Editing Cantharidin (section)

==Research==

===Mechanism of action===
{{missing information|section|toxicological mechanism when ingested|date=September 2022}}
Topical cantharidin is absorbed by the lipid membranes of [[Epidermis|epidermal cells]], causing the release of [[serine proteases]], [[enzymes]] that break the [[peptide bonds]] in proteins. This causes the disintegration of [[Desmosome|desmosomal plaques]], cellular structures involved in cell-to-cell adhesion, leading to detachment of the [[Tonofibril|tonofilaments]] that hold cells together. The process leads to the loss of cellular connections ([[acantholysis]]), and ultimately results in blistering of the skin. Lesions heal without scarring.<ref name=Moed2001>{{cite journal | vauthors = Moed L, Shwayder TA, Chang MW | title = Cantharidin revisited: a blistering defense of an ancient medicine | journal = Archives of Dermatology | volume = 137 | issue = 10 | pages = 1357–1360 | date = October 2001 | pmid = 11594862 | doi = 10.1001/archderm.137.10.1357 | doi-access = free }}</ref><ref name=Bertaux1988>{{cite journal | vauthors = Bertaux B, Prost C, Heslan M, Dubertret L | title = Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution | journal = The British Journal of Dermatology | volume = 118 | issue = 2 | pages = 157–165 | date = February 1988 | pmid = 3279999 | doi = 10.1111/j.1365-2133.1988.tb01769.x | s2cid = 45714898 }}</ref>

===Pharmaceutical use===
VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, was studied for the treatment of [[molluscum contagiosum]], [[wart|common warts]], and [[genital wart]]s.<ref>{{cite news | url = https://www.drugs.com/nda/vp_102_210528.html | title = Verrica Pharmaceuticals Announces Extension of FDA Review Period of its NDA for VP-102 for the Treatment of Molluscum Contagiosum | date = 28 May 2021 | publisher = [[drugs.com]] | access-date = 24 June 2021 | archive-date = 24 June 2021 | archive-url = https://web.archive.org/web/20210624205303/https://www.drugs.com/nda/vp_102_210528.html | url-status = live }}</ref> The efficacy of cantharidin was formally established for the treatment of molluscum in patients 2 years and older in two double-blind, randomized, placebo-controlled trials.  It is now FDA-approved for the treatment of molluscum contagiousum under the brand name Ycanth and is marketed by Verrica Pharmaceuticals.<ref name = "FDA_2023" />

===Toxicity===
The [[liver]], primarily responsible for metabolism and detoxification, often becomes damaged in cases of cantharidin poisoning. The [[hepatotoxicity]] of cantharidin arises from its inhibition of hepatocyte proliferation pathways, the promotion of hepatocyte [[apoptosis]] or [[autophagy]], and increased inflammation. <ref name="Jin_2023">{{cite journal | vauthors = Jin D, Huang NN, Wei JX | title = Hepatotoxic mechanism of cantharidin: insights and strategies for therapeutic intervention | journal = Frontiers in Pharmacology | volume = 14 | pages = 1201404 | date = 13 June 2023 | pmid = 37383714 | pmc = 10293652 | doi = 10.3389/fphar.2023.1201404 | doi-access = free }}</ref> Many studies have been conducted to elucidate the specific interactions cantharidin has in the liver, that lead to pathology. The poison has been found to inhibit PP1, PP2A (PP = [[protein phosphatase]]), TIL-4 (TIL = [[toll-like receptor]]), NF-KB (NF = [[nuclear factor]]), ERK, and DFF45. Cantharidin promotes TNF-α (TNF = tumor necrosis factor), FASL, ROS, caspase-4, caspase-6, caspase-8, caspase-9, caspase-12, protein kinase R-like ER kinase, inositol-requiring enzyme 1, ATF6 (transcription factor 6), ATF4, BID,BAK, BAX, cyto C, LC3-1, p150, Atg7, P13K Ⅲ, eIF2α, and CHOP pathways.<ref name="Jin_2023" /> Cantharidin has an diverse range of targets in the liver that have been discovered empirically. However, the exact chemical mechanisms by which cantharidin interferes with these structures are unknown.

===Bioactivities===
Cantharidin appears to have some effect in the topical treatment of [[cutaneous leishmaniasis]] in animal models.<ref>{{cite journal | vauthors = Ghaffarifar F | title = Leishmania major: in vitro and in vivo anti-leishmanial effect of cantharidin | journal = Experimental Parasitology | volume = 126 | issue = 2 | pages = 126–129 | date = October 2010 | pmid = 20435039 | doi = 10.1016/j.exppara.2010.04.004 | doi-access = free }}</ref> In addition to topical medical applications, cantharidin and its analogs are of particular interest for oncological applications as they may have toxic activity against cancer cells.<ref>{{cite journal | vauthors = Ratcliffe NA, Mello CB, Garcia ES, Butt TM, Azambuja P | title = Insect natural products and processes: new treatments for human disease | journal = Insect Biochemistry and Molecular Biology | volume = 41 | issue = 10 | pages = 747–769 | date = October 2011 | pmid = 21658450 | doi = 10.1016/j.ibmb.2011.05.007 | bibcode = 2011IBMB...41..747R }}</ref><ref>{{cite journal | vauthors = Chen YN, Cheng CC, Chen JC, Tsauer W, Hsu SL | title = Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells | journal = British Journal of Pharmacology | volume = 140 | issue = 3 | pages = 461–470 | date = October 2003 | pmid = 12970086 | pmc = 1574052 | doi = 10.1038/sj.bjp.0705461 }}</ref><ref>{{cite journal | vauthors = Zhang C, Peng Y, Wang F, Tan X, Liu N, Fan S, Wang D, Zhang L, Liu D, Wang T, Wang S, Zhou Y, Su Y, Cheng T, Zhuang Z, Shi C | title = A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma | journal = Biomaterials | volume = 31 | issue = 36 | pages = 9535–9543 | date = December 2010 | pmid = 20875681 | doi = 10.1016/j.biomaterials.2010.08.059 }}</ref>
Laboratory studies with cultured tumor cells suggest that this activity may be the result of [[PP2A]] inhibition.<ref>{{cite journal | vauthors = Dorn DC, Kou CA, Png KJ, Moore MA | title = The effect of cantharidins on leukemic stem cells | journal = International Journal of Cancer | volume = 124 | issue = 9 | pages = 2186–2199 | date = May 2009 | pmid = 19123473 | doi = 10.1002/ijc.24157 | s2cid = 38088568 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X | title = 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 | journal = Cancer Science | volume = 101 | issue = 5 | pages = 1226–1233 | date = May 2010 | pmid = 20331621 | doi = 10.1111/j.1349-7006.2010.01523.x | s2cid = 24345174 | doi-access = free | pmc = 11158714 }}</ref>

Recent research has identified many other pathways in cancer cells that may be interfered with by cantharidin. Generally, cantharidin's anticancer targets include numerous transcription factors, protein kinases, growth factors, and inflammatory cytokines.<ref name="Jin_2023" /> Cantharidin's general lack of target specificity in cancer cells and toxic effects towards healthy cells are limiting for clinical oncological applications.