The Non–neuronal and Nonmuscular Effects of Botulinum Toxin

An Opportunity for a Deadly Molecule to Treat Disease in the Skin and Beyond

S.A. Grando; C.B. Zachary

Disclosures

The British Journal of Dermatology. 2018;178(5):1011-1019. 

In This Article

Experimental Studies of Extracutaneous Effects of Botulinum Neurotoxins

Experimental studies have revealed extracutaneous effects of BoNT arising from its anti–inflammatory and anticancer properties.

Anti–inflammatory Properties

In experimental cystitis induced by cyclophosphamide in rats, intravesical BoNT/A administration decreased the inflammatory reaction, expression of COX–2 and the prostaglandin E2 receptor EP4 subtype, and also suppressed bladder hyperactivity.[89] In a complete Freund's adjuvant–induced arthritic knee–joint model of the hind leg in rats, BoNT/A abolished joint inflammation and destruction, reduced infiltration of monocytes and macrophages, lowered IL–1β immunoreactivity and decreased the number of IL–1β–positive immune–reactive cells.[90] The in vivo anti–inflammatory effects of BoNT/A might be related to its ability to suppress lipopolysaccharide–induced nitric oxide and tumour necrosis factor–α production at the transcriptional level by blocking activation of JNK, ERK, and p38 MAPK, which was demonstrated in in vitro experiments with RAW264.7 macrophages.[90]

Anticancer Properties

The anticancer effects of BoNT/A have been identified in three types of cancer cell line, i.e. prostate, breast and colon carcinoma. It was documented that BoNT/A inhibits the growth of LNCaP human prostate cancer cells in vitro and in vivo,[91] and also increases the phosphorylated form of phospholipase A2, which may represent one mechanism that explains how the toxin reduces cell growth and proliferation.[14] In rats, intraprostatic BoNT/A injection altered cellular dynamics by inducing apoptosis, inhibiting proliferation and downregulating α1–adrenergic receptors, which was associated with prostate apoptosis and atrophic change.[92,93] The toxin–treated rats showed reduced epithelial staining of Bcl–xL and consistently increased Bax and caspase–3 staining when compared with saline–treated animals.[94]

As breast and colon cell lines have been shown to respond to BoNT by changes in gene expression at the RNA and protein levels,[25,73] other types of cancer may become a potential target for the anticancer activity of BoNT.

Conclusions and Perspectives

There is overwhelming evidence that BoNTs exhibit biological effects on many human cell types, which is of enormous clinical relevance. Apparently, these toxins have a much wider zone of influence than originally understood, and these ubiquitous events are based on individual cellular responses to the cholinergic impacts of BoNT/A. The BoNT receptors and intracellular targets are not unique for neurotransmission, as several of these receptors and targets have been found in nonneuronal cells. There are differences in the characteristics of how BoNT binds to and acts on neuronal vs. non–neuronal cells. Much is yet to be learned about these toxins and their mechanism of action. As such, the evidence indicates that there is fertile ground for future study, which is highly likely to result in impactful discoveries. If there was ever a drug that was likely to affect every cell of the body, this is it.

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