Evaluation of [11C]MPC-6827 as a microtubule targeting PET radiotracer in cancer lines

Evaluation of [11C]MPC-6827 in cancer

  • DILEEP KUMAR New York State Psychiatric Institute/ Columbia University https://orcid.org/0000-0001-6688-3991
  • Jaya Prabhakaran
  • Naresh Damuka
  • Justin W Hines
  • Steven J Kridel
  • J John Mann
  • Akiva Mintz
  • Kiran Kumar Solingapuram Sai

Abstract

Microtubule (MTs) are implicated in the pathogenesis of cancer, and MT disruption with microtubule-targeted agents (MTA) is a valuable chemotherapeutic strategy. However, most MTAs developed to date are substrates for P-glycoprotein (p-GP) and multidrug resistance protein 1 (MDR1), preventing their use in the treatment of brain malignancies or as in vivo PET imaging agents in the brain.  [11C]MPC-6827 is the first brain-penetrating MTA based radiotracer, exhibits excellent uptake and specific binding in rodent brain. The objective of this study is to evaluate the uptake of [11C]MPC-6827 in cell lines of prostate, brain and breast malignancies. [11C]MPC-6827 provided the highest binding in breast cancer cell, MDA-MB-231, among all the cells studied, with 95% 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. These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of brain and peripheral cancers.

Keywords: PET, microtubule, radiotracer, cancer, cytoskeleton

Downloads

Download data is not yet available.

References

1. Dubey J, Ratnakaran N, Koushika SP. Neurodegeneration and microtubule dynamics: death by a thousand cuts. Front. Cell. Neurosci. 2015, 9, 343-357.
2 Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol. 2014, 206(4), 461-472
3. Barlan K, Gelfand VI. Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles. Cold Spring Harb. Perspect. Biol. 2017, 9(5), a025817.
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(6), 1525-1531.
6. Gadadhar S, Bodakuntla S, Natarajan K, Janke C. The tubulin code at a glance. J. Cell. Sci. 2017, 130(8), 1347-1353.
7. Li L, Yang XJ. Tubulin acetylation: responsible enzymes, biological functions and human diseases. Cell. Mol. Life Sci. 2015, 72(22), 4237-4255.
8. Song Y, Brady ST. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell. Biol. 2015, 25(3), 125-136.
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), 1-13.
11. Mollinedo F, Gajate C. Microtubules, microtubule-interfering agents and apoptosis. Apoptosis. 2003, 8(5), 413-450.
12. Varidaki A, Hong Y, Coffey ET. Repositioning Microtubule Stabilizing Drugs for Brain Disorders. Front. Cell Neurosci. 2018, 12, 226.
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(1), 5-7.
14. Pellegrini L, Wetzel A, Grannó S, Heaton G, Harvey K. Back to the tubule: microtubule dynamics in Parkinson's disease. Cell. Mol. Life Sci. 2017, 74(3), 409-434.
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(4), 171-178.
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 3rd, Trojanowski JQ, Ballatore C. Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs. Neurobiol. Dis. 2017, 105, 328-335.
18. Katsetos CD, Dráber P. Tubulins as therapeutic targets in cancer: from bench to bedside. Curr. Pharm. Des. 2012,18(19), 2778-2792.
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(8), 719-728.
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(7), 949-952.
21. Miconi G, Palumbo P, Dehcordi SR, La Torre C, Lombardi F, Evtoski Z, Cimini AM, Galzio R, Cifone MG, Cinque B. Immunophenotypic characterization of human glioblastoma stem cells: correlation with clinical outcome. J. Cell Biochem. 2015, 116(5), 864-876.
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(23), 5220-5236.
23. Mukhtar E, Adhami VM, Mukhtar H. Targeting microtubules by natural agents for cancer therapy. Mol. Cancer Ther. 2014, 13(2), 275-284.
24. Florian S, Mitchison TJ. Anti-Microtubule Drugs. Methods Mol. Biol. 2016, 1413, 403-421.
25. Wilson L, Jordan MA. New microtubule/tubulin-targeted anticancer drugs and novel chemotherapeutic strategies. J Chemother. 2004, 16(4), 83-5.
26. Dostál V, Libusová L. Microtubule drugs: action, selectivity, and resistance across the kingdoms of life, Protoplasma, 2014, 251(5), 991–1005.
27. Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, Ferlini C. ?III-Tubulin: biomarker of taxane resistance or drug target? Expert Opin. Ther. Targets. 2013, 17(4), 461-72.
28. Bukhari SNA, Kumar GB, Revankar HM, Qin HL. Development of combretastatins as potent tubulin polymerization inhibitors. Bioorg. Chem. 2017, 72, 130-147.
29. Sarkar T. Microtubule Targeting Anti-mitotic Agents as Anti-Cancer Drugs: A Review. Int. J. Multidisciplinary Approach and Studies, 2015, 0 (5), 187-194.
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(3), 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(22), 2523-2537.
33. van der Veldt AA, Hendrikse NH, Smit EF, Mooijer MP, Rijnders AY, Gerritsen WR, van der Hoeven JJ, Windhorst AD, Lammertsma AA, Lubberink M. Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients. Eur. J. Nucl. Med. Mol. Imaging. 2010, 37(10), 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(5), 2118-2123.
35. Solingapuram Sai KK, Prabhakaran J, Ramanathan G, Rideout S, Whitlow C, Mintz A, Mann JJ, Kumar JSD. Radiosynthesis and Evaluation of [11C]HD-800, a High Affinity Brain Penetrant PET Tracer for Imaging Microtubules. ACS Med. Chem. Lett. 2018, 9(5), 452-456.
36. Kasibhatla S, Baichwal V, Cai SX, Roth B, Skvortsova I, Skvortsov S, Lukas P, English NM, Sirisoma N, Drewe J, Pervin A, Tseng B, Carlson RO, Pleiman CM. MPC-6827: a small-molecule inhibitor of microtubule formation that is not a substrate for multidrug resistance pumps. Cancer Res. 2007, 67(12), 5865-5871.
37. De Martino G, La Regina G, Coluccia A, Edler MC, Barbera MC, Brancale A, Wilcox E, Hamel E, Artico M, Silvestri R. Arylthioindoles, potent inhibitors of tubulin polymerization. J. Med. Chem. 2004, 47(25),6120-3.
Statistics
23 Views | Downloads
How to Cite
DILEEP KUMAR, 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 Lines”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 12, no. 1, Nov. 2019, https://innovareacademics.in/journals/index.php/ijpps/article/view/35657.
Section
Original Article(s)