Therapeutic application of yessotoxins as inhibitors of human tumour cell growth

FIELD: medicine.

SUBSTANCE: invention concerns biochemistry and medicine. There is offered therapeutic application of yessotoxins as inhibitors of human tumour cell growth. The mechanism of action of yessotoxin (YTX) is associated with activation of cell phosphodiesterases and respectively with decreasing the content of cyclic adenosine monophosphate in cytosol. This cytotoxic effect of YTX with respect to tumour cells can be applied as a strategy to develop preparation effective in treating tumour processes.

EFFECT: inhibition of human hepatocellular carcinoma cell growth following introduction of YTX.

3 cl, 1 dwg, 1 tbl


The present invention relates to therapeutic use of exotoxins as a cytotoxic agent to tumor cells because of their ability to activate cellular phosphodiesterase.

Exotoxin, referred to in this description of YTX and its natural analogues represent a polycyclic ethers produced by dinoflagellates species Protoceratium reticulatum and Lingolodinium polyedrum, and originally they were isolated from the digestive system Patinopecten yessoensis (Murata, M., Kumagai, M. et al., 1987, Tetrahedron Letters, 28, 5869-5872). Its molecule represented in the drawing, is formed eleven rings with ether groups and unsaturated side chain, which has associated with it various radicals. This drawing shows some of YTX analogues, although there are more than 50 natural analogues derivatives.

YTX is a lipophilic compound that is not toxic when administered orally (Aune, T., Sorby, R. et al., 2002, Toxicon, 40, 77-82); however, it causes death after intraperitoneal injection (Tubaro, A., Sosa, S. et al., 2003, Toxicon, 41, 783-92), although this requires a very high dose.

YTX and its analogues have a mechanism of action that differs from the mechanism of action of another toxin. Initially, they were classified in the group of toxins that cause diarrhea, as they often find together; however, they differ in that they are not the mod who try diarrhea, and also not affect the cellular phosphatase, representing the cellular target of the toxins that cause diarrhea. Their mechanism of action relates to other enzymes; in this regard, it was described that YTX reduces the levels of cyclic adenosine monophosphate (camp) in the cytosol, because it increases the activity of cellular phosphodiesterase by calcinating mechanism (Alfonso, A., de la Rosa, L.A. et al., 2003, Biochem. Pharmacol., 65, 193-208). In addition, YTX increases the levels of calcium in the cytosol via the stimulation of its revenues through the channel localized in the cell membrane (De la Rosa, LA., Alfonso, A. et al., 2001, Biochem. Pharmacol., 61, 827-833; De la Rosa, LA, Alfonso, A. et al., 2001, Cell Signal, 13, 711-716). The effect of RBCs was used to develop sensitive methods of detecting the presence of these toxins in contaminated shellfish that have been recently published (Alfonso, A., Vieytes, M.R. et al., 2004, Analytical Biochem., 326, 93-99; Pazos, M.J., Alfonso, A. et al., 2004, Analytical Biochem., 335, 112-118). There are eleven families of RBCs, which are very important from a pharmacological point of view, because their modulation involved in the treatment of diseases, such as asthma, rheumatoid arthritis and cancer (Houslay, M.D. and Adams, D.R., 2003, Biochem. J. 370,1-18).

YTX induces apoptosis, programmed cell death in human neuroblastoma cell and cancer cells human cervical line (HeLa) because AK is ivali caspase (Leira, F., Alvarez, .et al., 2001, Toxicology in vitro, 15, 277-283; Malaguti, C., Ciminello, P. et al., 2002, Toxicol in Vitro, 16, 357-363). In addition, this toxin has a cytotoxic effect on cells of the hepatic cell cancer (HEP-G2) cells and HeLa229; therefore, a priori valid application as anticancer drugs.

Biochemical path of camp due to the levels of this second messenger, and activation taking place against a protein kinase involved in cell proliferation. Inhibition of protein kinases And gives antitumor activity (Wang, H., Cai, Q. et al., 1999, Proc Natl Acad Sci USA, 96, 13989-94), although it was also described that the resistance to anticancer drugs such as cisplatin, is associated with the inactivation of this protein (Cvijic, M.E., Yang, W.L et al., 1998, Pharmacol Ther, 78, 115-28). In addition, the levels of camp in turn are associated with cytotoxicity and resistance to drugs (Mann, S.C., Andrews, R.A., et al., 1991, Int J Cancer, 48, 866-72; von Knethen, A., Lotero, A. et al., 1998, Oncogene, 17, 387-94). In other words, the biochemical path camp plays an important and complex role in the regulation of cell growth. For this reason, description of the natural or synthetic molecules that affect phosphodiesterase, and methods of study of the activity of these enzymes, which can be used in protocols EPS (high throughput screening), is a very useful tool for the discovery of new therapies. In this sense, OPI is the W inhibitory effect of YTX on the growth of tumor cells indicates the pharmacological importance of these molecules for their potential therapeutic applications. In addition, some authors emphasize that YTX

due to their low toxicity should not be considered a toxin, but rather a natural product with different pharmacological applications.

A deeper explanation of the families of toxins, specific characteristics of YTX and mechanism of their action is given in the description of the main applications and divisional applications relating to the present invention.

In the proposed invention describes the use of YTX as an inhibitor of cell growth in accordance with their ability to activate cellular phosphodiesterase.

Application: APPLICATION activates phosphodiesterase YTX and compounds as inhibitors of proliferation of tumor cells

Inhibition of growth of tumor cells is an indicator of antitumor activity, is widely used to describe the antitumor properties of new drugs. Discovered that YTX is cytotoxic for cells of the hepatic cell carcinoma of the person, and, in addition, it was described that this toxin induces apoptosis in neuroblastoma cells (Leira, F., Alvarez, S. et al., 2001, Toxicology in vitro, 15, 277-283), all these data indicate that YTX is valid for use as anticancer drugs. The effectiveness of YTX as cytotoxic drugs to tumor cells and hepatic cell carcinoma opredelyayuschee in the present application. Inhibition of cell growth can be determined in accordance with the various protocols described in the literature. One of these protocols described below, in which the response is determined quantitatively in cell lines HEP-G2 by crystal violet staining and subsequent acetylation.


(a) Cells HEP-G2 plated on microtiter plate at a density of 10,000 cells per well. Cells incubated for 24 hours with growth medium at 37°C and 5% CO2.

b) Add various concentrations of YTX and incubated for 48 hours at 37°C and 5% CO2.

C) Add 10 ál of 11%glutaraldehyde for fixation of cells and incubated for 15 minutes. They are washed 3-4 times with distilled water.

g) Add 0.1%solution of crystal violet and the plate is shaken for 15 minutes.

d) the Dye is removed by rinsing with distilled water, and then dried.

e) Add 10%acetic acid and stirring is maintained for 15 minutes.

W) Absorption read on the spectrophotometer at 595 nanometers.

C) using this Protocol, it was found that 10 μm YTX induce inhibition of cell growth by approximately 82+/-1%.

Results induction of growth inhibition of cells

The concentration of YTX (M)% inhibition of cell growthSEM


1. Alfonso, A., de la Rosa, L.A., Vieytes, .R., Yasumoto, T. and Botana, L.. (2003). "Yessotoxin a novel phycotoxin, activates phosphodiesterase activity. Effect of yessotoxin on cAMP levels in human lymphocytes." Biochem. Pharmacol. 65: 193-208.

2. Alfonso, A., Vieytes, M.R., Yasumoto, T. and Botana, L.M. (2004). "A rapid fluorescent microplate method to detect yessotoxins based on their capacity to activate phosphodiesterases." Analytical Biochem. 326: 3-99.

3. Aune, T., Sorby, R., Yasumoto, T., Ramstad, H. and Landsverk, T. (2002). "Comparison of oral and intraperitoneal toxicity of yessotoxin towards mice." Toxicon 40(1): 77-82.

4. Cvijic, M.E., Yang, W.L. and Chin, K.V. (1998). "Cisplatin resistance in cyclic AMP-dependent protein kinase mutants." Pharmacol Ther 78(2): 115-28.

5. De la Rosa, L.A., Alfonso, A., Vilarino, N., Vieytes, M.R. and Botana, L.M. (2001). "Modulation of cytosolic calcium levels of human lymphocytes by yessotoxin, a novel marine phycotoxin." Biochem. Pharmacol. 61(7): 827-833.

6. De la Rosa, L.A., Alfonso, A., Vilarino, N., Vieytes, M.R., Yasumoto, T. and Botana, L.M. (2001). "Maitotoxin-induced calcium entry in human lymphocytes - Modulation by yessotoxin, Ca2+ channel blockers and kinases." Cell Signal 13(10): 711-716.

7. Houslay, M.D. and Adams, D.R. (2003). "PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desentization and compartmentalization." Biochem j 370: 1-18.

8. Leira, F., Alvarez, C., Vieites, J.M., Vieytes, M.R. and Botana, L.M. (2001). "Okadaic acid and yessotoxin induce caspase-3 mediated apoptosis in neuroblastoma cells. Characterization of distinct apoptotic changes induced by these phycotoxins in the BE(2)-M17 cell line by means of new fluorimetric microplate assays." Toxicology in vitro 15: 277-283.

9. Malaguti, C., Ciminello, P., Fattorusso, E. and Rossini, G.P. (2002). "Caspase activation and death induced by yessotoxin in HeLa cells." Toxicol in Vitro 16(4): 357-363.

10. Mann, S.., Andrews, P.A. and Howell, S.B. (1991). "Modulation of cis-diamminedichloroplatinum(ll) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells." Int J Cancer 48(6): 866-72.

11. Murata, M., Kumagai, M., Lee, J.S. and Yasumoto, T. (1987). "Isolation and structure of Yessotoxin, a novel polyether compound implicated in diarrhetic shellfish poisoning." Tetrahedron Letters 28: 5869-5872.

12. Pazos, M.J., Alfonso, A., Vieytes, M.R., Yasumoto, T., Vieites, J.M. and Botana, L.M. (2004). "Resonant mirror biosensor detection method based on yessotoxin-phosphodiesterase interactions." Analytical Biochem. 335: 112-118.

13. Tubaro, A., Sosa, S., Carbonatto, M., Altinier, G., Vita, F., Melato, M., Saake, M. and Yasumoto, T. (2003). "Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice." Toxicon 41(7): 783-92.

14. von Knethen, A., Lotero, A. and Brune, B. (1998). "Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMP-induced gene expression." Oncogene 17(3): 387-94.

15. Wang, H., Cai, Q., Zeng, X., Yu, D., Agrawal, S. and Zhang, R. (1999). "Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIalpha subunit of protein kinase A after oral administration." Proc NatI Acad Sci USA 96(24): 13989-94.

1. The use of exotoxins (YTXs) as activators of RBCs against tumor cells with altered activity of phosphodiesterase.

2. The use of exotoxins (YTXs) according to claim 1 for modulating the viability and growth of tumor cells.

3. The use of exotoxins (YTXs) according to claim 1 in the manufacture of compositions for the treatment of tumors involving the modulation of phosphodiesterase.


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