Cucurbitacin – a poison or a medicine?

By Fiona Zhang

Ever wondered why cucumbers and zucchinis can have a bitter taste? Try slicing off both ends of a cucumber and rubbing the flesh-exposed face of one sliced end with that of the cucumber. Soon you will extract a white foamy substance. Eat the cucumber after this, and the cucumber will no longer taste bitter. Why?

Members belonging to the Cucurbitaceae family, including cucumbers, contain cucurbitacin, which is the main source of their bitter taste.1 Cucurbitacin is a diverse family of organic compounds, all of which are highly oxygenated tetracyclic triterpenes.2 Members (derivatives) differ in the position of their oxygen atoms. Cucurbitacin is particularly abundant in Momordica charantia, known as the bitter melon1, which is a popular fruit in Asian cuisine and believed to have numerous health benefits, supported by recent studies investigating the effects of cucurbitacin compounds.2

However, evolutionarily, humans (and other animals) have acquired a sense of taste to help us identify and distinguish potentially toxic foods from those that are rich energy sources.1 Similarly, plants, such as those in the Cucurbitaceae family, evolved to taste bitter and unpleasant as this confers the evolutionary advantage of wading off herbivores and therefore increases chances of survival.3 This therefore led scientists to question if the bitterness of cucurbitacin is an indication of its toxicity.

Indeed, Lagenaria siceraria, a fruit popular in India known as bottle gourd, is rich in cucurbitacin and potentially poisonous. 4, 5 Verma & Jaiswal studied a case of cucurbitacin-induced poisoning, where after consuming bottle gourd juice, a 52-year-old woman experienced hematemesis (blood expelling from mouth, also known as blood vomiting), along with many other severe symptoms including weak pulse and hypotension (systolic blood pressure 70 mmHg, below 90 is considered low). 4 Ho et al. studied similar, some less severe, cases, where patients experienced vomiting, diarrhea, gastrointestinal bleeding, and hypotension, shortly after ingesting bottle gourd.5

Though such cases are rare, cucurbitacin poisoning is potentially life-threatening, with no known antidote,4 and investigating what distinguishes fruits that cause poisoning from those that do not (when both contain cucurbitacin) is important in preventing future cases of poisoning. Further research into the underlying causes of poisoning revealed that while most bottle gourds contain less than 130 mgL-1 of cucurbitacin, some may contain higher amounts, indicated by their extremely bitter taste.4, 5 This is problematic because cucurbitacin has cytotoxic activities, demonstrated by their dose-dependent inhibitory effect on cortisol’s binding to glucocorticoid receptors (GR) in HeLa cells.2, 5, 6

In humans, glucocorticoids regulate a wide variety of important physiological processes, ranging from basal metabolic processes and cardiovascular functions to maintaining stress-related homeostasis.7 GR is a nuclear receptor that regulates the action of glucocorticoids.7 In their ligand-bound state, they act as transcription factors that control the expression of different genes in different physiological contexts. Experiments investigating their roles in mice reported elevated levels of adrenocorticotropic hormone in mice hyposensitive to glucocorticoids, which stimulates the production of cortisol, leading to induced gastrointestinal stress.8 This is because adrenocorticotropic hormone triggers the release of glucocorticoids, which bind to GR9, and the insensitive GR underperceives the amount of glucocorticoids present, and further stimulates the expression of genes encoding adrenocorticotropic hormone as a feedback response. Since GR is a highly conserved receptor in most eukaryotes7, with little selection pressure acting upon it due to its fundamental role in maintaining homeostasis (a ubiquitous property of all forms of life), a similar pathway exists in humans. Applied to the previously mentioned cucurbitacin poisoning cases, inhibited GR leads to the production of stress hormones, including adrenocorticotropic hormone and cortisol, which explains the vomiting, diarrhea, and more severe hematemesis exhibited by patients.

However, despite their toxic properties, cucurbitacin is associated with numerous health benefits, including antitumor, anti-inflammatory, and anti-cancer activities. The major and most well-studied cucurbitacin compounds include cucurbitacin B, E, and R.

A recent study10 explored the antioxidant properties of cucurbitacin B and E glucosides through measuring the formation of compounds dependent on hydroxyl free radicals and superoxide free radicals. Results revealed statistically significant differences between control and experimental groups, demonstrating the antioxidant properties of cucurbitacin glucosides through directly scavenging for various free radicals.

Furthermore, Escandell et al. 10 investigated the anti-inflammatory and antitumor effects of cucurbitacin R in arthritic rats. Rats in the experimental group were injected with cucurbitacin R daily, and demonstrated reduced arthritis symptoms and joint damage, as well as lowered expression of proinflammatory enzymes and tumor necrosis factors (TNF). Elevated levels of TNF, on top of causing the proliferation of cancer cell and therefore the formation of tumors 2, 12, also cause insulin resistance, and therefore the reduction of it not only prevents metastasis, but also lowers the risk of type 2 diabetes.12 Results of other studies on cucurbitacin A and Q demonstrated similar antitumor and anti-inflammatory effects.13, 14

Finally, Alghasham2 discusses the role of cucurbitacin, presenting it as a promising target for the treatment of cancers. Cucurbitacin has been shown to have antiproliferative effects on numerous cancer cell lines, including breast, skin, lung, and brain cancers 2, and can directly inhibit DNA and RNA biosynthesis in the ‘immortal’ HeLa cells 15.

To conclude, while some derivatives of cucurbitacin, such as those present in bottle gourds, are toxic when consumed in excessive amounts, most cucurbitacin compounds exhibit promising anticancer, anti-inflammatory, and antitumor properties in several studies, both in vitro and in vivo.

References:

  1. Izawa K, Amino Y, Kohmura M, Ueda Y, Kuroda M. Human–environment interactions – taste. Comprehensive Natural Products II. 2010;:631–71.
  2. Alghasham AA. Cucurbitacins : A promising target for cancer therapy. International Journal of Health Sciences. 2013;7(1):77–89.
  3. Chen X-Y. Bitter but tasty cucumber. National Science Review. 2015;2(2):129–30.
  4. Verma A, Jaiswal S. Bottle Gourd (Lagenaria Siceraria) juice poisoning. World Journal of Emergency Medicine. 2015;6(4):308.
  5. Ho CH, Ho MG, Ho S-P, Ho HH. Bitter Bottle Gourd (lagenaria siceraria) toxicity. The Journal of Emergency Medicine. 2014;46(6):772–5.
  6. Rodriguez N, Vasquez Y, Hussein AA, Coley PD, Solis PN, Gupta MP. Cytotoxic cucurbitacin constituents from Sloanea zuliaensis. Journal of Natural Products. 2003;66(11):1515–6.
  7. Nicolaides NC, Galata Z, Kino T, Chrousos GP, Charmandari E. The human glucocorticoid receptor: Molecular basis of biologic function. Steroids. 2010;75(1):1–12.
  8. Bhatia Vikram, Tandon Rakeshk. Stress and the gastrointestinal tract. Journal of Gastroenterology and Hepatology. 2005;20(3):332–9.
  9. Bornstein SR, Engeland WC, Ehrhart-Bornstein M, Herman JP. Dissociation of ACTH and glucocorticoids. Trends in Endocrinology & Metabolism. 2008;19(5):175–80.
  10. Tannin-Spitz T, Bergman M, Grossman S. Cucurbitacin glucosides: Antioxidant and free-radical scavenging activities. Biochemical and Biophysical Research Communications. 2007;364(1):181–6.
  11. Escandell JM, Recio MC, Máñez S, Giner RM, Cerdá-Nicolás M, Ríos JL. Cucurbitacin R reduces the inflammation and bone damage associated with adjuvant arthritis in Lewis Rats by suppression of tumor necrosis factor-α in T lymphocytes and macrophages. Journal of Pharmacology and Experimental Therapeutics. 2006;320(2):581–90.
  12. Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacologica Sinica. 2008;29(11):1275–88.
  13. Sun J, Blaskovich MA, Jove R, Livingston SK, Coppola D, Sebti SM. Cucurbitacin Q: A selective STAT3 activation inhibitor with potent antitumor activity. Oncogene. 2005;24(20):3236–45.
  14. Jayaprakasam B, Seeram NP, Nair MG. Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita Andreana. Cancer Letters. 2003;189(1):11–6.
  15. Witkowski A, Woynarowska B, Konopa J. Inhibition of the biosynthesis of deoxyribonucleic acid, ribonucleic acid and protein in Hela S3 cells by cucurbitacins, glucocorticoid-like cytotoxic triterpenes. Biochemical Pharmacology. 1984;33(7):995–1004.

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