Our society has a fixation with the youth. Everywhere we look, there are emerging new products to overcome the aging process. Interestingly enough, a vast majority of these products employ the use of retinoid compounds, and a deeper understanding of retinoid metabolism in cancer cells could potentially yield a new target for anticancer drugs.
The retinoid class of chemical compounds is composed of retinols, retinals, and retinoic acids (Mukherjee et al., 2006). Derived from vitamin A, they share a chemical backbone consisting of 20 carbon atoms, a cyclohexene ring, a polyene side chain, and a polar end group that can be modified to form various derivatives (Figure 1;(Ross et al., 2003)
Retinols are oxidized by alcohol dehydrogenases to retinals, which are oxidized once more to produce the retinoic acids that are used in skincare products. In the cell, retinoic acids have two roles; the inhibition of collagen degradation and the activation of retinoic acid receptors (RARs) to induce proliferation (Mukherjee et al. 2006).
Under normal conditions, retinoid metabolism is tightly regulated at both ends. Without retinoic acid bound, RARs form a complex with Retinoic X Receptors (RSX) that binds to the promoter region of proliferative genes to prevent transcription. Additionally, the relative concentrations of the precursors for retinoic acid, retinol and retinal, are maintained by the enzyme Aldo Keto Reductase 1B10 (AKR1B10). This enzyme reduces excess retinals back to retinols to prevent the accumulation of retinoic acids (Figure 2)(Matsunaga et al. 2013).
When the cell is exposed to reactive oxidative species (ROS), whether from UV radiation, smoking, or exposure to carcinogens, the transcription of genes for the AKR1B10 enzyme is activated (Hyndman et al. 2005). This is accomplished by the Nrf2 transcription factor, which is typically inactive under regular conditions (Barski et al. 2009). When ROS accumulate within the cytosol, Nrf2 is activated and induces the transcription of AKR1B10 (Kansanen et al. 2013). The overexpression of AKR1B10 from ROS contributes to carcinogenesis through uncontrolled cell proliferation, a hallmark of cancer. As the excess AKR1B10 enzymes continue to push retinoid metabolism in the reverse direction by reducing retinals back to retinols, the retinoic acid levels begin to decline. In return, the cell attempts to compensate for the loss of retinoic acid and induces retinoid metabolism, constantly producing retinoic acids that will increase proliferation (Ruiz & Porté 2012). This loop of hyperactivity also facilitates chemoresistance, as the ROS generated by chemotherapeutic drugs can illicit this response, allowing cancer cells to survive and spread(Matsunaga et al. 2013).
While the mechanisms behind the regulation of retinoid metabolism remain complex and under active research, AKR1B10 poses as a potential target for future anticancer drugs as its overexpression has been found in lung, colon, and breast cancers, and especially in tumors that have become chemoresistant (Matsunaga et al. 2013). The application of skincare products that contain retinoic acid could prove to have preventative effects on carcinogenesis, as the presence of retinoic acid may limit the cell’s ability to hyperactivate retinoid metabolism. This effect has been indicated in animal studies, but future studies with humans will have to conclude this (Das et al., 2013).
WORKS CITED
Barski, O.A., Tipparaju, S.M. & Bhatnagar, A., 2009. The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification. Drug Metabolism Review, 40(1), pp.553–624.
Das, S. et al., 2013. Anti-Cancer Potential of All trans-Retinoic Acid: A Review. Proceedings of the Zoological Society, 66, pp.1–7.
Hyndman, D. et al., 2005. The aldo-keto reductase superfamily homepage. Chemico-Biological Interactions, 143, pp.621–631.
Kansanen, E. et al., 2013. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biology, 1(1), pp.45–49.
Matsunaga, T., El-kabbani, O. & Hara, A., 2013. Aldo-Keto Reductases as New Therapeutic Targets for Colon Cancer Chemoresistance B. Bonavida, ed. Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy, 1, pp.109–133. Available at: http://link.springer.com/10.1007/978-1-4614-7070-0 [Accessed October 18, 2013].
Mukherjee, S. et al., 2006. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical Interventions in Aging, 1(4), pp.327–348. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699641/.
Ross, S.A. et al., 2003. Retinoids in Embryonal Development. Physiological Reviews, 80(3), pp.1021–1054.
Ruiz, F.X. & Porté, S., 2012. Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling. Frontiers in Pharmacology, 3(58), pp.321–334.
Comments
20 Responses to “The Cure to Cancer could be Skin Deep”
Our drug discovery project focuses on enzyme activity and cell signalling pathways that are influenced by a multitude of biological, chemical, and environment factors. Additionally, through this project we have been introduced to how drug discoveries have sometimes arisen through drugs that are already in use, by noticing a side effect or pathway that a chemical takes part in. I wanted to illustrate this aspect of the drug discovery process, and how sometimes it is not always about synthesizing a new molecule but looking deeper into the ones we already have. I have always been quite fascinated by cancer, and I chose this topic because it integrated and extended these concepts of proteins in signalling pathways and chemical interactions with these molecules that we have been discussing in class recently.
I find this topic relevant because chemoresistance, as well as chemotherapy drug targets are a current issue within oncology that is under active research. I would really appreciate feedback on the title of my post, as I feel it is a bit too long. In addition, I feel my conclusion ends a bit too abruptly and would like any suggestions on how to strengthen it, and I’m also curious as whether my description of retinoid metabolism is confusing in any way.
Hi Keeran!
Interesting topic!
– Your blog is fairly technical and assumes much prior knowledge of different compounds in the first paragraph (collagen, retinol, retinal, etc.), which made it hard for myself as a reader to follow. It does however seem very preliminary to explaining the remainder of the content in the post.
– A personal preference instead of putting two brackets beside one another use a semi-colon (ie. (figure1)(reference) would become (figure 1; reference) )
– a comma could be placed after ‘meanwhile’ in your concluding paragraph
– I think your conclusion works considering how technical your piece is, it’s challenging to tie it back like a story. It provides a good summary!
Great work and best of luck with your edits!
Thanks for your feedback, I changed the order of my paragraphs to give a better understanding of retinoid compounds and their composition before I go into the pathway, I hope this helps with the understanding.
Hello Mankeeran.
I think you should re-word and/or re-write your first sentence. It is awkwardly phrased. Maybe by adding a second comma after the name of the drug?
It isn’t that your conclusion ends too abruptly, it’s that there is no conclusion whatsoever. What I would suggest is looking through your post to see what is unnecessary and removing it to make room for the conclusion. You are near the border of the word count as is.
“Naturally, vitamin A is not synthesized by the body and must supplied through dietary intake. It is present in the cytosol as retinyl esters that are oxidized to form retinols,” The first sentence adds nothing to the post(despite being interesting). Remove it and just start the second with “Vitamin A is present…”
Go through your post and look for words that aren’t needed, try to say things with fewer words.
Also, as someone not in biochem, I felt that the post was rather dense. This isn’t necessarily a bad thing, but if you want to cater to a larger audience then you may want to consider “dumbing it down” a bit.
Happy editing!
-Pratik
Thanks for your feedback, I agree that my word count was well over the limit and I’ve cut the post down quite a bit. I took out the random facts about vitamin A not being present naturally in the body, as well as the pathway for the transcription factor Nrf2 as I felt that took up a lot of my word count and made the post quite confusing and instead focused on the Retinoid pathway. I hope this can let a larger audience understand my post, it’s great that you pointed that out. In terms of my conclusion, I tried to put more of an emphasis on practical applications instead to make it more substantial.
Hey Keeran,
Great topic! I thought it was very interesting that retinoids can cause cancer even though vitamin A is an antioxidant, and so also has cancer preventative properties.
I think your conclusion is fine, but if you could expand a little more on it’s potential as a drug target, or if there are any ways to lower chemoresistant effects for cancer patients.
I agree that is gets a little dense in places but I don’t think you need to change the amount of information, just the language used to present it. For example, “teratogenicity” is a great term, but “birth defects” works just as well and is understood by a wider audience. Same with “heterodimerize”, in this case you could just say “RAR’s bond with…”
Great post!
Thanks for the comment, I tried to emphasize a bit more on how inhibiting AKR1B10 could limit the rate at which cancer cells proliferate by preventing the transcription of proliferative genes. I hope this is clarified better in the post now. I agree that my post definitely got too dense with the biochemistry at certain parts and like Pratik’s comment suggested – I removed the details on other pathways that are linked to Retinoid metabolism and just focused on that instead so that the reader doesn’t get lost while reading through my post.
Heyy Keeran
Great Post!
Just one thing other than what was mentioned above. Make sure you’re consistent with the spaces between your sentences and your citation.
Thanks, will do
Hey Keeran,
This was a really cool post (as usual)! I believe that everyone has pretty much pointed out a lot of things that I’ve noticed, so here are a few tips on grammar/flow/spacing:
– Consider taking out “usage” and add a comma after Tretinoin in your first sentence.
– Remove “the” in front of “various” in the last sentence of your intro.
– In case you keep the sentence, I believe you are missing the word “be” between “must” and “supplied” in the sentence: “Naturally, vitamin A is not synthesized by the body and must supplied through dietary intake.”
– In your second paragraph, there is a double space in front of “and the activation of retinoic acid…”
Happy editing!
-B
Thanks Bianca, I made the edits and I appreciate your feedback.
Hi Keeran!
Loved the blog, great choice of topic.
I just have a technical thing to point out. It seems like the beginnings of some of your paragraphs have a space before the first word, I’d go through and make sure there aren’t any. Also, there were instances where you need a space before your citation, like in your last paragraph.
Thanks for the read!
Natasha
Hey Keeran,
Cool title.
Here is a comment to help with your editing process:
-I agree that you could work on your conclusion a bit more. You start off by introducing Tretinoin as a retinoic acid that is used as a drug, and then you explain how retinoic acid metabolism can be linked to carcinogenesis. I was then expecting you to talk about what is being done to reduce the potentially carcinogenic effects of using Tretinoin. You do talk about how it has led to skin irritations and teratogenicity, but I feel like this could be elaborated. Were those the only side effects found? How severe were they? Did the FDA withdraw the drug or is the drug still in the market, and still actively being used? By talking about these, you might offer the reader a bit of a conclusion to your story.
Other than that, you did a great job of explaining a pretty technical topic. Thanks for the read and happy editing!
Alan
Thanks for your feedback Alan. It’s great that you brought up the skin irritations with Tretinoin because it forced me to go back to my sources and dig a little deeper into the controversy. There were mixed opinions about retinoid skin care products causing irritation and birth defects in pregnant women, but these cases had to do with excessive application. The truth is, they are not actually sure why these events happened, but at the same time this was with excessive application . Just simply googling this, you’ll see that some studies suggest that the overload of retinoic acids can cause immature cells in the fetus to rapidly divide, as well as the overload of vitamin A to the fetus can be toxic. There are regulations currently in place by the FDA for the concentrations of the drug Tretinoin (retinoic acid), and precautions for pregnant woman are quite evident (especially after these cases). In terms of the skin irritation, this might have actually occurred because of other products in the formula that may have interfered with the skin’s moisture barrier. Therefore, it’s still on the market and used quite a bit.
I’ve changed my post, because while I was looking up these cases I came across a paper that is quite recent and discusses the anticancer properties of retinoid compounds (in particular, retinoic acid). This paper is by Das et al. (2013), and it’s in my works cited if you are interested. I chose to focus on this instead because it was much more recent, and a reputable source in my opinion.
Hey Mankeeran,
Really cool post! I just have a couple of comments that I think might help
“However, closer investigation into the role of retinoic acids in the cell has yielded a peculiar result; retinoid metabolism itself could be linked to carcinogenesis and chemoresistance” If that is the result, put a colon not a semicolon
Also make sure you put a space between words and your citation. They are all attached
Your figure 2 is a full paragraph below where you reference it. I would move it up
I thought this post was really interesting. However, it is a little dense. There are a lot of chemical names and acronyms that are hard to follow. I would get rid of some of the names and just say “an enzyme” or “a molecule” to make it easier to follow.
Other than that, great job!
Lori
Thanks for your comment, I got a lot of feedback on how I should simplify things to allow a larger audience to read my post and I’ve edited my post accordingly.
Hey Keeran,
I really liked your creative new title for the piece, although I think it could be construed as a little bit corny. You did a good job to incorporate visuals into the text to help a reader gain understanding of the processes you describe. Very relevant to our recent foray into the realm of drug discovery, I can see you are learning lots in your group. A small improvement could be to add more comprehensive figure captions that briefly outlined the processes they depict. Good job, looking forward to reading the final product.
Trystan
Thanks, I changed my figure captions to be a bit more explanative
Hey Keeran,
GREAT TITLE! 🙂 I must compliment your ability to take complex mechanisms and ideas and simplify them into an understandable and interesting way. Good job in that sense. My only suggestion is in the last sentence of your piece where you state “Meanwhile AKR1B10 poses as a potential target for future chemotherapy drugs, as inhibiting its function may prevent tumor propagation, especially for chemoresistance”, you may want to reconsider your use of the word chemotherapy drug. Your piece implies that chemotherapy drugs can generate ROS that affects retinoid metabolism and lead to carcinogenesis, but inhibiting AKR1B10 may not illicit this accumulation of ROS and may serve the opposite function. Therefore you might want to say “… potential target for future cancer drugs, as ….” and avoid the use of “chemotherapy drug”.
GREAT JOB THOUGH KEERAN 🙂
-VINCENT
Thanks for the feedback, I didn’t realize how weird that sentence was until you pointed it out. I fixed that, as well as the pathway section because it was very complicated and hard to follow (as many of the previous comments pointed out).