EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES
DOI:
https://doi.org/10.22159/ijpps.2020v12i1.35657Keywords:
PET, Microtubule, Radiotracer, Cancer, CytoskeletonAbstract
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.
Downloads
References
Dubey J, Ratnakaran N, Koushika SP. Neurodegeneration and microtubule dynamics: death by a thousand cuts. Front Cell Neurosci 2015;9:343-57.
Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol 2014;206:461-72.
Barlan K, Gelfand VI. Microtubule-based transport and the distribution, tethering, and organization of organelles. Cold Spring Harb Perspect Biol 2017;9:1-12.
Nogales E. Structural insights into microtubule function. Ann Rev Biochem 2010;69:277-302.
Forth S, Kapoor TM. The mechanics of microtubule networks in cell division. J Cell Biol 2017;216:1525-31.
Gadadhar S, Bodakuntla S, Natarajan K, Janke C. The tubulin code at a glance. J Cell Sci 2017;130:347-53.
Li L, Yang XJ. Tubulin acetylation: responsible enzymes, biological functions and human diseases. Cell Mol Life Sci 2015;72:4237-55.
Song Y, Brady ST. Post-translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol 2015;25:125-36.
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.
Rank KC, Rayment I. Functional asymmetry in kinesin and dynein dimers. Biol Cell 2013;105:1-13.
Mollinedo F, Gajate C. Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 2003;8:413-50.
Varidaki A, Hong Y, Coffey ET. Repositioning microtubule stabilizing drugs for brain disorders. Front Cell Neurosci 2018;12:1-15.
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.
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.
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.
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.
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.
Katsetos CD, Draber P. Tubulins as therapeutic targets in cancer: from bench to bedside. Curr Pharm Des 2012;18:2778-92.
Katsetos CD, Draber P, Kavallaris M. Targeting βIII-tubulin in glioblastoma multiforme: from cell biology and histopathology to cancer therapeutics. Anticancer Agents Med Chem 2011;11:719-28.
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.
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.
Bordji K, Grandval A, Cuhna Alves L, Lechapt Zalcman E, Bernaudin M. Hypoxia-inducible factor-2α (HIF-2α), but not HIF-1α, is essential for hypoxic induction of class III β-tubulin expression in human glioblastoma cells. FEBS J 2014;281:5220-36.
Mukhtar E, Adhami VM, Mukhtar H. Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther 2014;13:275-84.
Florian S, Mitchison TJ. Anti-microtubule drugs. Methods Mol Biol 2016;1413:403-21.
Wilson L, Jordan MA. New microtubule/tubulin-targeted anticancer drugs and novel chemotherapeutic strategies. J Chemother 2004;16:83-5.
Dostal V, Libusova L. Microtubule drugs: action, selectivity, and resistance across the kingdoms of life. Protoplasma 2014;251:991–1005.
Karki R, Mariani M, Andreoli M, He S, Scambia G, Shahabi S, et al. βIII-tubulin: biomarker of taxane resistance or drug target? Expert Opin Ther Targets 2013;17:461-72.
Bukhari SNA, Kumar GB, Revankar HM, Qin HL. Development of combretastatins as potent tubulin polymerization inhibitors. Bioorg Chem 2017;72:130-47.
Sarkar T. Microtubule targeting anti-mitotic agents as anti-cancer drugs: a review. Int J Multidisciplinary Approach Studies 2015;10:187-94.
Zhao Y, Mu X, Du G. Microtubule-stabilizing agents: new drug discovery and cancer therapy. Pharmacol Ther 2016;162:134-43.
Cortes J, Vidal M. Beyond taxanes: the next generation of microtubule-targeting agents. Breast Cancer Res Treat 2012;133:821-30.
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.
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.
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.
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.
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.
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.
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-α receptors in neuroblastoma. Bioorg Med Chem lett 2017;27:1425-7.
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.
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.
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.
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.