Popularized by the hit TV show Breaking Bad, the protein Ricin is well known as one of the most common and toxic biological molecules. In a recent review published in the journal Toxins by Letizia Polito, the dangers and possible therapeutic effects are covered as well as the mechanism of action. Traces of ricin have been found as long as 24,000 years ago in a purified form and have been present in medical use dating as far back as 1500 B.C. in Egypt. Coming from the castor oil plant, the castor bean presents a source of easy purification which has led to added fear of Ricin. This combination has led to Ricin being labeled as a Category B substance. As for its bioterrorism capabilities, the toxin becomes impractical as eight tons would have to be aerosolized over a 100 km2 space for a 50% casualty, as compared to anthrax which requires only one kg for the same effect. However, ricin has been shown to inhibit cellular protein synthesis by 50% at doses from 0.1-1 pM, meaning it would be lethal in humans from ~5-10 chewed beans. Medically, Ricin has proven its worth as a laxative, diuretic, anti-inflammatory, and abortifacient, with promising research as an anti-cancer therapy. Due to its non-specific binding mechanism Ricin requires a carrier, typically an antibody, to form a conjugate called an immunotoxin. These immunotoxins have been shown in both pre-clinical and clinical studies to be effective toward different cancer types both in vitro and in vivo for humans. Part of the continued negatives of these treatments are the continued unspecific toxicity, organ toxicity, immunogenicity, fast removal from blood stream, and lysosomal degradation inside cells.
Ricin falls under the category of a “ribosome-inactivating protein” (RIP), and is specifically a Type 2 RIP. This means the protein contains two different chains, with the B-chain allowing easier entry into cells, making it potentially more dangerous. The mechanism of action for Ricin is the deletion of a single adenine base from the large subunit ribosomal sarcin-ricin RNA loop (SRL). This deletion of a highly conserved structure leads to a blockage of GTP hydrolysis and impedes translational machinery. This impeding of translational machinery appears to be what leads to cell, and organism, death.
Despite the bad name Ricin gets as a toxin, the possibility as an anti-cancer therapeutic lends itself to being a protein worth continued research.
This was a very interesting post. I did not know that Ricin was currently being researched as a cancer treatment despite the knowledge of how toxic it can be. I also did not realize that eight tons would need to be aerosolized for this to work as a weapon!
ReplyDeleteWhile reading your post I was wondering about the ethical implication of using such a toxin as anti-cancer treatment. I found an article that conducted a phase I study Ricin to treat metastatic colon cancer. The study found that large metastases were decreased and smaller lesions had disappeared and some side effects included increased unilateral tremor, transient but reversible mental status change, decrease in serum albumin levels, peripheral edema, mild fatigue and slurred speech compatible with mild toxic encephalopathy (Byers, V.S. et al., 1989). These side effects were fairly mild and worth the results of the treatment. Although more research needs to be conducted, as of now, this treatment appears ethical. This takes into consideration beneficence and nonmaleficence as treating cancer with a toxin seems to do more good than harm.
Byers, V. S., et al. “Phase I Study of Monoclonal Antibody-Ricin A Chain Immunotoxin XomaZyme-791 in Patients with Metastatic Colon Cancer.” Cancer Research, American Association for Cancer Research, 1 Nov. 1989, cancerres.aacrjournals.org/content/49/21/6153.
I found this post very interesting and this was also my first time hearing about the use of Ricin in the cancer treatment. While reading this post, I was thinking about how other toxins have been investigated for cancer treatment (ie. Coley’s Toxins) and have faced the same problems with unspecified toxicity.
ReplyDeleteThis inspired me to look into research regarding delivery methods for these toxins. Like you stated, antibodies have been investigated as was way to improve transport and specificity by making a immunotoxin complex. But, it has been suggested that this method has its limitations due to the quick development of neutralizing antibodies to the immunotoxin (Tyagi, et. al., 2015).
This has led to some research into other transport methods including the use of nanoparticles and specifically liposomes. Encapsulating the toxins in lipoproteins could potentially be a great way to achieve site specific targeting, while lowering toxicity for other tissues. In a recent study done by Loan, et. al., (2019), researchers were able to encapsulate Ricin in 4 different liposome complexes and found that they could increase specificity while maintaining anti-cancer effectiveness. I just thought that this was interesting can could lead to some unique drug delivery methods.
Tyagi, N., Tyagi, M., Pachauri, M., & Ghosh, P. C. (2015). Potential therapeutic applications of plant toxin-ricin in cancer: Challenges and advances. Tumor Biology, 36(11), 8239-8246. doi:10.1007/s13277-015-4028-4
Loan, N. T., Trung, N. N., Na, N. T., & Thang, N. D. (2019). Anticancer Activities of Ricin-Liposome Complexes on SKMEL-28 Cells. Asian Pacific Journal of Cancer Prevention, 20(7), 2117-2123. doi:10.31557/apjcp.2019.20.7.2117