12-O-Tetradecanoylphorbol-13-acetate

12-O-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein kinase C (PKC).[1][2][3] The effects of TPA on PKC result from its similarity to one of the natural activators of classic PKC isoforms, diacylglycerol. TPA is a small molecule drug.

12-O-Tetradecanoylphorbol-13-acetate
TPA
Names
Preferred IUPAC name
(1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b-Dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1,1a,1b,4,4a,5,7a,7b,8,9-decahydro-9aH-cyclopropa[3,4]benzo[1,2-e]azulene-9,9a-diyl 9a-acetate 9-tetradecanoate
Other names
TPA, PMA, Phorbol myristate acetate,
Tetradecanoylphorbol acetate.
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.109.485
KEGG
UNII
  • InChI=1S/C36H56O8/c1-7-8-9-10-11-12-13-14-15-16-17-18-29(39)43-32-24(3)35(42)27(30-33(5,6)36(30,32)44-25(4)38)20-26(22-37)21-34(41)28(35)19-23(2)31(34)40/h19-20,24,27-28,30,32,37,41-42H,7-18,21-22H2,1-6H3/t24-,27+,28-,30-,32-,34-,35-,36-/m1/s1 ☒N
    Key: PHEDXBVPIONUQT-RGYGYFBISA-N ☒N
  • InChI=1/C36H56O8/c1-7-8-9-10-11-12-13-14-15-16-17-18-29(39)43-32-24(3)35(42)27(30-33(5,6)36(30,32)44-25(4)38)20-26(22-37)21-34(41)28(35)19-23(2)31(34)40/h19-20,24,27-28,30,32,37,41-42H,7-18,21-22H2,1-6H3/t24-,27+,28-,30-,32-,34-,35-,36-/m1/s1
    Key: PHEDXBVPIONUQT-RGYGYFBIBK
  • CCCCCCCCCCCCCC(=O)O[C@@H]1[C@H]([C@]2([C@@H](C=C(C[C@]3([C@H]2C=C(C3=O)C)O)CO)[C@H]4[C@@]1(C4(C)C)OC(=O)C)O)C
  • CCCCCCCCCCCCCC(=O)O[C@@H]2C(C)[C@]1(O)C4/C=C(/C)C(=O)[C@@]4(O)CC(\CO)=C/[C@H]1[C@H]3[C@]2(OC(C)=O)C3(C)C
Properties
C36H56O8
Molar mass 616.83 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

In ROS biology, superoxide was identified as the major reactive oxygen species induced by TPA/PMA but not by ionomycin in mouse macrophages.[4] Thus, TPA/PMA has been routinely used as an inducer for endogenous superoxide production.[5]

TPA is also being studied as a drug in the treatment of hematologic cancer

TPA has a specific use in cancer diagnostics as a B-cell specific mitogen in cytogenetic testing. Cells must be divided in a cytogenic test to view the chromosomes. TPA is used to stimulate division of B-cells during cytogenetic diagnosis of B-cell cancers such as chronic lymphocytic leukemia.[6]

TPA is also commonly used together with ionomycin to stimulate T-cell activation, proliferation, and cytokine production, and is used in protocols for intracellular staining of these cytokines.[7]

TPA induces KSHV reactivation in PEL cell cultures via stimulation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. The pathway involves the activation of the early-immediate viral protein RTA that contributes to the activation of the lytic cycle.[8]

TPA was first found in the Croton plant, a shrub found in Southeast Asia, exposure to which provokes a poison ivy-like rash. It underwent a phase 1 clinical trial.[9]

References
  1. Castagna (1982). "Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters" (PDF). Journal of Biological Chemistry. 257 (13): 7847–7851. doi:10.1016/S0021-9258(18)34459-4. PMID 7085651.
  2. Blumberg (1988). "Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth Rhoads memorial award lecture". Cancer Research. 48 (1): 1–8. PMID 3275491.
  3. Niedel (1983). "Phorbol Diester Receptor Copurifies with Protein Kinase C". Proceedings of the National Academy of Sciences. 80 (1): 36–40. Bibcode:1983PNAS...80...36N. doi:10.1073/pnas.80.1.36. PMC 393304. PMID 6296873.
  4. Swindle (2002). "A Comparison of Reactive Oxygen Species Generation by Rat Peritoneal Macrophages and Mast Cells Using the Highly Sensitive Real-Time Chemiluminescent Probe Pholasin: Inhibition of Antigen-Induced Mast Cell Degranulation by Macrophage-Derived Hydrogen Peroxide" (PDF). The Journal of Immunology. 169 (10): 5866–5873. doi:10.4049/jimmunol.169.10.5866. PMID 12421969. S2CID 21433304.
  5. Huang (2014). "Megakaryocytic Differentiation of K562 Cells Induced by PMA Reduced the Activity of Respiratory Chain Complex IV". PLoS ONE. 9 (5): e96246. Bibcode:2014PLoSO...996246H. doi:10.1371/journal.pone.0096246. PMC 4015910. PMID 24817082.
  6. The AGT cytogenetics laboratory manual. 3rd ed. Barch, Margaret J., Knutsen, Turid., Spurbeck, Jack L., eds. 1997. Lippincott-Raven.
  7. "Flow Cytometry Intracellular Staining Guide". eBioscience, Inc. Retrieved 2011-09-25.
  8. Cohen, Adina; Brodie, Chaya; Sarid, Ronit (April 2006). "An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus". The Journal of General Virology. 87 (Pt 4): 795–802. CiteSeerX 10.1.1.321.5484. doi:10.1099/vir.0.81619-0. PMID 16528027.
  9. Schaar, Dale; Goodell, Lauri; Aisner, Joseph; Cui, Xiao Xing; Han, Zheng Tao; Chang, Richard; Martin, John; Grospe, Stephanie; Dudek, Liesel; Riley, Joan; Manago, Jacqueline; Lin, Yong; Rubin, Eric H.; Conney, Allan; Strair, Roger K. (June 2006). "A phase I clinical trial of 12- O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies". Cancer Chemotherapy and Pharmacology. 57 (6): 789–795. doi:10.1007/s00280-005-0125-1. ISSN 1432-0843. PMID 16231182. S2CID 33377618.
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