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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

  • GEORGE STUDZINSKI
  • Xuening Wang
  • Elzbieta Gocek
  • Edward Garay
  • Jing Zhang
  • Michael Danilenko
  • Hagar Sharabani
  • Qing Wang
  • Xiangwen Chen-Deutsch
  • Ayelet Shabtay
  • Milan R Uskokovic
  • Zeev Barvish
  • Michael Kafka
  • Yoav Sharoni
  • Joseph Levy
  • Yingyu Zhang
  • Ewa Marcinkowska
  • X Wang
  • Jonathan S Harrison
  • Chang Gong Liu
  • Rahul Patel
  • Doron Amichay
  • Pawel Jankowski
  • Tian Tian Wang
  • Hubert Maehr
  • Paulo Lizano
  • Gary H Posner
  • Stanislaw Marczak
  • Luciano Adorini
  • John H White
  • Milan Uskokovic
  • T T Wang
  • J H White
  • Eugene Izumchenko
  • Rita Kreinin
  • Agnieszka Chrobak
  • Michael Steiner
  • Hagar Salman

Detail Information

Publications17

  1. 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...
  2. 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...
  3. 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
    ....
  4. 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
    ....
  5. 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...
  6. 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...
  7. 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...
  8. 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
    ....
  9. 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...
  10. 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...
  11. 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...
  12. 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
    ....
  13. 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
    ....
  14. 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...
  15. 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...
  16. 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...
  17. 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...