

Detail Information

Publications35

  1. pmc Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1,25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling
    Farnaz Jamshidi
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey, USA
    Cell Cycle 7:917-24. 2008
    ..Identification of the strong antiproliferative activity of ASA/1,25D combinations associated with monocytic differentiation has implications for cancer chemoprevention in individuals who have a predisposition to myeloid leukemia...
  2. pmc Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor
    Edward Garay
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07103, USA
    J Cell Physiol 213:816-25. 2007
    ..Analysis of the mechanisms that underlie the reduction and potentiation of 1,25D-mediated changes in VDR activity may lead to the identification of new cellular targets that enhance 1,25D-induced monocytic differentiation...
  3. ncbi ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey
    J Cell Physiol 229:856-67. 2014
    ..We also found that in AML cells the transcription factor C/EBPβ is positively regulated, while C/EBPα is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia...
  4. ncbi Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells
    Elzbieta Gocek
    Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
    Crit Rev Clin Lab Sci 51:125-37. 2014
    ..This review deals with the structure, function, and signaling pathways of nine main families of NRTKs in normal and cancer cells...
  5. pmc Silibinin can induce differentiation as well as enhance vitamin D3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors
    Jing Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07103, USA
    Hematol Oncol 28:124-32. 2010
    ..Thus, SIL/deltanoid combinations warrant further consideration as preventive/therapeutic regimens in human leukaemia...
  6. pmc 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53
    Thelma Thompson
    Discovery Oncology, Roche Research Center, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Mol Cancer Ther 9:1158-68. 2010
    ....
  7. pmc Tumor suppressor p53 status does not determine the differentiation-associated G₁ cell cycle arrest induced in leukemia cells by 1,25-dihydroxyvitamin D₃ and antioxidants
    Thelma Thompson
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ, USA
    Cancer Biol Ther 10:344-50. 2010
    ....
  8. pmc Expression of MAP3 kinase COT1 is up-regulated by 1,25-dihydroxyvitamin D3 in parallel with activated c-jun during differentiation of human myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey, Medical School, Newark, NJ 07103, USA
    J Steroid Biochem Mol Biol 121:395-8. 2010
    ..These findings provide an additional insight into the 1,25D-regulation of MAPK pathways that contribute to monocytic differentiation process of myeloid leukemia cells...
  9. pmc Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D₃
    Jing Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey, Medical School, Newark, NJ 07103, USA
    Exp Cell Res 317:117-30. 2011
    ..This activation may result from the removal of feedback inhibition of an upstream regulator of those pathways, when p38MAPK alpha and beta are inhibited by SB...
  10. pmc Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvitamin D3-induced differentiation of human acute myeloid leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07101 1709, USA
    J Cell Physiol 226:1232-40. 2011
    ....
  11. pmc Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and up-regulates p27Kip1 concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D(3)
    Xuening Wang
    Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, USA
    Cell Cycle 9:4542-51. 2010
    ....
  12. pmc The Nrf2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid leukemia cells
    Irene Bobilev
    Department of Clinical Biochemistry, Faculty of Health Sciences, Ben Gurion University of the Negev, Petakh Tikva, Israel
    Cancer Biol Ther 11:317-29. 2011
    ..Our findings suggest that the Nrf2/ARE pathway plays an important part in the cooperative induction of myeloid leukemia cell differentiation by 1,25D and a plant polyphenol...
  13. doi MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis
    Elzbieta Gocek
    Department of Pathology and Laboratory Medicine, UMD New Jersey Medical School, Newark, New Jersey 07101, USA
    Cancer Res 71:6230-9. 2011
    ..Thus, agents which can inhibit miR-32 expression may offer clinical utility by enhancing therapeutic efficacy in human AML...
  14. pmc The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells
    Xiangwen Chen-Deutsch
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, NJ 07103, USA
    Leuk Res 36:884-8. 2012
    ..Although the magnitude and nature of these changes were not invariable, it is clear that caspase inhibitors warrant attention as components of differentiation therapy of leukemia, perhaps in combination with derivatives of vitamin D...
  15. pmc Vitamin D3-driven signals for myeloid cell differentiation--implications for differentiation therapy
    Philip J Hughes
    School of Immunity and Infection, College of Medical and Dental Sciences, The University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK
    Leuk Res 34:553-65. 2010
    ..An improved understanding of the mode of action of 1,25(OH)(2)D(3) is facilitating the development of new therapeutic regimens...
  16. pmc Vitamin D and differentiation in cancer
    Elzbieta Gocek
    Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
    Crit Rev Clin Lab Sci 46:190-209. 2009
    ..However, further studies are needed to fully understand the underlying mechanisms in order to improve the therapeutic approaches...
  17. pmc c-Jun N-terminal kinase 2 (JNK2) antagonizes the signaling of differentiation by JNK1 in human myeloid leukemia cells resistant to vitamin D
    Xiangwen Chen-Deutsch
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, 185 So Orange Avenue, Newark, NJ 07103, USA
    Leuk Res 33:1372-8. 2009
    ..In contrast, KD of JNK1p46 reduced the intensity of DCS-induced differentiation, and partially abrogated activation of c-Jun/AP-1 transcription factors...
  18. pmc The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway
    George P Studzinski
    Department of Pathology and Medicine, UMDNJ, New Jersey Medical School, Newark 07103, USA
    J Steroid Biochem Mol Biol 97:47-55. 2005
    ..These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPbeta bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation...
  19. pmc Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia
    Hagar Sharabani
    Department of Clinical Biochemistry, Ben Gurion University of the Negev, Beer Sheva, Israel
    Int J Cancer 118:3012-21. 2006
    ..These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia...
  20. ncbi AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells
    Yingyu Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey, USA
    Cell Cycle 5:447-51. 2006
    ..Thus, a combination of 1,25D with inhibitors of AKT pathway is strongly anti-proliferative and should therefore be considered for differentiation therapy of myeloid leukemia...
  21. pmc The requirement for and changing composition of the activating protein-1 transcription factor during differentiation of human leukemia HL60 cells induced by 1,25-dihydroxyvitamin D3
    Xuening Wang
    Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry New Jersey New Jersey Medical School, Newark, New Jersey 07103, USA
    Cancer Res 66:4402-9. 2006
    ....
  22. pmc Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3
    Ewa Marcinkowska
    Institute of Biochemistry and Molecular Biology, University of Wroclaw, Tamka 2, 50 137 Wroclaw, Poland
    Exp Cell Res 312:2054-65. 2006
    ....
  23. pmc Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, alpha25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5'-flanking region
    X Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, NJ 07103, USA
    Oncogene 25:7078-85. 2006
    ..Our findings offer a potential mechanism for a signaling pathway that contributes to 1,25D-induced monocytic differentiation of human myeloid leukemia cells...
  24. ncbi Vitamin D receptor signaling of monocytic differentiation in human leukemia cells: role of MAPK pathways in transcription factor activation
    G P Studzinski
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey 07103, USA
    Curr Top Med Chem 6:1267-71. 2006
    ..The details of the scheme will be discussed in the sections below...
  25. pmc Raf-1 signaling is required for the later stages of 1,25-dihydroxyvitamin D3-induced differentiation of HL60 cells but is not mediated by the MEK/ERK module
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, New Jersey
    J Cell Physiol 209:253-60. 2006
    ..These findings support the thesis that Raf-1 signals cell proliferation and cell differentiation through different intermediary proteins...
  26. pmc Calcitriol derivatives with two different side-chains at C-20. Part 4: further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells
    Edward Garay
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, NJ, USA
    Bioorg Med Chem 15:4444-55. 2007
    ....
  27. pmc Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway
    Jing Zhang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, NJ 07103, USA
    J Steroid Biochem Mol Biol 105:140-9. 2007
    ..Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias...
  28. pmc Expression of human kinase suppressor of Ras 2 (hKSR-2) gene in HL60 leukemia cells is directly upregulated by 1,25-dihydroxyvitamin D(3) and is required for optimal cell differentiation
    Xuening Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, 185 South Orange Avenue, C 543, Newark, NJ 07103, USA
    Exp Cell Res 313:3034-45. 2007
    ..These results demonstrate that hKSR-2 is a direct target of 1,25D in HL60 cells, and is required for optimal monocytic differentiation...
  29. pmc hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells
    Xuening Wang
    Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
    Mol Cancer Ther 7:2798-806. 2008
    ..Collectively, these results suggest that hKSR-2 may offer a new target for novel therapies of acute myelogenous leukemia...
  30. pmc Synergistic antileukemic activity of carnosic acid-rich rosemary extract and the 19-nor Gemini vitamin D analogue in a mouse model of systemic acute myeloid leukemia
    Ayelet Shabtay
    Department of Clinical Biochemistry, Ben Gurion University of the Negev, Beer Sheva, Israel
    Oncology 75:203-14. 2008
    ....
  31. pmc MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3
    Xuening Wang
    Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry, New Jersey, Newark, New Jersey 07101 1709, USA
    Cell Cycle 8:736-41. 2009
    ....
  32. ncbi Cooperation between antioxidants and 1,25-dihydroxyvitamin D3 in induction of leukemia HL60 cell differentiation through the JNK/AP-1/Egr-1 pathway
    Qing Wang
    Department of Pathology and Laboratory Medicine, UMDNJ New Jersey Medical School, Newark, 17103, USA
    J Cell Physiol 204:964-74. 2005
    ..Combinations of antioxidants with 1,25D(3) should be further evaluated for use in cancer chemoprevention and therapy...