Repurposing Miltefosine for the Treatment of Immune-Mediated Disease?

Abstract

Miltefosine is an ether lipid that was initially developed for cancer treatment in the early 1980s. Miltefosine largely failed development for oncology, although it was approved for the topical treatment of breast cancer metastasis. It was subsequently discovered that miltefosine is a highly effective treatment of visceral Leishmaniasis, a parasitic disease that affects millions worldwide and causes an estimated 30,000 fatalities each year. Oral treatment with miltefosine is generally well tolerated and has relatively few adverse effects. The exact mechanism of action of miltefosine treatment is still under investigation. Its close resemblance to phospholipids allows it to be quickly taken up by cell membranes and affect related processes, such as lipid metabolism and signaling through lipid rafts. These processes play an important role in the immune response and it comes as no surprise that miltefosine has been successfully tested for the treatment of a number of immune-mediated diseases in preclinical models of disease. Drug repurposing of miltefosine for immunemediated diseases may provide an opportunity to expand the limited number of drugs that are currently available for therapeutic use.

Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

“…It remains difficult to evaluate to what extent miltefosine immunomodulatory effects might be different from those of other antileishmanials, or whether observed effects result from decreasing parasite levels or rather direct effects on Th1 cell signaling. However, in contrast to other antileishmanials, immunomodulatory effects have been reported only for miltefosine in immune-mediated disorders such as rheumatoid arthritis, chronic urticaria, or malignant disease (22). Taken together, these findings illustrate that besides the direct killing of the parasite, miltefosine is also able to affect the host immune system by targeting Th1.…”

“…As mentioned, the immunomodulatory effects of miltefosine have also been demonstrated in the treatment of other immune-mediated disorders, such as inflammatory bowel disease (IBD) and chronic urticaria (22). In a mouse model of IBD, miltefosine was shown to block the proliferation of Th2 cytokines, subsequently increasing Th1 cytokines, which resulted in the decline of inflammation and less severe colitis (70).…”

“…Various direct and indirect antileishmanial mechanisms of action have been suggested for miltefosine, including disruption of (membrane) lipid metabolism, apoptosis-like cell death, induction of mitochondrial dysfunction, and also immunomodulatory effects involving Th1 cell response (20). Following the observation of the effects on Th cells in leishmaniasis, miltefosine has also been investigated in the treatment of other immune-mediated diseases, such as cancer, inflammatory bowel disease, and atopic dermatitis, showing promising preclinical results (22). Given the observed relationship between Th1/Th2 balance and control over the Leishmania infection, the potentiation of Th cell activation through the use of immunomodulators in addition to conventional chemotherapy has been hypothesized as a future therapeutic option for leishmaniasis (23, 24).…”

Mast Cell Activation and Microtubule Organization Are Modulated by Miltefosine Through Protein Kinase C Inhibition

“…A promising candidate is the lipid raft modulator miltefosine ( 15 ). The obvious advantages of miltefosine are known side effects, which are relatively safe, dose-dependent, and reversible ( 38 ). Clinical application has been limited to topical and oral treatments, and among major known side effects belong loss of appetite, vomiting, nausea, and diarrhea after long oral treatment of high daily dosages (150 mg and higher) ( 39 ).…”

<p>Alginate nanoparticles as non-toxic delivery system for miltefosine in the treatment of candidiasis and cryptococcosis</p>

“…Miltefosine (MFS) is an alkylphosphocholine analogue synthesized and evaluated in the 1980’s for antineoplastic activity 9. Currently, oral administration of MFS is recommended for visceral and cutaneous leishmaniasis treatments, whereas its topical administration is approved for management of skin metastases of breast cancer 9–12. In addition, MFS has considerable antifungal potential in vitro against a wide range of pathogenic fungi, including Candida spp., Cryptococcus spp., Aspergillus spp., Fusarium spp., Scedosporium spp., Sporothrix spp., Paracoccidioides spp., Histoplasma capsulatum, Coccidioides posadasii , and dermatophytes,13–18 and thus, could represent a potential alternative to the available drugs for treatment of IFIs.…”