There is currently an obesity epidemic that is facing not only the United States, but the entire world. From 1975 to 2016, children and young people’s age standardized mean BMI increased globally, as well as in most regions. The global rate of increase was 0.32 kg/m2 per decade.1This increase in BMI is not only an issue for health problems related to cholesterol levels and diabetes, but also for cancer. Obesity has been identified as a leading risk factor for cancer development, specifically colorectal cancer (CRC) which has become the fourth leading cause of cancer morbidities worldwide.2,3This has created a clear necessity for novel treatment for those with obesity related CRC. Currently, caloric restriction has been identified as having potential therapeutic effects against CRC, due primarily to its interference with the Warburg effect.4Other studies have been done with energy restriction mimetic agents (ERMAs) in the treatment of various cancers. ERMAs act by selectively targeting cancer cells that are addicted to glycolysis, essentially interfering with the Warburg effect and the need for energy in tumor cells, similar to caloric restriction’s effects. 5,6
A recent publication from Hersi et al. looked to identify ERMAs that could potentially be used as treatment for CRC by affecting the energy machinery of the cancer cells. Doing so could lead to the development of novel treatment that is less cytotoxic, and more potent than current CRC treatments.7,8The basis for the ERMAs being tested within this study was that a hybrid structure that contained an aminothiazole attached to a coumarin core had been reported to target survival signaling in cancers similarly to other ERMAs.8,9In order to identify an ERMA with a high efficacy of cellular metabolic disruption, the authors needed to design and synthesize numerous compounds with the aminothiazole moiety and coumarin core with differing substituents.8
The featured image within this post identifies what substituents made up the various ERMA compounds. Compounds with 9 had a methyl group, 10, had an ethyl group, and 11 had a propyl group. These three categories were further divided with other varying substituents with different properties (e.g. electron donating, electron withdrawing, etc.). Following an initial screening of these compounds based on their cell viability and potency in comparison to OSU-CG5 and OCU-CG12 (ERMA controls), compounds 9f and 9b were selected as the most potent and safest compound, respectively.8These compounds would be tested further for efficacy as anti-cancer treatment.
Previously synthesized ERMAs, including OSU-CG5 have shown the induction of energy restriction cellular responses.9Because of this, compounds 9f and 9b were investigated for their energy restriction mediated anticancer activity on two CRC cell lines; HT-29 and HCT116. This was done by determining the expression levels of various metabolically important proteins through Western Blot analysis. These proteins included Akt, AMPK, and beta-TrCP. Results from this experiment were promising. For example, introduction of 9f and 9b showed an enhancement of AMPK activation via phosphorylation in both cell lines. This result is typically a marker of glucose starvation, as AMPK plays a critical role in maintaining redox homeostasis, cell survival and has been characterized as having a role in tumor suppression.10These findings led the authors to further test compounds 9f and 9b’s ability to hinder the Warburg effect.8
A key component of the Warburg effect and its ability to assist growing tumor cells in proliferation, is an increase in glucose uptake for the fermentation of glucose to lactate.11This is why Hersi et al. tested compounds 9f and 9b’s effect on glucose uptake. To do so, CRC cell lines HT-29 and HCT116 were again treated with 9f and 9b at varying concentrations (0.5 – 4.0 mM) for 16 hours, and glucose uptake was measured using Glucose Uptake-Glo Assay.8Results indicated that in both cell lines, glucose uptake was inhibited significantly in a dose-dependent manner. This once again suggests a hindrance of the tumor cells’ energy machinery by the ERMA compounds due to glycolytic interference.8
In addition to the reduction in glucose uptake by the CRC cancer cells as a result of ERMA treatment, the cancer cells also displayed an accumulation of reactive oxygen species (ROS) as a result of a significant decrease in NADPH/NADP+ ratio.8The presence of reactive oxygen species often leads to oxidative stress and eventual cell death, but NADPH is responsible for its detoxification. However, NADPH cannot be regenerated as a result of the CRC cell’s reduction in glucose uptake, and thus cannot detoxify the ROS.12This could lead to extensive cell death, and act as another form of anti-cancer activity as a result of compound 9f and 9b treatment.
Although Hersi et al. provide a great deal of evidence for compounds 9f and 9b having significant anti-cancer activity, there is certainly always room for improvement. The authors suggest that compounds containing electron withdrawing groups at the phenyl ring of the thiazole moiety are more effective than those containing electron donating groups, perhaps there could be a different backbone for which electron withdrawing groups could be placed that would result in a compound that is more potent and less cytotoxic compared to 9f and 9b. Thus, in the future, the authors could screen other potential ERMA compounds for their anti-cancer capabilities. Additionally, other cancer cell lines aside from colorectal could be looked at to determine whether or not this same strategy could be applied to other cancers that act in similar ways.8
Given our class’ recent discussion on the Warburg effect, and its impact on glucose metabolism and cancer development, it’s interesting to see this as a place where researchers see the potential for therapeutics. Given how clear the Warburg effect’s impact is on the progression of cancer, (CRC in particular) it makes a lot of sense that Hersi et al. would investigate the potential for ERMAs to be used as a treatment for obesity linked cancer.
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(2) Stone, T. W.; McPherson, M.; Gail Darlington, L. Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. EBioMedicine2018, 30, 14–28. https://doi.org/10.1016/j.ebiom.2018.02.022.
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(6) Kuntz, S.; Mazerbourg, S.; Boisbrun, M.; Cerella, C.; Diederich, M.; Grillier-Vuissoz, I.; Flament, S. Energy Restriction Mimetic Agents to Target Cancer Cells: Comparison between 2-Deoxyglucose and Thiazolidinediones. Biochemical Pharmacology2014,92(1), 102–111. https://doi.org/10.1016/j.bcp.2014.07.021.
(7) Mohammadian, M.; Zeynali, S.; Azarbaijani, A. F.; Khadem Ansari, M. H.; Kheradmand, F. Cytotoxic Effects of the Newly-Developed Chemotherapeutic Agents 17-AAG in Combination with Oxaliplatin and Capecitabine in Colorectal Cancer Cell Lines. Res Pharm Sci2017,12(6), 517–525. https://doi.org/10.4103/1735-5362.217432.
(8) Hersi, F.; Omar, H. A.; Al-Qawasmeh, R. A.; Ahmad, Z.; Jaber, A. M.; Zaher, D. M.; Al-Tel, T. H. Design and Synthesis of New Energy Restriction Mimetic Agents: Potent Anti-Tumor Activities of Hybrid Motifs of Aminothiazoles and Coumarins. Scientific Reports2020,10(1), 1–17. https://doi.org/10.1038/s41598-020-59685-x.
(9) Arafa, E. A.; Abdelazeem, A. H.; Arab, H. H.; Omar, H. A. OSU-CG5, a Novel Energy Restriction Mimetic Agent, Targets Human Colorectal Cancer Cells in Vitro. Acta Pharmacologica Sinica2014,35(3), 394–400. https://doi.org/10.1038/aps.2013.183.
(10) Ren, Y.; Shen, H.-M. Critical Role of AMPK in Redox Regulation under Glucose Starvation. Redox Biology2019,25, 101154. https://doi.org/10.1016/j.redox.2019.101154.
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(12) Panieri, E.; Santoro, M. M. ROS Homeostasis and Metabolism: A Dangerous Liason in Cancer Cells. Cell Death & Disease2016, 7(6), e2253–e2253. https://doi.org/10.1038/cddis.2016.105.