Apitoxin and Its Components against Cancer, Neurodegeneration and Rheumatoid Arthritis: Limitations and Possibilities

Abstract

Natural products represent important sources for the discovery and design of novel drugs. Bee venom and its isolated components have been intensively studied with respect to their potential to counteract or ameliorate diverse human diseases. Despite extensive research and significant advances in recent years, multifactorial diseases such as cancer, rheumatoid arthritis and neurodegenerative diseases remain major healthcare issues at present. Although pure bee venom, apitoxin, is mostly described to mediate anti-inflammatory, anti-arthritic and neuroprotective effects, its primary component melittin may represent an anticancer therapeutic. In this review, we approach the possibilities and limitations of apitoxin and its components in the treatment of these multifactorial diseases. We further discuss the observed unspecific cytotoxicity of melittin that strongly restricts its therapeutic use and review interesting possibilities of a beneficial use by selectively targeting melittin to cancer cells.

Keywords: apamin; apitoxin; bee venom; cancer; melittin; neurodegeneration; phospholipase A2; rheumatoid arthritis.

Figure 1

Potential application of melittin in cancer therapy. While specific cytotoxic effects of melittin against cancer cells have been reported, melittin has also been shown to mediate unspecific toxicity towards healthy cells (illustrated as question mark). However, chemical modification, e.g., by conjugation of melittin to avidin, which is cleaved and activated by cancer cell-specific matrix metalloproteinase 2 (MMP2), or cancer cell-directed targeting of melittin with nanocarriers might be used to overcome this unspecific toxicity.

Figure 2

Postulated therapeutic effects of bee venom and melittin against neuroinflammation in diverse neurodegenerative diseases. The tumour necrosis factor α (TNF-α) pathway (illustrated in a simplified way) is an important mechanism by which inflammatory processes are activated and is overstimulated in various neurodegenerative disorders (red arrows), including Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). The protective effects of bee venom and melittin (shown with black arrows for activation and black bar-headed arrows for repression) are controversial (illustrated as question marks in the figure). Further research is required to characterize these effects and to evaluate, whether they are caused by a reduction in neuroinflammation or by other mechanisms. TNFR1/2 = Tumour necrosis factor receptor 1/2; IL-1α = Interleukin 1α; NF-κB = Nuclear factor kappa-light chain enhancer of activated B cells.

Figure 3

Proposed therapeutic effects of bee venom and melittin against inflammation and pain in rheumatoid arthritis. The protective effects of bee venom and melittin (shown as black arrows for activation and black bar-headed arrows for repression) are controversial (illustrated as question marks in the figure), and further investigation is needed to assess the usability of apitoxin and/or melittin as a novel treatment strategy in this multifactorial disease. NF-κB = Nuclear factor kappa light chain enhancer of activated B cells.