Sausville

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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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Sausville

  1. 1. AMINOFLAVONES: A POTENTIAL AhR-DIRECTED BREAST CANCER TREATMENT Edward A. Sausville, M.D., Ph.D University of Maryland Marlene and Stewart Greenebaum Cancer Center
  2. 2. AMINOFLAVONES Aminoflavone (NSC 686288) Aminoflavone Prodrug (NSC 710464) 2
  3. 3. IN VITRO ASSAY OF NSC 710305 IN THE 60 CELL LINE PANEL Cell Line Panel Log 10 GI 50 GI 50 -5.19 -5.06 -4.22 -4.71 -4.76 -4.54 -4.46 -4.00 -5.46 -4.23 -4.36 -4.27 -4.49 -4.28 -6.60 -4.38 -4.32 -4.53 -4.00 -4.00 -4.00 -4.19 -4.00 -4.00 -4.48 -4.18 -4.43 -4.00 -4.24 -4.00 -4.00 -4.66 -4.13 -4.16 -7.37 -6.26 -4.00 -4.00 -4.00 -4.37 -4.29 -4.17 -4.30 -6.73 -5.19 -4.00 -4.31 -7.50 -4.03 -4.16 -4.00 -4.10 -4.01 -4.18 -6.97 -4.61 2.66 3.50 Leukemia Non Small Cell Lung Cancer Colon Cancer CNS Cancer Melanoma Ovarian Cancer Renal Cancer Prostate Cancer Breast Cancer MG_MID Delta Range 3 2 1 0 -1 -2 -3
  4. 4. METABOLISM OF NSC 674495 BY MICROSOMES EXPRESSING HUMAN CYP ISOZYMES Cancer Res 60: 5196, 2000 Activity (pmol/pmol P450/2 hr) CYP Isoform 6-OH NSC 674495 Unknown Metabolite 1 Unknown Metabolite 2 Control CYP1A1 CYP1A2 CYP1B1 CYP2A6 CYP2C8 CYP2C9-Arg CYP2C9-Cys CYP2C19 CYP2D6 CYP2E1 CYP3A4 CYP4A11 350 300 250 200 150 100 50 0
  5. 5. AHR PATHWAY HSP90 TCDD X XX AHR AHR XX AHR X X XRE Genes ARNT
  6. 6. ANTITUMOR ACTIVITY OF AMINOFLAVONE AGAINST MCF-7 BREAST TUMOR XENOGRAFTS Loaiza-Perez et al, Mol Cancer Ther. 3:715, 2004
  7. 7. AMINOFLAVONE INDUCES CYP1A1 ACTIVITY IN AF-SENSITIVE MCF-7 CELLS BUT NOT IN RESISTANT CELLS Loaiza-Perez et al, Mol Cancer Ther. 3:715, 2004
  8. 8. AMINOFLAVONE INDUCES BINDING TO XRE SEQUENCES OF CYP1A1 IN MCF-7 CELLS Loaiza-Perez et al, Mol Cancer Ther. 3:715, 2004
  9. 9. AMINOFLAVONE INDUCES TRANSLOCATION OF THE AHR TO THE NUCLEUS IN AF-SENSITIVE MCF-7 CELLS Loaiza-Perez et al, Mol Cancer Ther. 3:715, 2004
  10. 10. GENERATION OF G-H2AX FOCI IN MCF-7 CELLS TREATED WITH AMINOFLAVONE Meng et al Cancer Res 65: 5337, 2005
  11. 11. 2 SO 3 Me AFP 464 NSC 710464 AF NSC 686288 Sensitive breast cancer cell AhR Insensitive breast cancer cell nucleus AhR: ligand Translocation to nucleus CYP1A1 Induction Covalent binding Reactive intermediate DNA adducts Single strand breaks Cell death ER Cell survival AhR Hsp 90 PROPOSED MODE OF ACTION OF AMINOFLAVONE
  12. 12. ER EXPRESSION IN A PANEL OF BREAST CELL LINES
  13. 14. Expression of ERa in MDA-MB-231 Restores Sensitivity to AF AhR ER α ER α & AhR ER α /AhR/DAPI MDA-MB-231/ ER 
  14. 15. COMBINATION OF AF WITH ER ANTAGONISTS SHOW INCREASEDANTI-PROLIFERATIVE EFFECT
  15. 16. CONCLUSIONS <ul><li>Aminoflavone active in all ER+ breast cancer </li></ul><ul><li>contexts </li></ul><ul><ul><li>Exogenous addition of ER sensitize </li></ul></ul><ul><li>Tamoxifen resistant breast cancer cells may </li></ul><ul><li>retain sensitivity to AF </li></ul><ul><li>Tamoxifen augment AF action </li></ul>
  16. 17. ACKNOWLEDGEMENTS ANGELIKA BURGER PHILLIP SHELTON AVERELL GNATT ANGELA BRODIE “ The Role of Aryl Hydrocarbon Receptor and Cross Talk with Estrogen Receptor in the Response of Breast Cancer Cells to the NovelAntitumor Agent Aminoflavone” Susan G. Komen for the Cure

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