TPA
[CAS# 16561-29-8]

Identification

• Classification: Chemical reagent >> Organic reagent >> Ester >> Acid ester compound
• Name: TPA
• Molecular Formula: C₃₆H₅₆O₈
• Molecular Weight: 616.84
• CAS Registry Number: 16561-29-8
• EC Number: 605-413-5
• SMILES: 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

Properties

• Density: 1.17±0.1 g/cm³ Calc.^*
• Boiling point: 698.1±55.0 ºC 760 mmHg (Calc.)^*
• Flash point: 208.1±25.0 ºC (Calc.)^*
• Solubility: Soluble 100 mM (DMSO) (Expl.)
• Index of refraction: 1.553 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H315
• Precautionary Statements: P264-P280-P302+P352-P321-P332+P317-P362+P364

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Carcinogenicity	Carc.	2	H351
Serious eye damage	Eye Dam.	1	H318
Eye irritation	Eye Irrit.	2	H319
Skin sensitization	Skin Sens.	1	H317
Acute toxicity	Acute Tox.	1	H330
Skin corrosion	Skin Corr.	1B	H314
Acute toxicity	Acute Tox.	3	H301
Acute toxicity	Acute Tox.	1	H310
Acute toxicity	Acute Tox.	3	H331
Respiratory sensitization	Resp. Sens.	1	H334
Acute toxicity	Acute Tox.	2	H300
Acute toxicity	Acute Tox.	3	H311

Discovory and Applicatios

TPA, or 12-O-tetradecanoylphorbol-13-acetate, is a synthetic derivative of phorbol ester originally isolated from the plant *Croton tiglium*. It is structurally related to diacylglycerol (DAG), a natural activator of protein kinase C (PKC), and mimics its activity by binding to the regulatory domain of PKC isoforms. Through this interaction, TPA induces a wide array of biological responses, including cell proliferation, differentiation, inflammation, and tumor promotion. Because of these potent effects, TPA has been extensively used in biomedical research, particularly in studies of cancer biology and signal transduction.

The discovery of TPA’s biological activity can be traced to investigations into the tumor-promoting properties of phorbol esters found in Euphorbiaceae plants. Researchers observed that extracts from these plants could enhance the growth of tumors in animal models after initial exposure to chemical carcinogens. Subsequent chemical characterization led to the identification of specific active phorbol esters, among which TPA became the most commonly used experimental agent. Its role as a tumor promoter in multistage carcinogenesis models made it a valuable tool for dissecting the mechanisms of cancer development and progression.

TPA’s principal mechanism involves the activation of PKC, a family of serine/threonine kinases that regulate diverse cellular functions. By mimicking DAG, TPA binds to the C1 domain of PKC and causes its translocation to the cell membrane, where it becomes catalytically active. Activated PKC phosphorylates multiple substrates involved in gene expression, cytoskeletal reorganization, cell cycle control, and apoptosis. TPA thus serves as a powerful modulator of intracellular signaling pathways, and its effects are both time- and concentration-dependent.

In cancer research, TPA has been used to study oncogene expression, cell cycle transitions, and the transformation of cultured cells. For instance, it can induce the expression of early response genes such as *c-fos*, *c-jun*, and *egr-1*, which are involved in the regulation of proliferation and differentiation. It also promotes the transformation of certain fibroblasts in conjunction with oncogenic Ras or other genetic lesions. These features made TPA essential in establishing in vitro models of transformation and in vivo models of multistage skin carcinogenesis.

In immunology, TPA has been widely employed to activate T cells in vitro. When combined with ionomycin, it triggers robust cytokine production, proliferation, and activation of T lymphocytes. This property has been utilized in functional assays to assess T-cell responses, investigate signaling cascades, and identify immune modulators. In neuroscience, TPA has contributed to understanding PKC’s role in synaptic plasticity and neurotransmitter release.

Despite its utility, TPA is not used therapeutically due to its potent tumor-promoting effects and the broad spectrum of cellular responses it elicits. Nevertheless, its impact on the understanding of PKC-mediated signaling and cellular regulation has been substantial. TPA remains a prototypical tool compound in experimental biology, particularly in the context of cell signaling and cancer research.

Over time, the study of TPA and related phorbol esters has led to the development of more selective PKC modulators, both activators and inhibitors, for research and potential clinical applications. These advances continue to build on foundational knowledge gained through the use of TPA, reinforcing its significance in the history of biomedical research.

References

2009. PKC-dependent stimulation of the human MCT1 promoter involves transcription factor AP2. American Journal of Physiology. Gastrointestinal and Liver Physiology, 296(2).
DOI: 10.1152/ajpgi.90503.2008

2010. Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion. Cancer Immunology, Immunotherapy, 60(2).
DOI: 10.1007/s00262-010-0891-4

1983. Affinity Modulation of Epidermal Growth Factor Membrane Receptors by Biologically Active Phorbol and Ingenol Esters. Biochemical and Biological Markers of Neoplastic Transformation.
DOI: 10.1007/978-1-4684-4454-4_24