Ricin and Ricin-Containing Immunotoxins: Insights into Intracellular Transport and Mechanism of action in Vitro

Abstract

Ricin is a type II ribosome inactivating protein (RIP) isolated from castor beans. Its high toxicity classifies it as a possible biological weapon. On the other hand, ricin linked to specific monoclonal antibodies or used in other conjugates has powerful medical applications. Ricin consists of an A-chain (RTA) that damages ribosomes and inhibits protein synthesis, and a B-chain that plays a role in binding and cellular uptake. A number of recent studies have demonstrated that ricin-induced inhibition of protein synthesis is not the only mechanism responsible for cell death. It turns out that ricin is able to induce apoptosis in different cell lines and multiple organs in animals. However, the molecular link between protein synthesis inhibition and ricin-dependent triggering of apoptotic cell death is unclear. This review describes the intracellular transport of ricin and ricin-based immunotoxins and their mechanism of action in different non-malignant and cancer cell lines. Moreover, various ricin-containing immunotoxins, their composition, medical applications and side-effects will be described and discussed. Understanding the mechanism of action of ricin-based immunotoxins will facilitate construction of effectively acting immunotoxins that can be used in the clinic for cancer treatment

A double safety lock tumor-specific device for suicide gene therapy in breast cancer

“…This system has shown promising results in vivo, thus providing direct proof that ELRs can be linked to aptamers for use in breast cancer suicide gene therapy. Most previous studies with ricin have been performed in immunotherapy with RTA or the holotoxin and blocking of the galactose binding sites [40]. To the best of our knowledge, this is the first time that the whole ricin gene has been transferred into target cells as part of suicide gene therapy in breast cancer.…”

“…Ricin-induced apoptosis mediated by different caspases, depending on the cell type, has been also described in in vitro studies [37][38][39]. Most of the research into ricin has been performed in cancer immunotherapy using chain A or blocking the galactose-binding sites from chain B [40]. The results showed the ability of these immunotoxins to kill human myeloma, lymphoma and lung cancer cells, amongst others [41][42][43][44].…”

The role of EDEM3, Derlin-1 and Derlin-2 proteins in the ricin P250A cytotoxicity and its retrotranslocation from the endoplasmic reticulum to the cytosol

“…Due to its high toxicity, ricin is considered as a biological weapon. On the other hand, detailed knowledge of the ricin intercellular transport mechanisms raises the possibility of using it in medicine as a component of modern immunotoxins and vaccines (Słomińska-Wojewódzka & Sandvig, 2013). The previous study reported that EDEM1 and EDEM2 are involved in ricin transport out of the ER (Sokołowska et al, 2011).…”

Immunotoxin: A new tool for cancer therapy

“…Cellular resistance is due to defect in delivery of toxin to the cytosol [37][38][39][40] and organismal resistance is because of failure to form ADPr EF2 41 or poor starting of apoptosis. Resistance to apoptosis is a major obstacle to effective cytotoxic cancer therapy.…”