Identification

Name
Cantharidin
Accession Number
DB12328
Type
Small Molecule
Groups
Approved, Investigational
Description

Cantharidin is a naturally occurring odorless, colorless fatty substance of the terpenoid class that is produced as an oral fluid in the alimentary canal of the male blister beetle [1, 2]. For its natural purpose, the male blister beetle secretes and presents the cantharidin to a female beetle as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with the substance as defense against predators.

Available synthetically since the 1950s, topical applications of cantharidin have been used predominantly as a treatment for cutaneous warts since that time [1, 2]. In 1962 however, marketers of cantharidin failed to produce sufficient efficacy data, resulting in the FDA revision of approval of cantharidin [2].

Today, topcial cantharidin products do not necessarily demonstrate any particular better effectiveness at treating topical skin conditions like warts than other commonly available vesicant and/or keratolytics although various studies have also investigated the possibility of using cantharidin as an inflammatory model or in cancer treatment [2]. Regardless, the onging lack of FDA approval is likely related to certain toxic effects that were observed following oral ingestion, which includes ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance in humans and animals [1].

Structure
Thumb
Synonyms
  • 1,2-Dimethyl-3,6-epoxyperhydrophthalic anhydride
  • Cantharidine
  • Cantharone
  • exo-1,2-cis-Dimethyl-3,6-epoxyhexahydrophthalic anhydride
  • Kantharidin
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Canthacur-PSCantharidin (1 %) + Podophyllin (5 %) + Salicylic acid (30 %)LiquidTopicalPaladin Labs Inc1983-12-31Not applicableCanada
Cantharone PlusCantharidin (1 %) + Podophyllin (2 %) + Salicylic acid (30 %)LiquidTopicalDormer Laboratories Inc.1984-12-31Not applicableCanada
Categories
UNII
IGL471WQ8P
CAS number
56-25-7
Weight
Average: 196.202
Monoisotopic: 196.073558866
Chemical Formula
C10H12O4
InChI Key
DHZBEENLJMYSHQ-XCVPVQRUSA-N
InChI
InChI=1S/C10H12O4/c1-9-5-3-4-6(13-5)10(9,2)8(12)14-7(9)11/h5-6H,3-4H2,1-2H3/t5-,6+,9+,10-
IUPAC Name
(1R,2S,6R,7S)-2,6-dimethyl-4,10-dioxatricyclo[5.2.1.0²,⁶]decane-3,5-dione
SMILES
[H][C@]12CC[C@]([H])(O1)[C@]1(C)C(=O)OC(=O)[C@]21C

Pharmacology

Indication

The only therapeutic use for which cantharidin is currently primarily indicated for is as an active ingredient in topical agents for treating common warts (verruca vulgaris), periungual warts, plantar warts, and molluscum contagiosum [1, 2, 7].

At the same time, such topical cantharidin applications have also been used for a number of off-label indications like callus removal, cutaneous leishmaniasis, herpes zoster, and acquired perforating dermatosis [2]. Furthermore, since most topical cantharidin applications are most commonly available in a 0.7% formulation or a more potent 1% mixture, the 0.7% formulation is most commonly indicated for the treatment of common warts, periungual warts, and molluscum contagiosum while the more potent 1% mixture is typically limited only for use by healthcare professionals in a clinical setting for treating plantar warts and other more specialized off-label conditions [1, 2, 7].

Moreover, there have also been studies into whether or not cantharidin could be effective at being used as an inflammatory model or in cancer treatment - either of which has yet to formally elucidate any results [2].

Associated Conditions
Pharmacodynamics

Cantharidin is a natural toxin produced by the blistering beetle that possesses both vesicant (blistering) and keratolytic effects [1, 2]. The substance elicits these effects by inducing acantholysis (loss of intercellular connections) through the targeting of the desmosomal dense plaque, resulting in the detachment of the desmosomes from the tonofilaments [1, 2]. Cantharidin's effectiveness against warts is proposed to be a result of the exfoliation of the wart body as a consequence of the compound's acantholytic action [7]. This acantholytic action generally does not go beyond the epidermal cells so that the basal layer remains intact and minimal effect occurs on the corium [7]. There is consequently no scarring from the topical application of cantharidin [7].

Mechanism of action

Cantharidin is specifically absorbed by lipids in the membrane of epidermal keratinocytes, where it activates the release of neutral serine proteases [1, 2]. These enzymes subsequently break the peptide bonds in surrounding proteins, leading to the progressive degeneration of desmosomal dense plaques, which are important cellular structures that participate in cell-to-cell adhesion [1, 2]. Such degeneration results in the detachment of the tonofilaments that hold cells together. This process as a whole leads to the selective acantholysis (loss of cellular connections) and blistering of the skin when the cantharidin topical application is applied upon specific topical developments like warts [1, 2]. A blister(s) at the application site develop within 24 to 48 hours of application and typically resolve within 4 to 7 days [1, 2]. Factors that can modify this proposed time frame include the volume or concentration of cantharidin used, physical contact time of the applied compound (usually between 4 to 24 hours), the presence of any occlusive dressings, or even patient sensitivity to cantharidin [1, 2]. The blistered lesions ultimately heal without scarring [1, 2].

Finally, there are some studies that suggest cantharidin's chemical profile as a potent and selective inhibitor of protein phosphatase 2A confers upon it an oxidative stress-independent growth inhibition of pancreatic cancer cells through cancer cell-cycle arrest and apoptosis [3].

Nevertheless, the fact that little data regarding the pharmacodynamics and pharmacokinetics of cantharidin in the human body exists [5] and certain toxic effects of cantharidin that have been observed following oral ingestion in humans like ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance [1] are strong reasons as to why the compound currently lacks FDA approval is used fairly limitedly for formal therapeutic indications.

TargetActionsOrganism
UAryl hydrocarbon receptor
agonist
Human
ASkin epithelial cells
Vesicant
Human
Absorption

Cantharidin is absorbed from the gastrointestinal tract, and, to a limited extent from the skin as well [6].

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Volume of distribution

After oral or IP injection of (3)H-labeled cantharidin, high levels of radioactivity distributed to and were exhibited in the bile, kidney, liver, stomach, and tumor cells of ascites hepatoma-bearing mice [6]. Such distribution suggests the agent has an affinity for liver and tumor tissues [6].

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Protein binding

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Metabolism

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Route of elimination

It has been observed that absorbed cantharidin is excreted by the kidney [6].

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Half life

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Clearance

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 [5]. There are however some studies regarding such data in animal models like beagle dogs [4].

Toxicity

Side effects observed from the topical application of cantharidin include blistering, erythema, pain, bleeding, ring warts, post-inflammatory hyperpigmentation, lymphangitis, secondary bacterial cellulitis, scarring, and varicelliform vesicular dermatitis [2].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Al-Dawsari NA, Masterpol KS: Cantharidin in Dermatology. Skinmed. 2016 Apr 1;14(2):111-4. eCollection 2016. [PubMed:27319954]
  2. Torbeck R, Pan M, DeMoll E, Levitt J: Cantharidin: a comprehensive review of the clinical literature. Dermatol Online J. 2014 Jun 15;20(6). [PubMed:24945640]
  3. Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X: Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 2010 May;101(5):1226-33. doi: 10.1111/j.1349-7006.2010.01523.x. Epub 2010 Feb 5. [PubMed:20331621]
  4. Dang Y, Zhu C: [Pharmacokinetics and bioavailability of cantharidin in beagle dogs]. Zhongguo Zhong Yao Za Zhi. 2009 Aug;34(16):2088-91. [PubMed:19938553]
  5. NIH ClinicalTrials.gov: First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699 [Link]
  6. NLM Toxnet: Catharidine [Link]
  7. Canthacur (cantharidin 0.7%) Solution for Topical Use Package Insert [File]
External Links
KEGG Compound
C16778
PubChem Compound
5944
PubChem Substance
347828590
ChemSpider
5731
BindingDB
50090505
ChEBI
64213
ChEMBL
CHEMBL48449
Wikipedia
Cantharidin
MSDS
Download (26.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceCardiovascular Function1
1Active Not RecruitingDiagnosticRheumatoid Arthritis1
1CompletedOtherInflammatory Reaction1
2CompletedTreatmentMolluscum Contagiosum2
4CompletedTreatmentWart, Genital1
Not AvailableCompletedTreatmentMolluscum Contagiosum, Skin Disease1
Not AvailableCompletedTreatmentVerruca Vulgaris1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidTopical
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility16.6 mg/mLALOGPS
logP1.1ALOGPS
logP1.06ChemAxon
logS-1.1ALOGPS
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area52.6 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity45.4 m3·mol-1ChemAxon
Polarizability18.54 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as furofurans. These are organic compounds containing a two furan rings fused to each other. Furan is a five-membered aromatic ring with four carbon atoms and one oxygen atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Furofurans
Sub Class
Not Available
Direct Parent
Furofurans
Alternative Parents
Dicarboxylic acids and derivatives / Tetrahydrofurans / Carboxylic acid anhydrides / Lactones / Oxacyclic compounds / Dialkyl ethers / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Furofuran / Dicarboxylic acid or derivatives / Tetrahydrofuran / Carboxylic acid anhydride / Lactone / Oxacycle / Ether / Dialkyl ether / Carboxylic acid derivative / Organic oxygen compound
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
monoterpenoid, cyclic dicarboxylic anhydride (CHEBI:64213)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Transcription regulatory region dna binding
Specific Function
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes...
Gene Name
AHR
Uniprot ID
P35869
Uniprot Name
Aryl hydrocarbon receptor
Molecular Weight
96146.705 Da
References
  1. Zhang S, Qin C, Safe SH: Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003 Dec;111(16):1877-82. [PubMed:14644660]
2. Skin epithelial cells
Kind
Group
Organism
Human
Pharmacological action
Yes
Actions
Vesicant
References
  1. Al-Dawsari NA, Masterpol KS: Cantharidin in Dermatology. Skinmed. 2016 Apr 1;14(2):111-4. eCollection 2016. [PubMed:27319954]
  2. Torbeck R, Pan M, DeMoll E, Levitt J: Cantharidin: a comprehensive review of the clinical literature. Dermatol Online J. 2014 Jun 15;20(6). [PubMed:24945640]

Drug created on October 20, 2016 15:57 / Updated on November 02, 2018 07:23