Cantharidin

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Identification

Summary

Cantharidin is a natured product indicated to treat molluscum contagiosum

Brand Names

Cantharone Plus, Ycanth

Generic Name

Cantharidin

DrugBank Accession Number

DB12328

Background

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. Post-copulation, the female beetle places the cantharidin over her eggs as protection against any potential predators.^1,2

Topical 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 ongoing lack of FDA approval is likely related to certain toxic effects that were observed following oral ingestion, which include ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance in humans and animals ¹.

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 Nevertheless, it gained its first FDA approval on Jul 21, 2023, under the brand name YCANTH™ by Verrica Pharmaceuticals for the treatment of molluscum contagiosum in adult and pediatric patients.⁸ The approval was based on positive results from 2 phase III trials, CAMP-1 and CAMP-2, where 46% and 52% of patients treated with cantharidin achieved complete molluscum clearance, respectively.⁸

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 196.202
Monoisotopic: 196.073558866
Chemical Formula: C₁₀H₁₂O₄

Synonyms

1,2-Dimethyl-3,6-epoxyperhydrophthalic anhydride
Cantharidin
Cantharidine
Cantharone
exo-1,2-cis-Dimethyl-3,6-epoxyhexahydrophthalic anhydride
Kantharidin

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Pharmacology

Indication

Cantharidin is approved by the FDA for the topical treatment of molluscum contagiosum in adult and pediatric patients 2 years of age and older.⁹ It has also been approved by Health Canada for the treatment of common warts (verruca vulgaris), periungual warts, and molluscum contagiosum as a standalone product and resistant and heavily keratinized plantar warts as a combination product with salicylic acid and podophyllin.¹⁰

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.^1,2,11

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 elucidate any results formally.²

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Dose Form
Treatment of	Molluscum contagiosum		••••••••••••	•••••• •••••••••	••••••••
Treatment of	Molluscum contagiosum		••••••••••••		••••••••
Treatment of	Molluscum contagiosum		••• •••
Treatment of	Periungual warts		••••••••••••		••••••••
Used in combination to treat	Plantar warts	Combination Product in combination with: Podophyllin (DB09094), Salicylic acid (DB00936)	••••••••••••		••••••••

Contraindications & Blackbox Warnings

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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.¹¹ 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. There is consequently no scarring from the topical application of cantharidin.¹¹

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 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 develops within 24 to 48 hours of application and typically resolves 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.

Target	Actions	Organism
ASerine/threonine-protein phosphatase PP1-alpha catalytic subunit	inhibitor	Humans
UAryl hydrocarbon receptor	agonist	Humans

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 has 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 were distributed to and exhibited in the bile, kidney, liver, stomach, and tumor cells of ascites hepatoma-bearing mice. Such distribution suggests the agent has an affinity for liver and tumor tissues.⁶

Protein binding

Metabolism

Route of elimination

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

Half-life

Clearance

Adverse Effects

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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

Oral ingestion of cantharidin has resulted in renal failure, blistering and severe damage to the gastrointestinal tract, coagulopathy, seizures, and flaccid paralysis. In the event that YCANTH topical solution is ingested, patients should seek medical attention immediately and contact a Poison Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.⁹

Carcinogenicity studies have not been conducted with cantharidin. Cantharidin was not mutagenic in a bacteria reverse mutation (Ames) assay. An in vitro chromosomal aberration assay in human lymphocytes with cantharidin was inconclusive. Cantharidin was positive in an in vitro micronucleus assay in TK6 cells, primarily through an aneugenic mechanism. The effects of cantharidin on fertility have not been evaluated.⁹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Cantharidin 0.7%	Liquid	0.7 g/100g	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable
Ycanth	Solution	3.20 mg/0.45mL	Topical	Verrica Pharmaceuticals Inc.	2023-07-21	Not applicable
Ycanth	Solution	3.20 mg/0.45mL	Topical	Verrica Pharmaceuticals Inc.	2023-07-21	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
CANTHACUR PS %1,%5,%30 TOPIKAL SOLUSYON 7,5 ML	Cantharidin (10.2 mg/ml) + Podophyllin (51 mg/ml) + Salicylic acid (306 mg/ml)	Solution	Topical	ASSOS İLAÇ KİMYA GIDA ÜRÜNLERİ ÜRETİM VE TİC. A.Ş.	2005-06-10	Not applicable
Canthacur-PS	Cantharidin (1 %) + Podophyllin (5 %) + Salicylic acid (30 %)	Liquid	Topical	Paladin Labs Inc	1983-12-31	2017-05-30
Cantharone Plus	Cantharidin (1 %) + Podophyllin (2 %) + Salicylic acid (30 %)	Liquid	Topical	Dormer Laboratories Inc.	1984-12-31	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cantharidin 0.7%	Cantharidin (0.7 g/100g)	Liquid	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable
Cantharidin 1% / Podophyllum Resin 5% / Salicylic Acid 30%	Cantharidin (1 g/100g) + Podophyllin (5 g/100g) + Salicylic acid (30 g/100g)	Liquid	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable

Chemical Identifiers

UNII: IGL471WQ8P
CAS number: 56-25-7
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

References

General References

Al-Dawsari NA, Masterpol KS: Cantharidin in Dermatology. Skinmed. 2016 Apr 1;14(2):111-4. eCollection 2016. [Article]
Torbeck R, Pan M, DeMoll E, Levitt J: Cantharidin: a comprehensive review of the clinical literature. Dermatol Online J. 2014 Jun 15;20(6). [Article]
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. [Article]
Dang Y, Zhu C: [Pharmacokinetics and bioavailability of cantharidin in beagle dogs]. Zhongguo Zhong Yao Za Zhi. 2009 Aug;34(16):2088-91. [Article]
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]
NLM Toxnet: Catharidine [Link]
TITCK Product Information: Canthacur (cantharidin) topical solution [Link]
Approval of YCANTH™ (cantharidin) topical solution as the First FDA approved Treatment of Pediatric and Adult Patients with Molluscum Contagiosum [Link]
FDA Approved Drug Product: YCANTHTM (cantharidin) topical solution [Link]
Health Canada Approved Drug Proucts: CANTHARONE (Cantharidin) and CANTHARONE PLUS (Cantharidin + salicylic acid + podophyllin) topical solution [Link]
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
RxNav: 1984
ChEBI: 64213
ChEMBL: CHEMBL48449
ZINC: ZINC000017611186
Wikipedia: Cantharidin

MSDS

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Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
4	Completed	Treatment	Molluscum Contagiosum Skin Infection / Verruca Vulgaris	1	somestatus	stop reason	just information to hide
4	Completed	Treatment	Warts, Genital	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Molluscum Contagiosum	2	somestatus	stop reason	just information to hide
2	Completed	Treatment	Condylomata Acuminata / Papilloma Viral Infection / Sexually Transmitted Disease (STD) / Sexually Transmitted Diseases, Viral / Skin Diseases / Skin Diseases, Infectious / Verruca (Warts) / Viral infections of the skin	1	somestatus	stop reason	just information to hide
2	Completed	Treatment	DNA Virus Infections / Papilloma Viral Infection / Skin Diseases / Skin Diseases, Infectious / Tumor Virus Infections / Verruca (Warts) / Verruca Vulgaris / Viral Disease / Viral infections of the skin / Warts Hand	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Topical	0.7 %
Solution	Topical
Liquid	Topical	0.7 g/100g
Liquid	Topical
Solution	Topical	3.20 mg/0.45mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11147790	No	2021-10-19	2038-08-22
US11052064	No	2021-07-06	2035-05-28

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	16.6 mg/mL	ALOGPS
logP	1.1	ALOGPS
logP	1.06	Chemaxon
logS	-1.1	ALOGPS
pKa (Strongest Basic)	-4.2	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	52.6 Å²	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	45.4 m³·mol^-1	Chemaxon
Polarizability	18.54 Å³	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0900000000-5d18c0d738f16ee2fef6
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0900000000-9c1327f4990426b67cd7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-3900000000-d254d7abb3ad3ba19da5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-0900000000-d0cdac726fbcbc5b1446
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01b9-4900000000-de68b7e43d4c795c5680
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-2900000000-d7bb09c895754c598054
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	140.03691	predicted	DeepCCS 1.0 (2019)
[M+H]+	142.4325	predicted	DeepCCS 1.0 (2019)
[M+Na]+	148.70927	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Serine/threonine-protein phosphatase PP1-alpha catalytic subunit

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Dephosphorylates CENPA (PubMed:25556658). Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy (PubMed:26083323)
Specific Function: Cadherin binding involved in cell-cell adhesion
Gene Name: PPP1CA
Uniprot ID: P62136
Uniprot Name: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit
Molecular Weight: 37511.695 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details2. Aryl hydrocarbon receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Ligand-activated transcription factor that enables cells to adapt to changing conditions by sensing compounds from the environment, diet, microbiome and cellular metabolism, and which plays important roles in development, immunity and cancer (PubMed:23275542, PubMed:30373764, PubMed:32818467, PubMed:7961644). Upon ligand binding, translocates into the nucleus, where it heterodimerizes with ARNT and induces transcription by binding to xenobiotic response elements (XRE) (PubMed:23275542, PubMed:30373764, PubMed:7961644). Regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immune modulation (PubMed:12213388). Xenobiotics can act as ligands: upon xenobiotic-binding, activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene) (PubMed:7961644). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons (PubMed:34521881, PubMed:7961644). Next to xenobiotics, natural ligands derived from plants, microbiota, and endogenous metabolism are potent AHR agonists (PubMed:18076143). Tryptophan (Trp) derivatives constitute an important class of endogenous AHR ligands (PubMed:32818467, PubMed:32866000). Acts as a negative regulator of anti-tumor immunity: indoles and kynurenic acid generated by Trp catabolism act as ligand and activate AHR, thereby promoting AHR-driven cancer cell motility and suppressing adaptive immunity (PubMed:32818467). Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1 (PubMed:28602820). Inhibits PER1 by repressing the CLOCK-BMAL1 heterodimer mediated transcriptional activation of PER1 (PubMed:28602820). The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28602820)
Specific Function: Cis-regulatory region sequence-specific dna binding
Gene Name: AHR
Uniprot ID: P35869
Uniprot Name: Aryl hydrocarbon receptor
Molecular Weight: 96146.705 Da

References

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. [Article]

Drug created at October 20, 2016 21:57 / Updated at August 26, 2024 19:24

Cantharidin

Identification

Structure for Cantharidin (DB12328)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

References