EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES

  • J. S. DILEEP KUMAR Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, 1051 Riverside Drive, New York, NY 10032, USA https://orcid.org/0000-0001-6688-3991
  • JAYA PRABHAKARAN Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, 1051 Riverside Drive, New York, NY 10032, USA, Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA
  • NARESH DAMUKA Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, NC 27157-1088, USA
  • JUSTIN W. HINES Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, NC 27157-1088, USA
  • STEVEN J. KRIDEL Department of Cancer Biology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, NC 27157-1088, USA
  • J. JOHN MANN Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, 1051 Riverside Drive, New York, NY 10032, USA, Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA, Department of Radiology, Columbia University Medical Center, 622 West 168th Street, PB-1-301, New York, NY 10032, USA
  • AKIVA MINTZ Department of Radiology, Columbia University Medical Center, 622 West 168th Street, PB-1-301, New York, NY 10032, USA
  • KIRAN KUMAR SOLINGAPURAM SAI Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, NC 27157-1088, USA

Abstract

Objective: The objective of this study was to evaluate the uptake and specificity of [11C]MPC-6827, a MT targeted PET ligand in prostate, glioblastoma and breast cancer cells.


Methods: [11C]MPC-6827 was synthesized by reacting corresponding desmethyl precursors with [11C]CH3I in a GE-FX2MeI/FX2M radiochemistry module. In vitro binding of [11C]MPC-6827 was performed in breast cancer MDA-MB-231, glioblastoma (GBM) patient-derived tumor (GBM-PDX), GBM U251 and prostate cancer 3 (PC3) cell lines at 37 °C in quadruplicate at 5, 15, 30, 60, and 90 minute incubation time. The nonspecific bindings were determined by incubation with unlabeled microtubule targeting agents MPC-6827, HD-800, colchicine, paclitaxel and docetaxel (5.0 mM).


Results: [11C]MPC-6827 provided the highest binding in the breast cancer cell, MDA-MB-231, among all the cells studied, with 90% specific binding. [11C]MPC-6827 binds to glioblastoma PDX and U251 cells with ~50% and 40% specific binding, whereas, prostate cancer cell line, PC3 cells showed 40% specific binding. [11C]MPC-6827 also exhibits binding to the taxane and colchicine binding sites of MTs, in MDA-MB-231 cells.


Conclusion: These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of the brain and peripheral cancers.

Keywords: PET, Microtubule, Radiotracer, Cancer, Cytoskeleton

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References

1. Dubey J, Ratnakaran N, Koushika SP. Neurodegeneration and microtubule dynamics: death by a thousand cuts. Front Cell Neurosci 2015;9:343-57.
2. Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol 2014;206:461-72.
3. Barlan K, Gelfand VI. Microtubule-based transport and the distribution, tethering, and organization of organelles. Cold Spring Harb Perspect Biol 2017;9:1-12.
4. Nogales E. Structural insights into microtubule function. Ann Rev Biochem 2010;69:277-302.
5. Forth S, Kapoor TM. The mechanics of microtubule networks in cell division. J Cell Biol 2017;216:1525-31.
6. Gadadhar S, Bodakuntla S, Natarajan K, Janke C. The tubulin code at a glance. J Cell Sci 2017;130:347-53.
7. Li L, Yang XJ. Tubulin acetylation: responsible enzymes, biological functions and human diseases. Cell Mol Life Sci 2015;72:4237-55.
8. Song Y, Brady ST. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol 2015;25:125-36.
9. Scholey JM. Kinesin-2 motors transport IFT-particles, dyneins and tubulin subunits to the tips of caenorhabditis elegans sensory cilia: relevance to vision research? Vision Res 2012;75:44-52.
10. Rank KC, Rayment I. Functional asymmetry in kinesin and dynein dimers. Biol Cell 2013;105:1-13.
11. Mollinedo F, Gajate C. Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 2003;8:413-50.
12. Varidaki A, Hong Y, Coffey ET. Repositioning microtubule stabilizing drugs for brain disorders. Front Cell Neurosci 2018;12:1-15.
13. Ballatore C, Brunden KR, Trojanowski JQ, Lee VM, Smith AB 3rd. Non-naturally occurring small molecule microtubule-stabilizing agents: a potential tactic for cns-directed therapies. ACS Chem Neurosci 2017;8:5-7.
14. Pellegrini L, Wetzel A, Granno S, Heaton G, Harvey K. Back to the tubule: microtubule dynamics in parkinson's disease. Cell Mol Life Sci 2017;74:409-34.
15. Hur EM, Lee BD. Microtubule-targeting agents enter the central nervous system (CNS): double-edged swords for treating CNS injury and disease. Int Neurourol J 2014;18:171-8.
16. Eira J, Silva CS, Sousa MM, Liz MA. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders. Prog Neurobiol 2016;141:61-82.
17. Brunden KR, Lee VM, Smith AB, Trojanowski JQ, Ballatore C. Altered microtubule dynamics in neurodegenerative disease: therapeutic potential of microtubule-stabilizing drugs. Neurobiol Dis 2017;105:328-35.
18. Katsetos CD, Draber P. Tubulins as therapeutic targets in cancer: from bench to bedside. Curr Pharm Des 2012;18:2778-92.
19. Katsetos CD, Draber P, Kavallaris M. Targeting ?III-tubulin in glioblastoma multiforme: from cell biology and histopathology to cancer therapeutics. Anticancer Agents Med Chem 2011;11:719-28.
20. Laggner U, Pipp I, Budka H, Hainfellner JA, Preusser M. Immunohistochemical detection of class III beta-tubulin in primary brain tumours: variable expression in most tumour types limits utility as a differential diagnostic marker. Histopathology 2007;50:949-52.
21. Miconi G, Palumbo P, Dehcordi SR, La Torre C, Lombardi F, Evtoski Z, et al. Immunophenotypic characterization of human glioblastoma stem cells: correlation with clinical outcome. J Cell Biochem 2015;116:864-76.
22. Bordji K, Grandval A, Cuhna Alves L, Lechapt Zalcman E, Bernaudin M. Hypoxia-inducible factor-2? (HIF-2?), but not HIF-1?, is essential for hypoxic induction of class III ?-tubulin expression in human glioblastoma cells. FEBS J 2014;281:5220-36.
23. Mukhtar E, Adhami VM, Mukhtar H. Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther 2014;13:275-84.
24. Florian S, Mitchison TJ. Anti-microtubule drugs. Methods Mol Biol 2016;1413:403-21.
25. Wilson L, Jordan MA. New microtubule/tubulin-targeted anticancer drugs and novel chemotherapeutic strategies. J Chemother 2004;16:83-5.
26. Dostal V, Libusova L. Microtubule drugs: action, selectivity, and resistance across the kingdoms of life. Protoplasma 2014;251:991–1005.
27. Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, et al. ?III-tubulin: biomarker of taxane resistance or drug target? Expert Opin Ther Targets 2013;17:461-72.
28. Bukhari SNA, Kumar GB, Revankar HM, Qin HL. Development of combretastatins as potent tubulin polymerization inhibitors. Bioorg Chem 2017;72:130-47.
29. Sarkar T. Microtubule targeting anti-mitotic agents as anti-cancer drugs: a review. Int J Multidisciplinary Approach Studies 2015;10:187-94.
30. Zhao Y, Mu X, Du G. Microtubule-stabilizing agents: new drug discovery and cancer therapy. Pharmacol Ther 2016;162:134-43.
31. Cortes J, Vidal M. Beyond taxanes: the next generation of microtubule-targeting agents. Breast Cancer Res Treat 2012;133:821-30.
32. Tangutur AD, Kumar D, Krishna KV, Kantevari S. Microtubule targeting agents as cancer chemotherapeutics: an overview of molecular hybrids as stabilizing and destabilizing agents. Curr Top Med Chem 2017;17:2523-37.
33. van der Veldt AA, Hendrikse NH, Smit EF, Mooijer MP, Rijnders AY, Gerritsen WR, et al. Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients. Eur J Nucl Med Mol Imaging 2010;37:1950-8.
34. Kumar JSD, Solingapuram Sai KK, Prabhakaran J, Dileep H, Mintz A, Mann JJ. Radiosynthesis and In vivo evaluation of [11C]MPC-6827, the first brain penetrant microtubule PET ligand. J Med Chem 2018;61:2118-23.
35. Solingapuram Sai KK, Prabhakaran J, Ramanathan G, Rideout S, Whitlow C, Mintz A, et al. Radiosynthesis and evaluation of [11C]HD-800, a high affinity brain penetrant PET tracer for imaging microtubules. ACS Med Chem Lett 2018;9:452-6.
36. Solingapuram Sai KK, Sattiraju A, Almaguel FG, Xuan A, Rideout S, Krishnaswamy. Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker. Oncotarget 2017;8:50997-1007.
37. Solingapuram Sai KK, Bashetti N, Chen X, Norman S, Hines JW, Meka O, et al. Initial biological evaluations of F-KS1, a novel ascorbate derivative to image oxidative stress in cancer. EJNMMI Res 2019;9:43-52.
38. Solingapuram Sai KK, Das BC, Sattiraju A, Almaguel FG, Craft S, Mintz A. Radiolabeling and initial biological evaluation of [F]KBM-1 for imaging RAR-? receptors in neuroblastoma. Bioorg Med Chem lett 2017;27:1425-7.
39. Inbathamizh L, Padmini E. Evaluation of growth inhibitory potential of moringa oleifera flowers on pc3 cell lines. Asian J Pharm Clin Res 2013;6:60-4.
40. Balashanmugam P, Mosa CK, Kowsalya E. In vitro cytotoxicity and antioxidant evaluation of biogenic synthesized gold nanoparticles from marsilea quadrifolia on lung and ovarian cancer cells. Int J Appl Pharm 2018;10:153-8.
41. Kasibhatla S, Baichwal V, Cai SX, Roth B, Skvortsova I, Skvortsov S, et al. MPC-6827: a small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps. Cancer Res 2007;67:5865-71.
42. De Martino G, La Regina G, Coluccia A, Edler MC, Barbera MC, Brancale A, et al. Arylthioindoles, potent inhibitors of tubulin polymerization. J Med Chem 2004;4725:6120-3.
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KUMAR, J. S. D., J. PRABHAKARAN, N. DAMUKA, J. W. HINES, S. J. KRIDEL, J. J. MANN, A. MINTZ, and K. K. SOLINGAPURAM SAI. “EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 12, no. 1, Nov. 2019, pp. 43-47, doi:10.22159/ijpps.2020v12i1.35657.
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